Hot-spot mimicry of a cytokine receptor by a small molecule

Protein-protein complexes remain enticing, but extremely challenging, targets for small-molecule drug discovery. In a rare example described earlier, a high-affinity small molecule, SP4206 (Kd approximately 70 nM), was found to block binding of the IL-2alpha receptor (IL-2Ralpha) to IL-2 (Kd approximately 10 nM). Recently, the structure of the IL-2/IL-2Ralpha complex was solved [Rickert, M., Wang, X., Boulanger, M. J., Goriatcheva, N., Garcia, K. C. (2005) Science 308:1477-1480]. Using structural and functional analysis, we compare how SP4206 mimics the 83-fold larger IL-2Ralpha in binding IL-2. The binding free energy per contact atom (ligand efficiency) for SP4206 is about twice that of the receptor because of a smaller, but overlapping, contact epitope that insinuates into grooves and cavities not accessed by the receptor. Despite its independent design, the small molecule has a similar, but more localized, charge distribution compared with IL-2Ralpha. Mutational studies show that SP4206 targets virtually the same critical "hot-spot" residues on IL-2 that drive binding of IL-2Ralpha. Moreover, a mutation that enhances binding to the IL-2Ralpha near these hot spots also enhances binding to SP4206. Although the protein and small molecule do bind the same hot spot, they trap very different conformations of IL-2 because of its flexible nature. Our studies suggest that precise structural mimics of receptors are not required for high-affinity binding of small molecules, and they show that there are multiple solutions to tight binding at shared and adaptive hot spots.     

Re-do aortic valve replacement: does a previous homograft influence the operative outcome?

BACKGROUND AND AIM OF THE STUDY: Late reoperation for failed aortic homograft is widely regarded as a high-risk procedure. A review is presented of the authors' experience of redo-aortic valve replacement (re-do AVR) examining factors which affect, and whether a previous aortic homograft replacement influences, operative outcome. METHODS: A retrospective review was conducted of consecutive re-do AVR performed at the authors' institution between 1998 and 2002. RESULTS: During the study period, 178 patients (125 males, 53 females; mean age 52.4 years; range: 16-85 years) underwent re-do AVR. The group included first-time (72%), second-time (20%), and more than third-time re-do AVR (8%). Forty-six patients (26%) received a homograft (group I), and 132 (74%) a stented biological/mechanical valve (group II). The two groups were matched for baseline clinical characteristics and operative variables. The type of explanted valve, and preoperative and operative variables, were analyzed using univariate and multivariate models. Primary outcome was defined as 30-day mortality, and secondary outcome as postoperative complications. The overall 30-day mortality was 12.3%, but was much lower (4.5%) for elective isolated and multiple re-do AVR. Univariate analysis showed significant predictors of 30-day mortality to be: age >65 years (p = 0.02); renal dysfunction (p = 0.005); preoperative unstable status (p = 0.03); preoperative NYHA class III/IV dyspnea (p = 0.02); non-elective operation (p = 0.01); preoperative arrhythmia (p = 0.005); history of chronic obstructive pulmonary disease (COPD) (p = 0.002); preoperative cardiogenic shock (p = 0.03); impaired left ventricular ejection fraction (LVEF) <50% (p = 0.04); and other valvular procedure(s) performed simultaneously (p = 0.01). In a multivariate analysis, the only significant predictors of 30-day mortality were impaired LVEF (p = 0.03) and a history of COPD (p = 0.007). Group I patients had a significantly shorter mean hospital stay (10.2+/-5.9 versus 14.1+/-12.5 days; p = 0.009), but there were no significant differences between groups in terms of postoperative complications. CONCLUSION: A previous aortic homograft replacement was not associated with an increased operative risk at the time of re-do AVR. A history was COPD was an important predictor of 30-day mortality, and this finding requires further investigation.     

Measuring health related quality of life in coronary heart disease: The importance of feeling well

Background

Atrial tachyarrhythmias are associated with patent foramen ovale. The objective was to determine the anti-arrhythmic effect of patent foramen ovale closure on pre-existing atrial tachyarrhythmias.

Methods

Medline, EMBASE, Cochrane Library, and Google Scholar databases were searched between 1967 and 2010. The search was expanded using the ‘related articles’ function and reference lists of key studies. All studies reporting pre- and post-closure incidence (or prevalence) of atrial tachyarrhythmia in the same patient population were included. Random and fixed effect meta-analyses were used to aggregate the data.

Results

Six studies were identified including 2570 patients who underwent percutaneous closure. Atrial fibrillation was in fact the only AT reported in all studies. Meta-analysis using a fixed effects model demonstrated a significant reduction in the prevalence of atrial fibrillation with an OR of 0.43 (95% CI 0.26-0.71). When using the random-effects model, OR was 0.44 (95% CI 0.18-1.04) with a statistically significant trend demonstrated (test for overall effect: Z = 1.87, p = 0.06).

Conclusion

Closure of a patent foramen ovale may be associated with reduction in the prevalence of atrial fibrillation.     

