Circular RNA in colorectal cancer

Circular RNA (circRNA) is a highly abundant type of single-stranded non-coding RNA. Novel research has discovered many roles of circRNA in colorectal cancer (CRC) including proliferation, metastasis and apoptosis. Furthermore, circRNAs also play a role in the development of drug resistance and have unique associations with tumour size, staging and overall survival in CRC that lend circRNAs the potential to serve as diagnostic and prognostic biomarkers. Among cancers worldwide, CRC ranks second in mortality and third in incidence. In order to have a better understanding of the influence of circRNA on CRC development and progression, this review summarizes the role of specific circRNAs in CRC and evaluates their potential value as therapeutic targets and biomarkers for CRC. We aim to provide insight in the development of therapy and clinical decision-making.     

Non-basic ligands for aminergic GPCRs: The discovery and development diaryl sulfones as selective,orally bioavailable 5-HT2A receptor antagonists for the treatment of sleep disorders

Scaffold hopping from a non-basic series of 5-HT_2A receptor antagonists developed in-house that possessed reduced activity in vivo enabled the discovery of a novel series of diaryl sulfones that gave excellent occupancy on oral dosing. Not only does this work further demonstrate that oral bioavailability of a given series can be enhanced by improving physicochemical parameters such as log P, but it corroborates the growing evidence that a protonated amine is not essential for affinity at aminergic GPCRs.     

Analysis of Bacteria Contaminating Ultrapure Water in Industrial Systems

Bacterial populations inhabiting ultrapure water (UPW) systems were investigated. The analyzed UPW systems included pilot scale, bench scale, and full size UPW plants employed in the semiconductor and other industries. Bacteria present in the polishing loop of the UPW systems were enumerated by both plate counts and epifluorescence microscopy. Assessment of bacterial presence in UPW by epifluorescence microscopy (cyanotolyl tetrazolium chloride [CTC] and DAPI [4′,6′-diamidino-2-phenylindole] staining) showed significantly higher numbers (10 to 100 times more bacterial cells were detected) than that determined by plate counts. A considerable proportion of the bacteria present in UPW (50 to 90%) were cells that did not give a positive signal with CTC stain. Bacteria isolated from the UPW systems were mostly gram negative, and several groups seem to be indigenous for all of the UPW production systems studied. These included Ralstonia pickettii, Bradyrhizobium sp., Pseudomonas saccharophilia, and Stenotrophomonas strains. These bacteria constituted a significant part of the total number of isolated strains (≥20%). Two sets of primers specific to R. pickettii and Bradyrhizobium sp. were designed and successfully used for the detection of the corresponding bacteria in the concentrated UPW samples. Unexpectedly, nifH gene sequences were found in Bradyrhizobium sp. and some P. saccharophilia strains isolated from UPW. The widespread use of nitrogen gas in UPW plants may be associated with the presence of nitrogen-fixing genes in these bacteria.     

Multifaceted intervention to improve diagnosis and treatment of osteoporosis in patients with recent wrist fracture: a randomized controlled trial

Background

Older patients who experience a fragility fracture are at high risk of future fractures but are rarely tested or treated for osteoporosis. We developed a multifaceted intervention directed at older patients with wrist fractures (in the form of telephone-based education) and their physicians (in the form of guidelines endorsed by opinion leaders, supported by reminders) to improve the quality of osteoporosis care.

Methods

In a randomized controlled trial with blinded ascertainment of outcomes, we compared our intervention with usual care (provision of printed educational materials to patients). Eligible patients were those older than 50 years of age who had experienced a wrist fracture and were seen in emergency departments and fracture clinics; we excluded those who were already being treated for osteoporosis. The primary outcome was bisphosphonate treatment within 6 months after the fracture. Secondary outcomes included bone mineral density testing, “appropriate care” (consisting of bone mineral density testing with treatment if bone mass was low) and quality of life.

Results

We screened 795 patients for eligibility and randomly assigned 272 to the intervention (137 patients) or control (135 patients) group. The median age was 60 years; 210 (77%) of the subjects were women, and 130 (48%) reported a previous fracture as an adult. Six months after the fracture, 30 (22%) of the intervention patients, as compared with 10 (7%) of the control patients, were receiving bisphosphonate therapy for osteoporosis (adjusted relative risk [RR] 2.6, 95% confidence interval [CI] 1.3–5.1, p = 0.008). Intervention patients were more likely than control patients to undergo bone mineral density testing (71/137 [52%] v. 24/135 [18%]; adjusted RR 2.8, 95% CI 1.9–4.2, p < 0.001) and to receive appropriate care (52/137 [38%] v. 15/135 [11%]; adjusted RR 3.1, 95% CI 1.8–5.3, p < 0.001). There were no differences between the groups in other outcomes. One patient died, and 4 others experienced recurrent fracture.

