Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma.

CONTEXT.­: Pembrolizumab is used in patients with metastatic head and neck squamous cell carcinoma contingent upon the programmed death ligand-1 (PD-L1) combined positive score (CPS). OBJECTIVE.­: To compare PD-L1 CPS scores derived from paired resected primary tumors (PTs) and lymph node metastases (LMs) in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC). DESIGN.­: We identified 38 resected p16+ OPSCCs for which paired PTs and LMs were available. PD-L1 immunohistochemistry using the SP263 antibody clone was done on both the PT and the LM. CPS scoring was performed by 4 observers, and data were analyzed at the CPS cut points of greater than or equal to 1 and 20 in regard to interobserver and interspecimen agreement. RESULTS.­: Overall agreement between consensus CPS scoring of PT and LM was seen in 76% of paired specimens (κ = 0.53). No specimen received a negative consensus score. Interobserver agreement for both PT and LM was fair to substantial (κ = 0.54 and 0.51, respectively) and was inferior to that seen in a prospective series of unselected head and neck squamous carcinoma cases evaluated at our institution (κ = 0.84). CONCLUSIONS.­: Given the high rates of interobserver and interspecimen variability, evaluation of additional material or by additional observers may be of value in performing CPS scoring in cases of p16+ OPSCC. This is particularly the case when a negative or low-positive result is being evaluated in a patient who is otherwise a good candidate for immunotherapy.

Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult DBA/2J mice: relationship with ventral striatum dopamine concentrations.

The principal polyunsaturated fatty acid acids found in brain, arachidonic acid (AA) and docosahexaenoic acid (DHA), preferentially accumulate in synaptic membranes. Although neurochemical studies have found that dietary-induced deficits in rat brain DHA composition significantly alter mesocorticolimbic dopamine (DA) neurotransmission, its impact on DA-mediated behavior remains poorly understood. In the present study, we determined the effects of dietary-induced deficits in brain DHA composition on amphetamine (AMPH)-induced locomotor activity and sensitization in DBA/2J mice, an inbred strain previously found to be hyporesponsive to AMPH, as well as monoamine concentrations in the PFC and ventral striatum following the AMPH challenge. Chronic dietary omega-3 fatty acid deficiency significantly decreased PFC (-25%) and ventral striatum (-20%) DHA composition, increased PFC (+7%) and ventral striatum (+6%) AA composition, and increased the AA:DHA ratio in PFC (+30%) and ventral striatum (+24%). The development and expression of AMPH-induced sensitization was significantly increased in DHA-deficient mice, whereas novelty- and acute AMPH-induced locomotor activity were not altered. DHA-deficient mice exhibited significantly greater ventral striatum, but not PFC, DA and DA metabolite concentrations following the AMPH challenge, whereas serotonin and noradrenalin concentrations were not altered. Ventral striatum AA composition and the AA:DHA ratio were both positively correlated with DA concentrations, and both ventral striatum AA composition and DA concentrations were positively correlated with locomotor activity during the preceding AMPH challenge. These results demonstrate that dietary-induced brain DHA deficiency, and associated elevation in the AA:DHA ratio, augment AMPH-induced sensitization in DBA/2J mice, and that this augmented response is associated with selective alterations in the mesolimbic DA pathway.

The value of idiosyncratic markers and changes to conserved tRNA sequences from the mitochondrial genome of hard ticks (Acari: Ixodida: Ixodidae) for phylogenetic inference.

Idiosyncratic markers are features of genes and genomes that are so unusual that it is unlikely that they evolved more than once in a lineage of organisms. Here we explore further the potential of idiosyncratic markers and changes to typically conserved tRNA sequences for phylogenetic inference. Hard ticks were chosen as the model group because their phylogeny has been studied extensively. Fifty-eight candidate markers from hard ticks (family Ixodidae) and 22 markers from the subfamily Rhipicephalinae sensu lato were mapped onto phylogenies of these groups. Two of the most interesting markers, features of the secondary structure of two different tRNAs, gave strong support to the hypothesis that species of the Prostriata (Ixodes spp.) are monophyletic. Previous analyses of genes and morphology did not strongly support this relationship, instead suggesting that the Prostriata is paraphyletic with respect to the Metastriata (the rest of the hard ticks). Parallel or convergent evolution was not found in the arrangements of mitochondrial genes in ticks nor were there any reversals to the ancestral arthropod character state. Many of the markers identified were phylogenetically informative, whereas others should be informative with study of additional taxa. Idiosyncratic markers and changes to typically conserved nucleotides in tRNAs that are phylogenetically informative were common in this data set, and thus these types of markers might be found in other organisms.