Analytical Concordance of PD-L1 Assays Utilizing Antibodies From FDA-Approved Diagnostics in Advanced Cancers: A Systematic Literature Review.

Four programmed death ligand 1 (PD-L1) immunohistochemistry assays (28-8, 22C3, SP263, and SP142) have been approved for use by the US Food and Drug Administration (FDA). Analytical concordance between these assays has been evaluated in multiple studies. This systematic review included studies that investigated the analytical concordance of immunohistochemistry assays utilizing two or more PD-L1 antibodies from FDA-approved diagnostics for evaluation of PD-L1 expression on tumor or immune cells across a range of tumor types and algorithms. METHODS: Literature searches were conducted in MEDLINE (via PubMed) and EMBASE to identify studies published between January 1, 2010, and March 31, 2019, that evaluated analytical concordance between two or more assays based on antibodies from FDA-approved assays. Proceedings of key oncology and pathology congresses that took place between January 2016 and March 2019 were searched for abstracts of studies evaluating PD-L1 assay concordance. RESULTS: A total of 42 studies across a range of tumor types met the selection criteria. Concordance between 28-8-, 22C3-, and SP263-based assays in lung cancer, urothelial carcinoma, and squamous cell carcinoma of the head and neck was high when used to assess PD-L1 expression on tumor cells (TCs). SP142-based assays had overall low concordance with other approved assays when used to assess PD-L1 expression on TCs. Analytical concordance for assessment of PD-L1 expression on immune cells was variable and generally lower than for PD-L1 expression on TCs. CONCLUSION: A large body of evidence supports the potential interchangeability of 28-8-, 22C3-, and SP263-based assays for the assessment of PD-L1 expression on TCs in lung cancer. Further studies are required in tumor types for which less evidence is available.

Analysis of real-world PD-L1 IHC 28-8 and 22C3 pharmDx assay utilisation, turnaround times and analytical concordance across multiple tumour types.

AIMS: Programmed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitor therapy is accompanied by companion or complementary PD-L1 testing in some tumour types. We investigated utilisation of the Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays and the Ventana PD-L1 (SP142) assay and evaluated concordance between the 28-8 and 22C3 assays in a real-world cohort of patients tested at a single US national reference laboratory. METHODS: NeoGenomics Laboratories performed PD-L1 testing on tumour samples between October 2015 and March 2018. PD-L1 test results were matched with patient characteristics using unique identifiers. Concordance between the 28-8 and 22C3 assays was evaluated in matched tumour samples. Data were evaluated across multiple tumour types and in subgroups of patients with lung cancer, melanoma, squamous cell carcinoma of the head and neck, and urothelial carcinoma. RESULTS: 62 180 individual PD-L1 tests were conducted on samples from 55 652 patients. PD-L1 test volume increased ~10-fold over the period evaluated. Test failure rates were typically low, and test turnaround time (TAT) ranged between 2 and 4 days. Concordance between the 28-8 and 22C3 assays was strong in the overall population and across tumour type subgroups (Kendall's tau correlations of 0.94 and 0.92-0.98, respectively). CONCLUSIONS: Test failure rates for PD-L1 tests were low and TAT remained reasonable despite marked increases in test volume. Concordance was high between the 28-8 and 22C3 assays across a range of tumour types and biopsy locations. These findings add to the literature showing high concordance between the 28-8 and 22C3 assays.

On the Enjoyment of Sad Music: Pleasurable Compassion Theory and the Role of Trait Empathy.

Drawing on recent empirical studies on the enjoyment of nominally sad music, a general theory of the pleasure of tragic or sad portrayals is presented. Not all listeners enjoy sad music. Multiple studies indicate that those individuals who enjoy sad music exhibit a particular pattern of empathic traits. These individuals score high on empathic concern (compassion) and high on imaginative absorption (fantasy), with only nominal personal distress (commiseration). Empirical studies are reviewed implicating compassion as a positively valenced affect. Accordingly, individuals who most enjoy sad musical portrayals experience a pleasurable prosocial affect (compassion), amplified by empathetic engagement (fantasy), while experiencing only nominal levels of unpleasant emotional contagion (commiseration). It is suggested that this pattern of trait empathy may apply more broadly, accounting for many other situations where spectators experience pleasure when exposed to tragic representations or portrayals.

Tonal and "Anti-Tonal" Cognitive Structure in Viennese Twelve-Tone Rows.

We show that the twelve-tone rows of Arnold Schoenberg and Anton Webern are "anti-tonal"-that is, structured to avoid or undermine listener's tonal schemata. Compared to randomly generated rows, segments from Schoenberg's and Webern's rows have significantly lower fit to major and minor key profiles. The anti-tonal structure of Schoenberg's and Webern's rows is still evident when we statistically controlled for their preference for other row features such as mirror symmetry, derived and hexachordal structures, and preferences for certain intervals and trichords. The twelve-tone composer Alban Berg, by contrast, often wrote rows with segments that fit major or minor keys quite well.

Musical Aesthetics: Uncertainty and Surprise Enhance Our Enjoyment of Music.

