Elevated expression of human bHLH factor ATOH7 accelerates cell cycle progression of progenitors and enhances production of avian retinal ganglion cells.

The production of vertebrate retinal projection neurons, retinal ganglion cells (RGCs), is regulated by cell-intrinsic determinants and cell-to-cell signaling events. The basic-helix-loop-helix (bHLH) protein Atoh7 is a key neurogenic transcription factor required for RGC development. Here, we investigate whether manipulating human ATOH7 expression among uncommitted progenitors can promote RGC fate specification and thus be used as a strategy to enhance RGC genesis. Using the chicken retina as a model, we show that cell autonomous expression of ATOH7 is sufficient to induce precocious RGC formation and expansion of the neurogenic territory. ATOH7 overexpression among neurogenic progenitors significantly enhances RGC production at the expense of reducing the progenitor pool. Furthermore, forced expression of ATOH7 leads to a minor increase of cone photoreceptors. We provide evidence that elevating ATOH7 levels accelerates cell cycle progression from S to M phase and promotes cell cycle exit. We also show that ATOH7-induced ectopic RGCs often exhibit aberrant axonal projection patterns and are correlated with increased cell death during the period of retinotectal connections. These results demonstrate the high potency of human ATOH7 in promoting early retinogenesis and specifying the RGC differentiation program, thus providing insight for manipulating RGC production from stem cell-derived retinal organoids.

Durable response using regorafenib in an elderly patient with metastatic colorectal cancer: case report.

Regorafenib, an oral multikinase inhibitor, was approved in September 2012 by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer. Since this time, however, few case reports outlining real-world usage have been published in the literature. Here, we detail the clinical history of an elderly woman with KRAS wild-type colon cancer who received regorafenib after prior treatment with other agents. We show that by employing dose modification strategies to address adverse events, this patient was able to remain on therapy for 11 months and achieve stable disease.

Biomechanical evaluation of pediatric anterior cruciate ligament reconstruction techniques.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction rates in skeletally immature patients have risen recently because of increased injury frequency combined with growing awareness of the importance of treating them in an acute setting. Concerns over potential growth disturbances caused by traditional tunnel placement have prompted the description of several partial and complete physeal-sparing techniques. HYPOTHESIS: Native knee kinematics will most closely be restored by the all-epiphyseal technique because it best re-creates the intra-articular ACL anatomy. STUDY DESIGN: Controlled laboratory study. METHODS: Six cadaveric knees were subjected to static anteroposterior, varus, and internal rotation forces at 0°,15°, 30°, 45°, 60°, and 90° of flexion. Displacement and rotation of the tibia with respect to the femur were measured in the intact knee, after ACL disruption, and again after ACL reconstruction using all-epiphyseal, transtibial over-the-top, and iliotibial band physeal-sparing techniques. RESULTS: Peak anteroposterior translation in the ACL intact and deficient states was 2.8 ± 1.4 mm and 7.2 ± 2.7 mm, respectively, at 30°. The all-epiphyseal reconstruction had a peak translation of 5.1 ± 2.3 mm at 30°, and the transtibial over-the-top reconstruction had a peak of 4.8 ± 1.8 mm at 30°, both significantly greater than the ACL intact state. The iliotibial band technique had a peak anteroposterior translation of 1.7 ± 1.1 mm at 45°, which was significantly less than the ACL-deficient state. Internal rotation was significantly increased in the all-epiphyseal reconstruction compared with the ACL intact state and significantly decreased at all flexion angles except 0° in the iliotibial band reconstruction. The only technique to affect varus rotation was the iliotibial band reconstruction, which significantly decreased varus rotation from the ACL-deficient state at flexion angles greater than 30°. CONCLUSION: All physeal-sparing reconstruction techniques restored some stability to the knee. The iliotibial band reconstruction best restored anteroposterior stability and rotational control, although it appeared to overconstrain the knee to rotational forces at some flexion angles. CLINICAL RELEVANCE: This study provides orthopaedic surgeons with objective knee kinematic data to help guide them in making more informed decisions on the optimal technique for ACL reconstruction in skeletally immature patients.