Interpretation

A multifaceted intervention directed at high-risk patients and their physicians substantially increased rates of testing and treatment for osteoporosis. Nevertheless, more than half of the patients in the intervention group were not receiving appropriate care 6 months after their fracture, which suggests that additional strategies should be explored. (ClinicalTrials.gov trial register no. NCT00152321.)Osteoporosis is a common, chronic and costly condition affecting at least 25% of women and 12% of men over 50 years of age.^1–3 Without better prevention strategies, the incidence of and costs related to osteoporotic fractures are expected to increase by 50% over the next 2 decades.³ Case-finding and secondary prevention (e.g., by identifying patients who have experienced a fragility fracture, ensuring that their bone mineral density is tested and offering efficacious osteoporosis treatments to those with low bone mass) constitute the most cost-effective strategy for reducing future fractures.^4–6An obvious target group for case-finding consists of older patients who experience a wrist fracture. Wrist fracture is the most common symptomatic fracture related to osteoporosis; its occurrence is a powerful forecaster of future fractures, and these fractures typically occur 10–20 years before the more devastating osteoporosis-related fractures of the spine or the hip.⁷ Unfortunately, although most older patients with wrist fractures have low bone mass and are eligible for treatment,^4,7 less than about 10% to 20% are tested or treated for osteoporosis in the 6 to 12 months after a wrist fracture.^4–9We previously reported a nonrandomized study of an intervention that incorporated patient education, physician reminders and treatment guidelines endorsed by opinion leaders, to improve osteoporosis treatment in patients with wrist fractures; in that study, which involved 102 patients, the rate of treatment was 40% in the intervention group but only 10% in the group receiving usual care.⁷ Several concerns were raised about the internal and external validity of that small study, so we conducted a randomized controlled trial of the intervention, which is reported here.     

Enzyme-retting of flax and characterization of processed fibers

Enzyme-retting formulations consisting of Viscozyme L, a pectinase-rich commercial enzyme product, and ethylenediaminetetraacetic acid (EDTA) were tested on Ariane fiber flax and North Dakota seed flax straw residue. Flax stems that were crimped to disrupt the outer layers were soaked with various proportions of Viscozyme-EDTA solutions, retted, and then cleaned and cottonized with commercial processing equipment. Fiber properties were determined and crude test yarns were made of raw and Shirley cleaned flax fibers and cotton in various blend levels. Cleaned fibers were obtained from both seed and fiber flax types, but with variations due to treatment. Retting formulations produced fibers having different properties, with enzyme levels of 0.3% (v/v as supplied) giving finer but weaker fibers than 0.05% regardless of EDTA level. Experimental yarns of blended flax and cotton fibers varied in mass coefficient of variation, single end strength, and nep imperfections due to sample and formulation. With cost and fiber and yarn quality as criteria, results established a range in the amounts of components comprising retting formulations as a basis for further studies to optimize enzyme-retting formulations for flax. Under conditions examined herein, Viscozyme L at 0.3% (v/v) plus 25 mM EDTA produced the best test yarns and, therefore, established a base for future studies to develop commercial-grade, short staple flax fibers for use in textiles.     

Evidence of suboptimal management of cardiovascular risk in patients with type 2 diabetes mellitus and symptomatic atherosclerosis

Background

Given that most deaths among patients with diabetes mellitus are due to cardiovascular disease, we sought to determine the extent to which medications proven to reduce cardiovascular mortality are prescribed for patients with type 2 diabetes who have symptomatic atherosclerosis (i.e., coronary artery disease [CAD], cerebrovascular disease [CBVD] or peripheral arterial disease [PAD]).

Methods

Administrative records from Saskatchewan Health were used to evaluate the use of antiplatelet agents, statins and angiotensin-converting enzyme (ACE) inhibitors by people with treated type 2 diabetes with and without symptomatic atherosclerosis. CAD and CBVD were defined by International Classification of Diseases (ninth revision) codes, and PAD was defined on the basis of pentoxifylline use or lower limb amputation. Multivariate logistic regression analysis was used to compare medication use in patients with and without PAD, with adjustments for differences in age, sex and comorbidity.

