hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas

The c-Met receptor tyrosine kinase (MetR) is frequently overexpressed and constitutively phosphorylated in a number of human malignancies. Activation of the receptor by its ligand, hepatocyte growth factor (HGF), leads to increased cell proliferation, motility, survival and disruption of adherens junctions. In this study, we show that hTid-1, a DNAJ/Hsp40 chaperone, represents a novel modulator of the MetR signaling pathway. hTid-1 is a co-chaperone of the Hsp70 family of proteins, and has been shown to regulate a number of cellular signaling proteins including several involved in tumorigenic and apoptotic pathways. In this study we demonstrate that hTid-1 binds to unphosphorylated MetR and becomes dissociated from the receptor upon HGF stimulation. Overexpression of the short form of hTid-1 (hTid-1(S)) in 786-0 renal clear cell carcinomas (RCCs) enhances MetR kinase activity leading to an increase in HGF-mediated cell migration with no discernible effect on cell proliferation. By contrast, knockdown of hTid-1 markedly impairs both the onset and amplitude of MetR phosphorylation in response to HGF without altering receptor protein levels. hTid-1-depleted cells display defective migratory properties, coincident with inhibition of ERK/MAP kinase and STAT3 pathways. Taken together, our findings denote hTid-1(S) as an essential regulatory component of MetR signaling. We propose that the binding of hTid-1(S) to MetR may stabilize the receptor in a ligand-competent state and this stabilizing function may influence conformational changes that take place during the catalytic cycle that promote kinase activation. Given the prevalence of HGF/MetR pathway activation in human cancers, targeted inhibition of hTid-1 may be a useful therapeutic in the management of MetR-dependent malignancies.     

Effect of repeat acute injury on contractile function of the external anal sphincter in an animal model

Introduction and hypothesis

Our aim was to estimate the physiologic effects of early repeat transection and repair on the contractile properties of the external anal sphincter (EAS) in a rat model.

Methods

Eighty young female rats underwent anal sphincter transection and repair. After 7 days, they were randomized to repeat sphincter transection (injury–injury, n?=?40) or sham operation (injury–sham, n?=?40). Thereafter, the anal sphincter complex was dissected, mounted, and analyzed for contractile function 7  days, 21 days, 3 months, or 6 months after the second operation. Contractile function was also determined in 40 age-matched unoperated controls (n?=?10 for each time point). Statistical analysis was performed using analysis of variance (ANOVA) with Tukey–Kramer adjustment for multiple testing. P?≤?0.05 was considered significant.

Results

Although single injury (injury–sham) resulted in modest compromise of sphincter function, repeat injury (injury–injury) resulted in profound impairment of twitch tension, maximal tetanic responses, and maximal electrical-field stimulation (EFS) induced-force generation at 7 days. After single injury, parameters of contractile function returned to baseline uninjured levels by 21 days. In contrast, sphincter function remained reduced 21 days after repeat injury. Contractile function of sphincters from both injury–sham and injury–injury animals were no longer impaired at 3 and 6 months.

Conclusion

In this animal model, repeat injury and repair of the EAS 7 days after the initial injury resulted in prolonged compromise of EAS function compared with single injury. Nevertheless, contractile function of the double-injured sphincter fully recovered with time, resulting in no long-term impairment.     

Nurse educators are key to a best practices implementation program.

In a statewide Best Practices Project, the involvement of nurse educators in the implementation process improved the overall success of participating long-term care facilities in improving the quality of resident care. Two nurse educators provided consultation and training to nursing facility staff on three best practice protocols: prevention of decline in the activities of daily living of eating and dressing, pain, and depression. Facility staff were given protocols to follow, together with documentation forms to assist in determining resident appropriateness for participation in the assigned best practice, assessing resident involvement in the protocol over time, and tracking staff progress with the implementation. The success of the 2-year first phase of the project in significantly improving measurable resident quality of care in best practice protocol areas has resulted in a second phase involving additional facilities and protocols.     

A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27.

Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of North-Eastern Indian origin including 535 individuals. Families were ascertained through a proband with CHD before 52 years of age and additional sibs with myocardial infarction (MI) or T2DM. Model-free two-point and multipoint linkage analysis were performed using the Mapmarker-Sibs (MLS) and maximum-likelihood-binomial (MLB) programs for autosomal markers and the Aspex program for chromosome X markers. In a second step, additional markers were studied to increase the genetic map density in three regions on chromosomes 3, 8 and 16 where initial indication for linkage was found. Our data show suggestive linkage with CHD on chromosome 16p13-pter with the MLS statistics at 8.69 cM (LOD = 3.06, P = 0.00017) which partially overlaps with a high pressure (HBP) peak. At the same locus, a nominal indication for linkage with T2DM was found in 35 large T2DM Pondicherian families also having Indian origin. With respect to region 8q23, we found suggestive linkage with T2DM (LOD = 2.55, P = 0.00058) as well as with HBP. On 3q27, we replicated previous indication for linkage found in Caucasians (for the metabolic syndrome and for diabetes) according to the categorized trait for CHD and MI with the MLB statistics (LOD = 2.13, P = 0.0009). The genome scan also revealed nominal evidence of linkage with CHD on 10q23 (LOD = 2.06, P = 0.00188). Interestingly, we detected in the same region overlapping linkages with three QTLs: age of onset of CHD (LOD = 2.03), HDL cholesterol (LOD = 1.48) and LDL/HDL ratio (LOD = 1.34). Ordered-subset analysis based on family body mass index ranking replicated finding on 2q37 for T2DM (at Calpain 10 locus). These results show the first evidence for susceptibility loci that predispose to CHD, T2DM and HBP in the context of the metabolic syndrome.     

Effect of anatomic urethral length on the correlation between the Q-tip test and descent at point Aa of the POP-Q system

The objective of this study is to evaluate the effect of anatomic urethral length on the relationship between descent at point Aa of the pelvic organ prolapse quantification (POP-Q) system and the Q-tip straining angle. The records of 323 patients who were evaluated for urinary incontinence were reviewed. Prolapse staging was performed using the POP-Q system. Urethrovesical junction hypermobility defined as a maximal straining angle ≥30° was assessed with the Q-tip test. Urethral length was measured with a urethral profilometer. A substantial correlation was found between descent at point Aa and the straining Q-tip angle (r = 0.65, p < 0.0001). There was no correlation between the anatomic urethral length and straining Q-tip angle (r = −0.01, p = 0.8). Urethral length does not affect the straining Q-tip angle. Point Aa is a strong predictor of an abnormal straining Q-tip angle in women with stage I anterior vaginal wall prolapse or greater.