Friday, May 28, 2010

Stem-cell-like properties of normal and malignant epithelial cells contribute to cell-death resistance

It is not well understood why carcinomas reemerge after chemotherapy and/or radiation treatments. Cancer recurrence and treatment failure seems to be associated with stem-cell-like properties and resistance to apoptosis (programmed cell death) in a subset of cells that have been previously isolated from human epithelial cancers.
One study investigated the mechanisms of apoptosis resistance of cells with stem-cell-like properties in both normal and malignant human epithelia, and whether altered cell cycle regulation played a role.

To address these questions, the following methodology was employed:
  • Cells were isolated from fresh human head and neck carcinomas (n = 11), cell lines derived from head and neck, prostate and breast human carcinomas (n = 7), and from normal human oral mucosa (n = 5)
  • All cells were exposed to various apoptosis-inducing stimuli (UV, tumour necrosis factor, cisplatin, etoposide, and neocarzinostatin)
  • The subset of cells with stem-cell-like properties were identified by flow cytometry for CD44 and epithelial-specific antigen (ESA) expression, colony morphology, tumour sphere formation and rapid adherence assays
  • Apoptosis, cell cycle and expression of various cell cycle checkpoint proteins were assessed by Western Blot and quantitative PCR (qPCR)
  •  Debromohymenialdisine (DBH) and small interfering RNA (siRNA) were used to investigate the role of G2-checkpoint regulators Chk1 and Chk2
 The study demonstrated the following:
  •  A subset of CD44high cells were found in both cancer biopsies and carcinoma cell lines that showed increased clonogenicity, a significantly lower rate of apoptosis, and a significantly higher proportion of cells in the G2-phase of the cell cycle. An inverse correlation between the Percentage of cells in G2-phase and the rate of apoptosis revealed an inverse correlation.
  • It appeared that CD44high carcinoma cells spent longer time in G2, even in untreated controls as shown by pulse-chase with iododeoxyuridine (IdU). These cells expressed higher levels of G2 checkpoint proteins, and their release from G2 with BDH or Chk1 siRNA increased their rate of apoptosis.
  • Interestingly, low passage cultures of normal keratinocytes were found to contain a subset of CD44high cells which also showed increased clonogenicity, and a similar pattern of G2-block associated with apoptotic resistance.

Conclusions
The results of this study suggested that not only malignant, but also normal human epithelial cells with stem-cell-like properties have extended G2 cell cycle phase which is associated with greater resistance to apoptosis, and that this property is not a consequence of neoplastic (cancerous) transformation (i.e. not unique to cancer cells). This knowledge provides an opportunity for novel therapeutic approaches targeting G2 checkpoint proteins to release these cells from the G2-block and make them more prone to apoptosis.

Abbreviations
PCR = polymerase chain reaction; RNA = ribonucleic acid

Reference
Harper LJ, Costea DE, Gammon L, et al. Normal and malignant epithelial cells with stem-like properties have an extended G2 cell cycle phase that is associated with apoptotic resistance. BMC Cancer 2010, 10:166doi:10.1186/1471-2407-10-166.

Free full-text article available at: http://www.biomedcentral.com/1471-2407/10/166



Monday, May 24, 2010

Exercise and its effects on perceived symptoms and physical function in adults with fibromyalgia: results from a randomized trial

Adults with fibromyalgia (FM) have been shown to benefit from exercise and its therapeutic effects on their condition. However, FM symptoms often limit the ability to exercise and create obstacles that discourage an active lifestyle and physical activity.


One study evaluated the effects of accumulating at least 30 minutes of self-selected lifestyle physical activity (LPA) on perceived physical function, pain, fatigue, body mass index, depression, tenderness, and the six-minute walk test in adults with FM.

Eighty-four minimally active adults with FM were randomized to either LPA or a FM education control (FME) group. Participants in the LPA group worked toward accumulating 30 minutes of self-selected moderate-intensity LPA, 5–7 days per week, while the FME participants received only information and support.

Of the 84 participants, 73 (87%) completed the 12-week trial. The LPA group increased their average daily steps by 54%. As well, the LPA group reported significantly less perceived functional deficits (P = 0.032) and less pain (P = 0.006) compared to the FME group. No differences between the groups were seen on the six-minute walk test (P = 0.067), fatigue, depression, body mass index, or tenderness.

This study demonstrated that accumulating as little as 30 minutes of LPA throughout the day can produce clinically relevant changes in how previously minimally active adults with FM perceive physical function and pain.

Reference

Fontaine KR, Conn L, and Clauw DJ. Effects of lifestyle physical activity on perceived symptoms and physical function in adults with fibromyalgia: results of a randomized trial. Arthr ResTher 2010; 12:R55doi:10.1186/ar2967

Article URL: http://arthritis-research.com/content/12/2/R55


Saturday, May 22, 2010

Effect of Tai Chi on psychological well-being: systematic review and meta-analysis


Psychological health seems to benefit from physical activity and exercise, but the effects of Tai Chi on psychological well-being have rarely been examined quantitatively. In this study, a systematic review of the effects of Tai Chi on stress, anxiety, depression and mood disturbance in eastern and western populations was performed.

