Zyxin phosphorylation at serine 142 modulates the zyxin head-tail interaction to alter cell-cell adhesion

Zyxin is an actin regulatory protein that is concentrated at sites of actin–membrane association, particularly cell junctions. Zyxin participates in actin dynamics by binding VASP, an interaction that occurs via proline-rich N-terminal ActA repeats. An intramolecular association of the N-terminal LIM domains at or near the ActA repeats can prevent VASP and other binding partners from binding full-length zyxin. Such a head–tail interaction likely accounts for how zyxin function in actin dynamics, cell adhesion, and cell migration can be regulated by the cell. Since zyxin binding to several partners, via the LIM domains, requires phosphorylation, it seems likely that zyxin phosphorylation might alter the head–tail interaction and, thus, zyxin activity. Here we show that zyxin point mutants at a known phosphorylation site, serine 142, alter the ability of a zyxin fragment to directly bind a separate zyxin LIM domains fragment protein. Further, expression of the zyxin phosphomimetic mutant results in increased localization to cell–cell contacts of MDCK cells and generates a cellular phenotype, namely inability to disassemble cell–cell contacts, precisely like that produced by expression of zyxin mutants that lack the entire regulatory LIM domain region. These data suggest that zyxin phosphorylation at serine 142 results in release of the head–tail interaction, changing zyxin activity at cell–cell contacts.     

Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis

Background

Erythropoiesis-stimulating agents are used to treat anemia in patients with cancer. However, their safety and effectiveness is controversial. We did a systematic review of the clinical efficacy and harms of these agents in adults with anemia related to cancer or chemotherapy.

Methods

We conducted a systematic review of published and unpublished randomized controlled trials (RCTs) using accepted methods for literature searches, article selection, data extraction and quality assessment. We included RCTs involving anemic adults with cancer. We compared the use of erythropoiesis-stimulating agents with nonuse and assessed clinical outcomes (all-cause mortality, cardiovascular events and hypertension, health-related quality of life, blood transfusions and tumour response) and harms (serious adverse events) between groups.

Results

We identified 52 trials (n = 12 006) that met our selection criteria. The pooled all-cause mortality during treatment was significantly higher in the group receiving erythropoiesis-stimulating therapy than in the control group (relative risk [RR] 1.15, 95% confidence interval [CI] 1.03 to 1.29). Compared with no treatment, use of erythropoiesis-stimulating agents led to clinically detectable improvements in disease-specific measures of quality of life. It also reduced the use of blood transfusions (RR 0.64, 95% CI 0.56 to 0.73). However, it led to an increased risk of thrombotic events (RR 1.69, 95% CI 1.27 to 2.24) and serious adverse events (RR 1.16, 95% CI 1.08 to 1.25).

Interpretation

Use of erythropoiesis-stimulating agents in patients with cancer-related anemia improved some disease-specific measures of quality of life and decreased the use of blood transfusions. However, it increased the risk of death and serious adverse events. Our findings suggest that such therapy not be used routinely as an alternative to blood transfusion in patients with anemia related to cancer.Anemia related to cancer may be due to the cancer itself or it may be a complication of chemotherapy. Because anemia is associated with adverse clinical outcomes in people with cancer, including impaired quality of life¹ and decreased survival,² treatment with erythropoiesis-stimulating agents has been widely used. These agents are costly, and reimbursement policies for their use in patients with cancer-related anemia vary across Canadian jurisdictions. Recent studies suggest that their use in such patients may be associated with an increased risk of adverse events such as thromboembolism.³ Potential adverse effects have also been identified in patients with chronic kidney disease.^4,5Therefore, an assessment of the efficacy and harms of erythropoiesis-stimulating agents in patients with cancer-related anemia would be useful to clinicians, and to jurisdictions that seek to develop an evidence-based reimbursement policy for these drugs. We conducted a systematic review based on work done for the Canadian Agency for Drugs and Technologies in Health⁶ to summarize the clinical efficacy and harms of these agents in adults with anemia related to cancer.     

