GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.

B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.

The Effect of Achieving Immediate Target Angle on Success of Strabismus Surgery in Children.

PURPOSE: To determine if achieving the ideal postoperative target range increases the long-term success of pediatric strabismus surgery. DESIGN: Interventional case series. METHODS: Children below 12 years old with horizontal strabismus who underwent surgical correction by recession, resection, advancement, or a combination of both between 1996 and 2011 were included. Alignment was measured within 1 week and at a minimum of 6 months after surgery. The ideal postoperative target range was defined as 0-8 prism diopters (PD) of esotropia in exotropic patients and within 4 PD of orthotropia in esotropic patients measured within 1 week after the surgery. Success was defined as a measurement within 10 PD of orthotropia at the latest postoperative visit. The main outcome measures were surgical success rate and the factors affecting it. RESULTS: We included 352 patients with mean follow-up of 18 months. Overall, patients within the target range had a higher success rate than those outside it (75.6% vs 57% P = .0004). This was highly significant for exotropia (P = .0002) but not for esotropia (P = .4). Multiple regression analysis revealed that being within target range was the strongest predictor of long-term success (odds ratio [OR] = 2.3, range 1.4-3.7). Overall, surgeries on patients with esotropia were more likely to be successful than on those with exotropia (OR = 1.9, range 1.2-3), and premature patients had poorer outcomes (OR = 0.2, range 0.1-0.8). CONCLUSION: Achieving the ideal target range within 1 week after surgery is associated with a high rate of long-term success in exotropia surgery in children.

Achieving postoperative target range increases success of strabismus surgery in adults: a case for adjustable sutures?

BACKGROUND/AIMS: To evaluate the role of achieving immediate target angles on the success of strabismus surgery. METHODS: We performed a retrospective cohort study of all patients over 12 years old undergoing strabismus surgery with either adjustable or non-adjustable sutures. Target angle for patients with esotropia and vertical deviation was within 4 prism dioptres (PD) of orthotropia and for patients with exotropia between orthotropia and 8 PD of esotropia. Success was defined as alignment within 10 PD for horizontal rectus surgery and within 5 PD of orthotropia for vertical rectus surgery, without diplopia or reoperations. The main outcome measure was surgical success rate. RESULTS: Three hundred and fifty-three patients were included in the study with mean follow-up of 13.9 (4-132) months. Patients achieving the target angle immediately postoperatively had higher success rate than patients who did not (83.6% vs 63.7%, p<0.0001, OR 2.9, 95% CI 1.8 to 4.9). When target angle was achieved, adjustable and non-adjustable sutures had similar success (84.8% and 80.9%, respectively, p=0.46, OR 1.3, CI 0.58 to 2.9). However, patients undergoing adjustable surgery were more likely to obtain the target angle (75.5% vs 54%, p<0.0001, OR 2.7, CI 1.7 to 4.2). Success for exotropia surgery was significantly higher when the immediate target angle was achieved (86.4% vs 58.7%, p<0.0001, OR 4.47, CI 2.3 to 8.6). For esotropia and vertical deviations, a similar beneficial effect was not shown (p=0.31, OR 1.6, CI 0.65 to 4.0 and p=0.33, respectively). On multiple logistic regressions, sex, amblyopia, binocularity and reoperations were not significant factors in surgical success. CONCLUSIONS: Our results suggest that achieving the immediate target angle is the most significant factor in the success of strabismus surgery for exotropia. Adjustable suture surgery results in higher proportion of patients achieving this target angle.

Anatomic dorsal and volar radioulnar ligament reconstruction with Mersilene augmentation for distal radioulnar joint instability.

Instability of the distal ulna is a fairly common problem after acute distal radius fracture (DRF), distal radius malunion, triangular fibrocartilage complex injury, and a host of other types of trauma. We present a new anatomic technique to stabilize the distal ulna with a tendon graft augmented with Mersilene tape, which has been used primarily to treat unidirectional (dorsal or volar) instability, but could be used for global instability as well. Of the 12 patients who underwent this procedure, 9 had stability fully restored and the remaining 3 had only mild instability after surgery. The procedure is an effective treatment for distal radioulnar joint instability and we believe that this surgical technique will be a valuable adjunct to the existing described procedures for hand surgeons. We present a retrospective single-surgeon case series with outcome measures.

Utility of adjustable sutures in primary strabismus surgery and reoperations.

PURPOSE: To evaluate the success of adjustable suture (AS) and nonadjustable suture (NAS) strabismus surgery in primary procedures and reoperations. DESIGN: Retrospective case series. PARTICIPANTS: Four hundred four patients older than 12 years who underwent strabismus surgery over a 13-year period. METHODS: All eyes underwent the same hang-back suturing technique by a single surgeon (S.P.K.) in both the AS and NAS groups. Success was defined as alignment within 10 prism diopters (PD) for horizontal recti and within 5 PD of orthophoria for vertical recti without diplopia or further surgery. MAIN OUTCOME MEASURES: Surgical success rate of AS and NAS primary surgery or reoperations was the primary outcome measure. Effects of amblyopia, binocularity, and strabismus type on success were secondary outcome measures and were analyzed using multiple logistic regression. RESULTS: Patients in the AS group required adjustment in 28.8% of cases. Higher overall success was seen with AS (77.7%) compared with NAS (69.1%) surgery, although this did not reach significance (P = 0.059). Overall success for AS in exotropia surgery (80.8%) was significantly higher than that in the NAS group (65.9%; P = 0.011). This was because of higher success in patients undergoing primary surgery (82.5% vs. 50%; P = 0.003), but not in patients undergoing reoperation (80.2% vs. 77.6%; P = 0.71). On multiple regression analysis, male gender and not having a mechanical or neurogenic cause for strabismus were significant factors for a successful outcome. Overall, other factors including amblyopia, binocularity, strabismus type, and primary or reoperation were not significant. CONCLUSIONS: These results suggest that primary surgery in adults with exotropia has a more successful outcome with AS surgery. This advantage was not present with esotropia and vertical deviations in this series.

Ligament reconstruction tendon interposition with mersilene augmentation.

Many surgical procedures have been described for the treatment of thumb basilar joint osteoarthritis. Augmentation of the standard ligament reconstruction tendon interposition procedure with the use of a Mersilene suture tape suspension-plasty, to recreate the stability provided by the anterior oblique ligament and increase pinch strength, will be described. Satisfaction with this procedure was evaluated through surveys completed by patients. In addition, independent physical assessments were performed to demonstrate stability, range of motion, and strength.

Search algorithms as a framework for the optimization of drug combinations.

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms -- originally developed for digital communication -- modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs using only one-third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.