Eleven databases (8 English and 3 Chinese) were searched through March 2009. The studies examined included: randomized controlled trials, non-randomized controlled studies and observational studies reporting at least 1 psychological health outcome. Data extraction and verification was analyzed by 3 reviewers. Meta-analysis was performed on randomized trials in each subcategory of health outcomes using a random-effects model, and the quality of each study was assessed.

Forty studies were identified with a total of 3817 subjects. Approximately 29 psychological measurements were assessed. Twenty-three of 33 randomized and non-randomized trials demonstrated that a duration of 1 hour to 1 year of regular Tai Chi significantly increased psychological well-being including reduction of stress (effect size [ES], 0.66; 95% confidence interval [CI], 0.23 to 1.09), anxiety (ES, 0.66; 95% CI, 0.29 to 1.03), and depression (ES, 0.56; 95% CI, 0.31 to 0.80), and enhanced mood and emotion (ES, 0.45; 95% CI, 0.20 to 0.69) in community-dwelling healthy participants as well as in patients with chronic conditions. Seven observational studies with relatively large sample sizes confirmed the beneficial link between Tai Chi practice and psychological health.

Overall, Tai Chi appears to be associated with improvements in psychological well-being including reduced stress, anxiety, depression and mood disturbance, and increased self-esteem.

Variation in designs, comparisons, heterogeneous outcomes and inadequate controls of the studies reviewed were the limiting factors towards drawing definitive conclusions. Well-controlled, high quality randomized trials of longer durations are needed to confirm the findings of this review in order to make more informed clinical decisions.

Reference
Wang C, Bannuru R, Ramel J, et al. Tai Chi on psychological well-being: systematic review and meta-analysis. BMC Complem Alter Med 2010, 10:23doi:10.1186/1472-6882-10-23

Article URL http://www.biomedcentral.com/1472-6882/10/23


Wednesday, May 19, 2010

Caffeine and upper body strength enhancement in resistance-trained women
Research has shown that low-to-moderate dosages of caffeine supplementation are ergogenic for sustained endurance efforts and high-intensity exercise. The effects of caffeine supplementation on strength-power performance are conflicting since some studies have indicated a benefit while others suggested no change in performance. While the majority of research that has examined the effects of caffeine supplementation on strength-power performance has been done in both trained and untrained men, no equivalent studies have been performed in women. The purpose of this study was to determine the acute effects of caffeine supplementation on strength and muscular endurance in resistance-trained women.

Fifteen women were randomized to consume caffeine (6 mg/kg) or placebo (PL) seven days apart. Sixty minutes after caffeine supplementation, participants performed a one-repetition maximum (1RM) barbell bench press test and repetitions to failure (RF) at 60% of 1RM. Heart rate (HR) and blood pressure (BP) were assessed at rest, 60 minutes post-consumption, and immediately following completion of repetitions to failure.

It was demonstrated that significantly greater bench press maximum was achieved with caffeine (p≤0.05) (52.9 ± 11.1 kg vs. 52.1 ± 11.7 kg) with no significant differences between conditions in 60% 1RM repetitions (p=0.81).* Further, post-exercise systolic blood pressure was significantly greater with caffeine vs. placebo (p<0.05)>

*Repeated measures ANOVA

Reference
Goldstein ER, Jacobs PL, Michael Whitehurst M, et al. Caffeine enhances upper body strength in resistance-trained women. J Int Soc Sports Nutr 2010, 7:18doi:10.1186/1550-2783-7-18

Article URL http://www.jissn.com/content/7/1/18


Wednesday, May 12, 2010

Greater lean tissue and skeletal muscle mass in children contributes to higher bone mineral content

In a recent study, the relationship of skeletal muscle mass with bone mineral content was compared in an ethnically diverse group of 6–18 year old boys and girls.

Body mass, height, and Tanner stage were assessed in 175 healthy children (103 boys, 72 girls). Dual-energy X-ray absorptiometry (DXA) was used to assess whole body bone mineral content, non-bone lean body mass, skeletal muscle mass, and fat mass. To estimate muscle mass, an equation using appendicular lean soft tissue measured by DXA, weight and height was used. Whole body multi-slice magnetic resonance imaging (MRI) was used to estimate skeletal muscle mass and adipose tissue.

