The prefrontal cortex is a higher brain region that regulates thought, behavior, and emotion using representational knowledge, operations often referred to as working memory. We tested the influence of protein kinase C (PKC) intracellular signaling on prefrontal cortical cognitive function and showed that high levels of PKC activity in prefrontal cortex, as seen for example during stress exposure, markedly impair behavioral and electrophysiological measures of working memory. These data suggest that excessive PKC activation can disrupt prefrontal cortical regulation of behavior and thought, possibly contributing to signs of prefrontal cortical dysfunction such as distractibility, impaired judgment, impulsivity, and thought disorder.

No abstract

Cognitive deficits in psychiatric and age-related disorders generally involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), but there are few treatments for these debilitating symptoms. Group II metabotropic glutamate receptors (mGluR2/3), which couple to Gi/Go, have been a focus of therapeutics based on rodent research, where mGluR2/3 have been shown to reduce axonal glutamate release and increase glial glutamate uptake. However, this strategy has had mixed results in patients, and understanding mGluR2/3 mechanisms in primates will help guide therapeutic interventions. The current study examined mGluR2/3 localization and actions in the primate dlPFC layer III circuits underlying working memory, where the persistent firing of “Delay cells” is mediated by NMDA receptors and weakened by cAMP-PKA-potassium channel signaling in dendritic spines. Immunoelectron microscopy identified postsynaptic mGluR2/3 in the spines, in addition to the traditional presynaptic and astrocytic locations. In vivo iontophoretic application of the mGluR2/3 agonists (2R, 4R)-APDC or LY379268 onto dlPFC Delay cells produced an inverted-U effect on working memory representation, with enhanced neuronal firing following low doses of mGluR2/3 agonists. The enhancing effects were reversed by an mGluR2/3 antagonist or by activating cAMP signaling, consistent with mGluR2/3 inhibiting postsynaptic cAMP signaling in spines. Systemic administration of these agonists to monkeys performing a working memory task also produced an inverted-U dose-response, where low doses improved performance but higher doses, similar to clinical trials, had mixed effects. Our data suggest that low dose mGluR2/3 stimulation may have therapeutic effects through unexpected postsynaptic actions in dlPFC, strengthening synaptic connections and improving cognitive function.

The dielectric and structural properties of LaAlO3 make it an attractive epitaxial gate oxide for nanometer-scale field effect transistors. However, the growth of epitaxial LaAlO3 directly on Si has not been possible to date. In order to achieve LaAlO3 epitaxy, we use a SrTiO3 template layer whose thickness minimizes elastic strain and atomic-level buckling at the interface. We find that LaAlO3 grown on this template layer is crystalline and initially strained, but relaxes to its bulk lattice constant within 7 unit cells. Cross-sectional transmission electron microscopy and inelastic electron tunneling spectroscopy studies of the LaAlO3/SrTiO3/Si structure show no evidence of an amorphous SiO2 layer. Capacitance-voltage measurements on thin films of epitaxial LaAlO3/SrTiO3/Si with LaAlO3 thicknesses between 13 and 110 nm show a dielectric constant for the LaAlO3 layer of 24, the same value as for the bulk. After a post-deposition low temperature anneal, these oxide heterostructures show no Fermi level pinning and an interface state density of ∼8×1010 cm−2 eV−1.

Electron tunneling spectroscopy (ETS) was used to study amorphous LaAlO3 and LaScO3 thin film gate dielectrics for silicon metal-oxide-semiconductor structure. These gate dielectrics were prepared by molecular-beam deposition on (100) Si substrates. The authors have obtained vibrational modes for amorphous LaAlO3 and LaScO3 thin films from the ETS spectra, which provide information about the chemical bonding in these films and the interface with silicon. Traps and defects in amorphous LaAlO3 thin films are revealed in the ETS spectra, and their physical locations and energy levels are identified.

No abstract

Immunosuppressive calcineurin inhibitors (CNI) have been shown to increase the rates of skin cancers in solid organ transplant recipients (SOTR). Belatacept, a CTLA-4 fusion protein, is an immunosuppressant that is also used in SOTR populations. However, how belatacept affects skin cancer risk is not well characterized; the existing data compared to CNI are equivocal. We investigated the rate of skin cancer development in a retrospective study of 110 kidney transplant recipients who switched from CNI to belatacept. Of these patients, 66 were included for final analysis as they were followed by dermatology for at least 2 years after switching to belatacept. 24 patients developed a total of 128 cutaneous malignancies (38 basal cell carcinomas [BCC], 83 SCC, and 7 melanomas or atypical melanocytic proliferations). The rate of developing keratinocyte carcinomas (KC), in particular cutaneous squamous cell carcinomas (SCC) decreased after switching to belatacept. While on CNI, the incidence of developing a cutaneous KC or SCC increased by 2.6 events per 100 patients per year and 1.7 events per 100 patients per year, respectively. The incidence continued to increase to a maximum at 6 months after switching to belatacept. Thereafter, the incidence of developing cutaneous KCs or SCCs decreased at a rate of 5.9 events per 100 patients per year for SCCs and 7.1 events per 100 patients per year for KCs. The differences in rates prior to and post switch to belatacept were statistically significant: p¼0.0030 and p¼0.0068 for KCs and SCCs respectively. BCC and melanocytic lesion incidence rates were unchanged. Unlike CNI, belatacept has not been shown to have direct effects on cutaneous carcinogenesis. Belatacept has previously been shown to have better patient and graft survival compared to CNI. Our results demonstrate that it may also offer SOTR a better risk-benefit profile with regards to skin cancer. Background: A significant proportion of advanced basal cell carcinomas (BCCs) are incompletely treated with current therapies. As BCCs have particularly high mutational burdens and can express Programmed Death ligand (PDL)-1, we performed a proof-of-concept study of the PD-1 inhibitor, pembrolizumab, for advanced BCCs. Objectives: To assess the clinical effects of pembrolizumab on advanced BCCs. Methods: In this single-institution, two-cohort, nonrandomized study (NCT02690948), responses and adverse events (AEs) were assessed in patients who received 1 dose of pembrolizumab (200 mg every 3 weeks), with or without vismodegib (150mg daily). Findings: Sixteen eligible patients were enrolled and were evaluable. Overall response rate (ORR) was 38% (6/16) [95% confidence interval (CI): 15-65%], p¼0.003, at 18 weeks. ORR for pembrolizumab monotherapy group was 44% (4/9) [95% CI: 14-79%], p¼0.008 and pembrolizumab plus vismodegib group was 29% (2/7) [95% CI: 4-71%], p¼0.15. Three patients (2 with partial response and 1 with stable disease) continued to receive off-label treatment through their community oncologists and achieved comple...