How does music give pleasure? A recent study of harmony in popular music suggests that the pleasure of listening to music is linked to two characteristic interactions between uncertainty and surprise.

Word Intelligibility in Multi-voice Singing: The Influence of Chorus Size.

OBJECTIVE: This study investigated how the intelligibility of sung words is influenced by the number of singers in a choral music style. METHODS: The study used repeated measures factorial. One hundred forty-nine participants listened to recordings of spoken and sung English words and attempted to identify the words. Each stimuli word was sung or spoken in sync by either one, four, eight, sixteen, or twenty-seven members of a high-quality Soprano Alto Tenor Bass (SATB) choir. RESULTS: In general, single-voice word recognition was higher than multi-voice word recognition in the sung condition. However, the difference between four concurrent singers and the full choir was negligible; that is, reduced intelligibility with multiple singers shows little sensitivity to the number of singers. The principal effect of voice density on intelligibility is found to occur with coda consonants-a result consistent with the importance many choral conductors attribute to coordinating word offsets. In particular, the plosives /b/, /d/, /g/, and /p/ are easily confused. Coda liquids (/l/,/r/) were also found to be a source of confusion. Finally, an increasing density of voices appears to have a facilitating effect for the coda nasal /m/. CONCLUSIONS: Groups of four or more choral singers do appear to be less intelligible than single singers, although the observed effect is modest. However, increasing the number of singers in a choral texture beyond four singers does not appear to further degrade intelligibility.

The sounds of safety: stress and danger in music perception.

As with any sensory input, music might be expected to incorporate the processing of information about the safety of the environment. Little research has been done on how such processing has evolved and how different kinds of sounds may affect the experience of certain environments. In this article, we investigate if music, as a form of auditory information, can trigger the experience of safety. We hypothesized that (1) there should be an optimal, subjectively preferred degree of information density of musical sounds, at which safety-related information can be processed optimally; (2) any deviation from the optimum, that is, both higher and lower levels of information density, should elicit experiences of higher stress and danger; and (3) in general, sonic scenarios with music should reduce experiences of stress and danger more than other scenarios. In Experiment 1, the information density of short music-like rhythmic stimuli was manipulated via their tempo. In an initial session, listeners adjusted the tempo of the stimuli to what they deemed an appropriate tempo. In an ensuing session, the same listeners judged their experienced stress and danger in response to the same stimuli, as well as stimuli exhibiting tempo variants. Results are consistent with the existence of an optimum information density for a given rhythm; the preferred tempo decreased for increasingly complex rhythms. The hypothesis that any deviation from the optimum would lead to experiences of higher stress and danger was only partly fit by the data. In Experiment 2, listeners should indicate their experience of stress and danger in response to different sonic scenarios: music, natural sounds, and silence. As expected, the music scenarios were associated with lowest stress and danger whereas both natural sounds and silence resulted in higher stress and danger. Overall, the results largely fit the hypothesis that music seemingly carries safety-related information about the environment.

Affect induction through musical sounds: an ethological perspective.

How does music induce or evoke feeling states in listeners? A number of mechanisms have been proposed for how sounds induce emotions, including innate auditory responses, learned associations and mirror neuron processes. Inspired by ethology, it is suggested that the ethological concepts of signals, cues and indices offer additional analytic tools for better understanding induced affect. It is proposed that ethological concepts help explain why music is able to induce only certain emotions, why some induced emotions are similar to the displayed emotion (whereas other induced emotions differ considerably from the displayed emotion), why listeners often report feeling mixed emotions and why only some musical expressions evoke similar responses across cultures.

The psychological functions of music listening.

Why do people listen to music? Over the past several decades, scholars have proposed numerous functions that listening to music might fulfill. However, different theoretical approaches, different methods, and different samples have left a heterogeneous picture regarding the number and nature of musical functions. Moreover, there remains no agreement about the underlying dimensions of these functions. Part one of the paper reviews the research contributions that have explicitly referred to musical functions. It is concluded that a comprehensive investigation addressing the basic dimensions underlying the plethora of functions of music listening is warranted. Part two of the paper presents an empirical investigation of hundreds of functions that could be extracted from the reviewed contributions. These functions were distilled to 129 non-redundant functions that were then rated by 834 respondents. Principal component analysis suggested three distinct underlying dimensions: People listen to music to regulate arousal and mood, to achieve self-awareness, and as an expression of social relatedness. The first and second dimensions were judged to be much more important than the third-a result that contrasts with the idea that music has evolved primarily as a means for social cohesion and communication. The implications of these results are discussed in light of theories on the origin and the functionality of music listening and also for the application of musical stimuli in all areas of psychology and for research in music cognition.

Eyebrow movements and vocal pitch height: evidence consistent with an ethological signal.

When asked to sing a high pitch, people produce a facial expression that is judged more friendly compared with singing a low pitch [Huron et al. (2009). Empirical Musicology Rev. 4(3), 93-100]. This effect was observed even when judges viewed only the face above the tip of the nose, and implies a relationship between pitch height and eyebrow height. In the current study, we examine the reverse relationship. Thirty-one participants were asked to read aloud standard texts while holding their eyebrows in a raised, neutral, or lowered position. Average F0 was found to correlate positively with eyebrow position, with higher vocal pitch associated with higher eyebrow placement. However, manipulating eyebrow placement produces a considerably smaller effect (on pitch) compared with the effect of manipulating pitch (on eyebrows). Results are discussed from the perspective of ethological signals [Lorenz (1939). Zool. Anz. 12, 69-102].