The 1990 James A. F. Stevenson Memorial Lecture. Gonadotropin-releasing hormone and its actions

Gonadotropin-releasing hormone (GnRH) stimulates the release and biosynthesis of gonadotropins, luteinizing hormone, and follicle-stimulating hormone from the pituitary gland. Additionally, GnRH regulates the number of its own receptors on pituitary gonadotropes causing both up- and down-regulation of receptors as well as biosynthesis of GnRH receptors. After exposure to GnRH, gonadotropes become desensitized to further stimulation by GnRH. The mechanisms through which these actions of GnRH are mediated appear to differ. Effects dependent upon extracellular calcium include gonadotropin biosynthesis and release as well as up-regulation of GnRH receptors. Additional actions of GnRH, such as down-regulation of receptors, biosynthesis of receptors, and desensitization, appear to be independent of extracellular calcium. Subsequent studies have ascribed roles for calmodulin and protein kinase C in mediating specific effects of GnRH.     

Impact of nitrate on the structure and function of bacterial biofilm communities in pipelines used for injection of seawater into oil fields

We studied the impact of NO(3)(-) on the bacterial community composition, diversity, and function in in situ industrial, anaerobic biofilms by combining microsensor profiling, (15)N and (35)S labeling, and 16S rRNA gene-based fingerprinting. Biofilms were grown on carbon steel coupons within a system designed to treat seawater for injection into an oil field for pressurized oil recovery. NO(3)(-) was added to the seawater in an attempt to prevent bacterial H(2)S generation and microbially influenced corrosion in the field. Microprofiling of nitrogen compounds and redox potential inside the biofilms showed that the zone of highest metabolic activity was located close to the metal surface, correlating with a high bacterial abundance in this zone. Upon addition, NO(3)(-) was mainly reduced to NO(2)(-). In biofilms grown in the absence of NO(3)(-), redox potentials of <-450 mV at the metal surface suggested the release of Fe(2+). NO(3)(-) addition to previously untreated biofilms induced a decline (65%) in bacterial species richness, with Methylophaga- and Colwellia-related sequences having the highest number of obtained clones in the clone library. In contrast, no changes in community composition and potential NO(3)(-) reduction occurred upon subsequent withdrawal of NO(3)(-). Active sulfate reduction was below detection levels in all biofilms, but S isotope fractionation analysis of sulfide deposits suggested that it must have occurred either at low rates or episodically. Scanning electron microscopy revealed that pitting corrosion occurred on all coupons, independent of the treatment. However, uniform corrosion was clearly mitigated by NO(3)(-) addition.     

Differences in intragastric pH in diabetic vs. idiopathic gastroparesis: relation to degree of gastric retention

Evidence suggests that distinct mechanisms underlie diabetic and idiopathic gastroparesis. Differences in gastric acid in gastroparesis of different etiologies and varying degrees of gastric stasis are uninvestigated. We tested the hypotheses that 1) gastric pH profiles show differential alteration in diabetic vs. idiopathic gastroparesis and 2) abnormal pH profiles relate to the severity of gastric stasis. Sixty-four healthy control subjects and 44 gastroparesis patients (20 diabetic, 24 idiopathic) swallowed wireless transmitting capsules and then consumed (99m)Tc-sulfur colloid-labeled meals for gastric scintigraphy. Gastric pH from the capsule was recorded every 5 s. Basal pH was higher in diabetic (3.64 +/- 0.41) vs. control subjects (1.90 +/- 0.18) and idiopathic subjects (2.41 +/- 0.42; P < 0.05). Meals evoked initial pH increases that were greater in diabetic (4.98 +/- 0.32) than idiopathic patients (3.89 +/- 0.39; P = 0.03) but not control subjects (4.48 +/- 0.14). pH nadirs prior to gastric capsule evacuation were higher in diabetic patients (1.50 +/- 0.23) than control subjects (0.58 +/- 0.11; P = 0.003). Four-hour gastric retention was similar in diabetic (18.3 +/- 0.5%) and idiopathic (19.4 +/- 0.5%) patients but higher than control subjects (2.2 +/- 0.5%; P < 0.001). Compared with control subjects, those with moderate-severe stasis (>20% retention at 4 h) had higher basal (3.91 +/- 0.55) and nadir pH (2.23 +/- 0.42) values (P < 0.05). In subgroup analyses, both diabetic and idiopathic patients with moderate-severe gastroparesis exhibited increased pH parameters vs. those with mild gastroparesis. In conclusion, diabetic patients with gastroparesis exhibit reduced gastric acid, an effect more pronounced in those with severely delayed gastric emptying. Idiopathic gastroparetic subjects exhibit nearly normal acid profiles, although those with severely delayed emptying show reduced acid vs. those with mild delays. Thus both etiology and degree of gastric stasis determine gastric acidity in gastroparesis.