Automated Method for Small-Animal PET Image Registration with Intrinsic Validation

Purpose  We propose and compare different registration approaches to align small-animal PET studies and a procedure to validate the results by means of objective registration consistency measurements. Procedures  We have applied a registration algorithm based on information theory, using different approaches to mask the reference image. The registration consistency allows for the detection of incorrect registrations. This methodology has been evaluated on a test dataset (FDG-PET rat brain images). Results  The results show that a multiresolution two-step registration approach based on the use of the whole image at the low resolution step, while masking the brain at the high resolution step, provides the best robustness (87.5% registration success) and highest accuracy (0.67-mm average). Conclusions  The major advantages of our approach are minimal user interaction and automatic assessment of the registration error, avoiding visual inspection of the results, thus facilitating the accurate, objective, and rapid analysis of large groups of rodent PET images.     

Major role for neuronal death during brain development: refinement of topographical connections.

The precision of the topographic projection from the isthmo-optic nucleus (ION) to the retina has been examined in chicken embryos and chicks by the retrograde transport of a fluorescent carbocyanine dye from restricted retinal sites. At all ages, the labeled neurons are most numerous in the topographically appropriate part of the ION, but in younger embryos up to 49% of them are found outside this region. The distribution of these "aberrantly" projecting neurons is variable, but they generally occur throughout the entire ION. They all die during the ION's period of neuronal death, accounting for most of the 60% cell loss that then occurs. We therefore suggest that a major role of neuronal death during brain development is to reduce the imprecision of neuronal connections.     

Colorectal endoscopic submucosal dissection: Systematic review of mid‐term clinical outcomes

With a drive towards minimally invasive surgery, endoscopic submucosal dissection (ESD) is now gaining popularity. In a number of East Asian countries, ESD is now the treatment of choice for early non‐metastatic gastric cancer, but the outcomes of ESD for colorectal lesions are unclear. The present review summarizes the mid‐term outcomes of colorectal ESD including complication and recurrence rates. A systematic literature search was done in May 2014, identifying 20 publications reporting the outcomes of colorectal ESD which were included in this review. En‐bloc resection rates, complete (R0) resection rates, endoscopic clearance rates, complication and recurrences rates were analyzed. Statistical pooling was done to calculate weighted means using random effects modeling. Twenty studies reporting the outcomes of 3060 colorectal ESD procedures were reported. Overall weighted en‐bloc resection rate was 89% (95% CI: 83–94%), R0 resection rate 76% (95% CI: 69–83%), endoscopic clearance rate 94% (95% CI: 90–97%) and recurrence rate 1% (95% CI: 0.5–2%). Studies that followed up patients for over 1 year were found to have an en‐bloc resection rate of 91% (95% CI: 86–96%), R0 resection rate of 81% (95% CI: 75–88%), endoscopic clearance rate 93% (95% CI: 90–97%) and recurrence rate of 0.8% (95% CI: 0.4–1%). Colorectal ESD can be carried out effectively and safely with a 1% recurrence rate. Further studies with longer follow‐up periods are required to determine whether colorectal ESD is a viable alternative to conventional surgical therapy.     

Neurodegenerative disease and obesity: what is the role of weight loss and bariatric interventions?

Neurodegenerative diseases are amongst the leading causes of worldwide disability, morbidity and decreased quality of life. They are increasingly associated with the concomitant worldwide epidemic of obesity. Although the prevalence of both AD and PD continue to rise, the available treatment strategies to combat these conditions remain ineffective against an increase in global neurodegenerative risk factors. There is now epidemiological and mechanistic evidence associating obesity and its related disorders of impaired glucose homeostasis, type 2 diabetes mellitus and metabolic syndrome with both AD and PD. Here we describe the clinical and molecular relationship between obesity and neurodegenerative disease. Secondly we outline the protective role of weight loss, metabolic and caloric modifying interventions in the context of AD and PD. We conclude that the application of caloric restriction through dietary changes, bariatric (metabolic) surgery and gut hormone therapy may offer novel therapeutic strategies against neurodegenerative disorders. Investigating the protective mechanisms of weight loss, metabolic and caloric modifying interventions can increase our understanding of these major public health diseases and their management.     

Treatment of bladder carcinoma with irradiation combined with misonidazole

One hundred patients suffering from cancer of the bladder were treated by external beam irradiation, 400 cGy twice a week to a total dose of 4800 cGy. One half of the patients were randomized to receive the electron affinic sensitizer agent, misonidazole, at a dose of 1 gr/m2 and a total dose of 12 gr/m2. There was no statistically significant difference in tumor responses and in recurrence--free survival time between the patients who received irradiation and misonidazole as compared to those who received irradiation and placebos.     

Monoclonal antibody HMB-45 in diagnosis of intra-ocular melanoma]

69 eyes, which had to be enucleated because of an uveal melanoma, were investigated immunohistologically. HMB-45-antigen, which is supposed to be highly specific for melanocytic tumours, was found in 68 cases (sensitivity 99%) with a monoclonal antibody. S 100-antigen was positive in 63 cases (sensitivity 91%) using a polyclonal antibody. The addition of HMB-45-immunohistochemistry to routine histological diagnostic procedures is valuable, when a non-melanocytic uveal tumour cannot be ruled out or when the degree of melanoma-invasion has to be determined with greater accuracy. At the site of melanoma-invasion changes of cellular reactivity seem to occur, as 11 of the 69 studied tumours (16%) showed an increased HMB-45-expression in this area. HMB-45-antigen was detectable even in paraffin embedded material obtained from eyes enucleated 30 years ago.