Exposure of isolated xenogeneic islets of Langerhans to blood, both in vitro and in vivo, resulted in acute islet damage. Complement and platelets seem to have a central role in the reactions described. Strategies to efficiently inhibit these reactions will be crucial for clinical intraportal islet xenotransplantation to be successful.

We have studied the morphology of the central sulcus and the cytoarchitecture of the primary sensorimotor cortex in 20 human brains obtained at autopsy. Although the surface appearance of the central sulcus varies greatly from brain to brain (and between hemispheres of individual brains), its deep structure is remarkably consistent. The fundus of the central sulcus is divided into medial and lateral limbs by a complex junction midway between the sagittal and Sylvian fissures. Based on functional imaging studies, this junction appears to be a structural hallmark of the sensorimotor representation of the distal upper extremity. We also identified and measured area 4 (primary motor cortex) and area 3 (primary somatic sensory cortex) in Nissl-stained sections cut orthogonal to the course of the central sulcus. Although the positions of the cytoarchitectonic boundaries in the paracentral lobule showed considerable interindividual variation, the locations of the borders of areas 4 and 3 along the course of the sulcus were similar among the 40 hemispheres examined. In addition to describing more thoroughly this portion of the human cerebral cortex, these observations provide a basis for evaluating lateral symmetry of the human primary sensorimotor cortex.

The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.

We have evaluated the lateral symmetry of the human central sulcus, brainstem and spinal cord using quantitative histological and imaging techniques in specimens from 67 autopsy cases. Our purpose was to determine whether the preferred use of the right hand in the majority of humans is associated with grossly discernible asymmetries of the neural centers devoted to the upper extremities. In the accompanying report, we described a consistent set of morphological features in the depths of the central sulcus that localize the sensorimotor representation of the distal upper extremity. Measurements of the cortical surface in this region, and indeed throughout the entire central sulcus, showed no average lateral asymmetry. Cytoarchitectonic measurements of area 4 and area 3 confirmed this similarity between the left and right hemispheres. The medullary pyramids, which contain the corticospinal tracts, were also symmetrical, as were the cross-sectional areas of white and gray matter in the cervical and lumbar enlargements of the spinal cord. Finally, we found no lateral difference in the size and number of motor neurons in the ventral horns at these levels of the cord. Based on these several observations, we conclude that the preferred use of the right hand in humans occurs without a gross lateral asymmetry of the primary sensorimotor system.

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