Changing the Tune: Listeners Like Music that Expresses a Contrasting Emotion.

Theories of esthetic appreciation propose that (1) a stimulus is liked because it is expected or familiar, (2) a stimulus is liked most when it is neither too familiar nor too novel, or (3) a novel stimulus is liked because it elicits an intensified emotional response. We tested the third hypothesis by examining liking for music as a function of whether the emotion it expressed contrasted with the emotion expressed by music heard previously. Stimuli were 30-s happy- or sad-sounding excerpts from recordings of classical piano music. On each trial, listeners heard a different excerpt and made liking and emotion-intensity ratings. The emotional character of consecutive excerpts was repeated with varying frequencies, followed by an excerpt that expressed a contrasting emotion. As the number of presentations of the background emotion increased, liking and intensity ratings became lower compared to those for the contrasting emotion. Consequently, when the emotional character of the music was relatively novel, listeners' responses intensified and their appreciation increased.

Two challenges in cognitive musicology.

Two themes in music cognition research are highlighted--inspired by the contributions in this volume: (a) statistical learning and (b) evolutionary theorizing. Our ability to test alternatives to statistical learning is threatened by the rapidly diminishing opportunities for cross-cultural studies unconfounded by bimusicalism. Our ability to infer possible evolutionary origins for music is confounded by the "hedonic plenitude" of modern music-making--where multiple pleasure channels are activated simultaneously. Cognitively inspired music research will benefit by studying a wider range of musical cultures. Evolutionary theorizing will benefit by further work involving comparative animal behavior.

Soluble adenylyl cyclase is required for netrin-1 signaling in nerve growth cones.

Growth cones at the tips of nascent and regenerating axons direct axon elongation. Netrin-1, a secreted molecule that promotes axon outgrowth and regulates axon pathfinding, elevates cyclic AMP (cAMP) levels in growth cones and regulates growth cone morphology and axonal outgrowth. These morphological effects depend on the intracellular levels of cAMP. However, the specific pathways that regulate cAMP levels in response to netrin-1 signaling are unclear. Here we show that 'soluble' adenylyl cyclase (sAC), an atypical calcium-regulated cAMP-generating enzyme previously implicated in sperm maturation, is expressed in developing rat axons and generates cAMP in response to netrin-1. Overexpression of sAC results in axonal outgrowth and growth cone elaboration, whereas inhibition of sAC blocks netrin-1-induced axon outgrowth and growth cone elaboration. Taken together, these results indicate that netrin-1 signals through sAC-generated cAMP, and identify a fundamental role for sAC in axonal development.

Bicarbonate-responsive "soluble" adenylyl cyclase defines a nuclear cAMP microdomain.

Bicarbonate-responsive "soluble" adenylyl cyclase resides, in part, inside the mammalian cell nucleus where it stimulates the activity of nuclear protein kinase A to phosphorylate the cAMP response element binding protein (CREB). The existence of this complete and functional, nuclear-localized cAMP pathway establishes that cAMP signals in intracellular microdomains and identifies an alternate pathway leading to CREB activation.

A novel pyridopyrimidine inhibitor of abl kinase is a picomolar inhibitor of Bcr-abl-driven K562 cells and is effective against STI571-resistant Bcr-abl mutants.

Inhibition of the constitutively active Bcr-abl tyrosine kinase(TK) by STI571 has proven to be a highly effective treatment for chronic myelogenous leukemia (CML). However, STI571 is only transiently effective in blast crisis, and drug resistance emerges by amplification of or development of mutational changes in Bcr-abl. We have screened a family of TK inhibitors of the pyrido [2,3-d]pyrimidine class, unrelated to STI571, and describe here a compound with substantial activity against STI-resistant mutant Bcr-abl proteins. This compound, PD166326, is a dual specificity TK inhibitor and inhibits src and abl in vitro with IC(50)s of 6 and 8 nM respectively. PD166326 inhibits the growth of K562 cells with IC(50) of 300 pM, leading to apoptotic G(1) arrest, whereas non-Bcr-abl cell types require >1000 times higher concentrations. We tested the effects of PD166326 on two of the clinically observed STI571-resistant Bcr-abl mutants. PD166326 potently inhibits the E255K mutant Bcr-abl protein and the growth of Bcr-ablE255K-driven cells. The T315I mutant Bcr-abl protein, which is mutated within the ATP-binding pocket, is resistant to PD166326; however, the growth of Bcr-ablT315I-driven cells is partially sensitive to this compound, likely through the inhibition of Bcr-abl effector pathways. These findings show that TK drug resistance is a structure-specific phenomenon and can be overcome by TK inhibitors of other structural classes, suggesting new approaches for future anticancer drug development. PD166326 is a prototype of a new generation of anti-Bcr-abl compounds with picomolar potency and substantial activity against STI571-resistant mutants.