This study, which was among the first to describe and compare the relationship of skeletal muscle to bone using both MRI and DXA estimates, demonstrated that greater skeletal muscle mass was associated with greater bone mineral content (p<0.001). The skeletal muscle mass assessed by MRI provided a better model for the relationship of skeletal muscle to bone compared with assessment by DXA for predicting bone mineral content. The proportion of skeletal muscle mass in non-bone lean body mass was significantly associated with greater bone mineral content adjusted for total non-bone lean body mass. Children of Hispanic origin had greater bone mineral content compared to other race and ethnic groups after adjusting for sex, age, adipose tissue, skeletal muscle mass, and height.


* To determine whether skeletal muscle mass assessed by DXA or by MRI were better predictors of bone mineral content compared with non-bone lean body mass after adjusting for sex, age, race or ethnicity, and Tanner stage, linear regression model as determined by R2 statistic was used.

Reference
Dorsey KB, John C Thornton JC, Heymsfield SB, Gallagher D. Greater lean tissue and skeletal muscle mass are associated with higher bone mineral content in children. Nutrition & Metabolism 2010, 7:41 doi:10.1186/1743-7075-7-41

Article URL http://www.nutritionandmetabolism.com/content/7/1/41

Tuesday, May 11, 2010

Possible link between proton pump inhibitors and increase of bone fractures and risk of bacterial infection

Each year, 113.4 million prescriptions for proton pump inhibitors (PPIs) are filled in the United States, making this class of drugs, the third highest seller at $13.9 billion in sales. PPIs have demonstrated efficacy for treatment of erosive and ulcerative esophagitis, Barrett esophagus, Zollinger-Ellison syndrome, and gastroesophageal reflux disease (GERD), as well as for short-term treatment of ulcer disease, as part of a combination regimen for Helicobacter pylori eradication and for prevention of ulcers due to nonsteroidal anti-inflammatory drugs. These indications, however, do not account for more than a hundred million prescriptions, which is supported by evidence that PPIs have been shown to be overprescribed, where between 53% and 69% of PPI prescriptions are prescribed off-label.

Recent research published in the Archives of Internal Medicine (Arch Intern Med. 2010;170(9):747-748), demonstrated (PPIs) increase the risk of bone fractures in older woman and are also associated with an increased risk of Clostridium difficile (C. difficile) infection.

In one study, data was analyzed on 161, 806 women aged 50 to 79 without a history of hip fracture enrolled in the Women's Health Initiative. After eight years, 21, 247 bone fractures were observed. Women who were on PPIs had 47% increased risk of spinal fracture, 26% increased risk for forearm or wrist fracture, and 25% increased risk of total fractures, compared to women who did not take PPIs. However, the use of PPIs was not associated with an increased risk of hip fracture and only a minimal effect on bone mineral density was observed over three years.

Another study examined the records of 101,796 patients discharged from a Massachusetts hospital between 2004 and 2008. The study demonstrated that patients treated with PPIs had 74% increase of C. difficile infections compared with those not taking the drugs. In addition, a different study on 1,200 patients treated for the bacterial infection demonstrated a 42% increased risk of recurrent infection in patients taking PPIs compared to those not taking the drugs. According to researcher Michael Howell, it appears that the acidity of the stomach may confer immunity to C. difficile, and suppressing the acidity with PPIs, increases the risk of C. difficile infection.

The results of these studies suggest that although PPIs do work, PPI-related adverse effects may outweigh the benefits for some patients and should be used with caution. Further research through prospective, controlled studies is necessary to establish a link between PPIs and fractures, and PPIs and C. difficile infections.

Reference
Katz MH. LESS IS MORE: Failing the Acid Test. Benefits of Proton Pump Inhibitors May Not Justify the Risks for Many Users. Arch Intern Med. 2010;170(9):747-748.

Related Articles
Grady D and Redberg RF. Less Is More: How Less Health Care Can Result in Better Health. Arch Intern Med. 2010;170(9):749-750.

Gray SL, LaCroix AZ, Larson J, et al. Proton Pump Inhibitor Use, Hip Fracture, and Change in Bone Mineral Density in Postmenopausal Women: Results From the Women's Health Initiative. Arch Intern Med. 2010;170(9):765-771.

Howell MD, Novack V, Grgurich P, et al. Iatrogenic Gastric Acid Suppression and the Risk of Nosocomial Clostridium difficile Infection. Arch Intern Med. 2010;170(9):784-790.

Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton Pump Inhibitors and Risk for Recurrent Clostridium difficile Infection. Arch Intern Med. 2010;170(9):772-778.

Wang C-H, Ma M H-M, Chou H-C, Yen Z-S, et al. High-Dose vs Non–High-Dose Proton Pump Inhibitors After Endoscopic Treatment in Patients With Bleeding Peptic Ulcer: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2010;170(9):751-758.

Yachimski PS, Farrell EA, Hunt DP, Reid AE. Proton Pump Inhibitors for Prophylaxis of Nosocomial Upper Gastrointestinal Tract Bleeding: Effect of Standardized Guidelines on Prescribing Practice. Arch Intern Med. 2010;170(9):779-783.