Results

In this cohort of 12 106 patients with type 2 diabetes (mean age 64 years, 55% male, mean follow-up 5 years), fewer than 25% received an antiplatelet agent or statin, and fewer than 50% received an ACE inhibitor. Although patients with CAD were more likely to receive antiplatelet agents, statins or ACE inhibitors than people without CAD (p < 0.001 for all), the overall use of these medications was suboptimal (37%, 29% and 60% respectively among patients with symptomatic CAD). Similar patterns of practice were found for patients with symptomatic CBVD and PAD. All 3 proven efficacious therapies were prescribed for only 11% of patients with CAD, 22% with CBVD and 12% with PAD. Patients with PAD who had undergone lower limb amputation were no more likely to subsequently receive antiplatelet agents or statins than those without an amputation.

Interpretation

Diabetic patients with symptomatic atherosclerotic disease are undertreated with medications known to reduce cardiovascular morbidity and mortality, perhaps because of a “glucocentric” view of diabetes. Programs to improve the quality of cardiovascular risk reduction in these high-risk patients are needed.Diabetes mellitus in adults is associated with an annual rate of death of about 5%, approximately double the rate for age- and sex-matched control subjects without diabetes. Most of this excess mortality risk is attributable to macrovascular atherosclerotic disease.¹ Thus, it has been recommended that medical management to decrease cardiovascular risk should start when type 2 diabetes mellitus is diagnosed.^2,3 At the very least, medications proven to reduce cardiovascular risk should be prescribed for patients with diabetes and established atherosclerotic disease.In addition to smoking cessation and control of blood pressure, strategies proven to reduce cardiovascular risk in patients with diabetes and established atherosclerotic disease include therapy with antiplatelet agents, statins and angiotensin-converting enzyme (ACE) inhibitors.² Coronary artery disease (CAD), cerebrovascular disease (CBVD) and peripheral arterial disease (PAD) are all manifestations of established atherosclerosis.⁴ Recent epidemiologic studies have suggested that PAD may be present in one-quarter to one-half of all adults with type 2 diabetes and have confirmed that PAD is a powerful predictor of cardiovascular death.⁴ In fact, the survival rate for patients with PAD is worse than that for patients with breast cancer (72% v. 85% at 5 years).⁴ However, a recently published survey suggested that clinicians were less likely to prescribe antiplatelet therapy for patients with PAD than for patients with CAD.⁵We sought to evaluate the use of antiplatelet agents, statins and ACE inhibitors among diabetic patients with and without symptomatic atherosclerotic vascular disease. Given the high prevalence of symptomatic PAD among diabetic patients and suggestions that it is often neglected as a marker of atherosclerotic disease, we were particularly interested in examining patterns of care for overall cardiovascular risk reduction in patients with this condition.⁴     

Developmental plasticity in Macrophiothrix brittlestars: are morphologically convergent larvae also convergently plastic?

The pluteus larval forms of sea urchins (echinoids) and brittlestars (ophiuroids) use an internal skeleton to project arms that bear a long ciliated band used in swimming and feeding. The length of this ciliated band influences rates of maximum food clearance for larvae of both echinoderm classes and affects rates of growth and development in the plankton. Phylogenetic and morphological evidence, however, tend to support the view that the pluteus morphologies of the two classes are independently derived. Studies with echinoplutei have shown that investment in skeletal growth and ciliated band length changes in response to food conditions, with poorly fed larvae investing more in growth of the larval skeleton and arms either absolutely or in relation to other larval or developing postlarval structures. We present evidence for similar plasticity of skeletal growth in ophioplutei. We examined four species in the brittlestar genus Macrophiothrix that spanned a 3.8-fold range in egg size. Sibling larvae in 14 male-female crosses were reared with high (H) or low (L) food rations, and measurements were recorded for five skeletal arm rods and three non-arm body dimensions. The expression of adaptive plasticity (significantly longer arms in L versus H cultures on a given day) was apparent for most crosses in M. koehleri, the species with the smallest egg size. In the single cross for M. longipeda, larvae from L cultures had longer arms for their body length or stomach width than did larvae from H cultures. In these cases, plasticity was similar in timing, persistence, and magnitude to previously published results from echinoplutei. If internal skeletons are independently derived in the two classes, then plasticity in the expression of this homoplastic trait may itself be homoplastic.