Use of tamibarotene, a potent and selective RARα agonist, in combination with azacitidine in patients with relapsed and refractory AML with RARA gene overexpression.

Tamibarotene-based therapy is a novel targeted approach for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with retinoic acid receptor alpha (RARA) gene overexpression. Approximately, 50% of higher-risk myelodysplastic syndrome (MDS) patients and approximately 30% of AML patients are positive for RARA overexpression using a blood-based biomarker test that measures RARA expression in peripheral blasts. A phase 2 study investigating the activity of tamibarotene in patients with RARA overexpression was conducted in patients with AML and MDS (NCT02807558). In 28 patients with R/R AML and RARA overexpression treated with tamibarotene in combination with azacitidine, the median overall survival was 5.9 months. In 21 response-evaluable patients, the complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 19%, and median time to initial CR/CRi was 1.2 months. The favorable safety profile and preliminary clinical activity support the development of combination therapies with tamibarotene in myeloid malignancies with RARA overexpression.

2,6-Bis(pyrazol-1-yl)pyridine (1-bpp) as a General Ligand for the Negishi Alkylation of Alkylpyridinium Salts.

A Ni/1-bpp catalyst was demonstrated to be effective in the Negishi alkylation with multiple classes of alkylpyridinium salts, including α-primary and α-secondary. These conditions are also effective for benzylic pyridinium salts, demonstrating the successful Negishi alkylation of benzylic pyridinium salts for the first time. Further, 14 derivatives of 1-bpp were prepared with a variety of steric and electronic properties to study how these changes impact the success of the Negishi alkylation.

Unfamiliar face matching ability predicts the slope of face learning.

We provide the first examination of individual differences in the efficiency of face learning. Investigating individual differences in face learning can illuminate potential mechanisms and provide greater understanding of why certain individuals might be more efficient face learners. Participants completed two unfamiliar face matching tasks and a learning task in which learning was assessed after viewing 1, 3, 6, and 9 images of to-be-learned identities. Individual differences in the slope of face learning (i.e., increases in sensitivity to identity) were predicted by the ability to discriminate between matched (same-identity) vs. mismatched (different-identity) pairs of wholly unfamiliar faces. A Dual Process Signal Detection model showed that three parameters increased with learning: Familiarity (an unconscious type of memory that varies in strength), recollection-old (conscious recognition of a learned identity), and recollection-new (conscious/confident rejection of novel identities). Good (vs. poor) matchers had higher Recollection-Old scores throughout learning and showed a steeper increase in Recollection-New. We conclude that good matchers are better able to capitalize on exposure to within-person variability in appearance, an effect that is attributable to their conscious memory for both learned and novel faces. These results have applied implications and will inform contemporary and traditional models of face identification.

Event-Related Potentials Index Prediction Error Signalling During Perceptual Processing of Emotional Facial Expressions.

Humans use socially relevant stimuli to guide perceptual processing of the surrounding environment, with emotional stimuli receiving preferential attention due to their social importance. Predictive coding theory asserts this cognitive process occurs efficiently by combining predictions about what is to be perceived with incoming sensory information, generating prediction errors that are then used to update future predictions. Recent evidence has identified differing neural activity that demonstrates how spatial and feature-based attention may interact with prediction, yet how emotion-guided attention may influence this relationship remains unknown. In the present study, participants viewed a display of two faces in which attention, prediction, and emotion were manipulated, and responded to a face expressing a specific emotion (anger or happiness). The N170 was found to be enhanced by unpredictable as opposed to predictable stimuli, indicating that it indexes general prediction error signalling processes. The N300 amplitudes were also enhanced by unpredictable stimuli, but they were also affected by the attentional status of angry but not happy faces, suggesting that there are differences in prediction error processes indexed by the N170 and N300. Overall, the findings suggest that the N170 and N300 both index violations of expectation for spatial manipulations of stimuli in accordance with prediction error responding processes.

Targeting RARA overexpression with tamibarotene, a potent and selective RARα agonist, is a novel approach in AML.

A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid leukemia (AML) and in ∼50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models. The combination of oral tamibarotene plus azacitidine was evaluated in a phase 2 clinical study in 51 newly diagnosed unfit patients with AML identified as RARA-positive (n = 22) or RARA-negative (n = 29) for RARA mRNA overexpression in peripheral blasts using a blood-based biomarker test. In 18 response-evaluable RARA-positive patients, complete remission (CR)/CR with incomplete hematologic recovery rate was 61%, CR rate was 50%, and time to initial composite CR was rapid at 1.2 months. Transfusion independence was attained by 72% of RARA-positive patients. In contrast, 28 response-evaluable RARA-negative patients had response rates that were consistent with azacitidine monotherapy. Tamibarotene in combination with azacitidine was well tolerated. The majority of nonhematologic adverse events were low grade and hematologic adverse events were comparable to single-agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine. These results support further evaluation of tamibarotene-based treatment strategies in patients with AML or MDS with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02807558.

Design, Synthesis, and Physicochemical Studies of Configurationally Stable ß-Carboline Atropisomers.

Axially chiral atropisomers have energetic barriers to rotation, ΔGrot, that prevent racemization of the respective enantiomers. We used computational modeling to develop a suite of 10 bio-inspired 1-aryl-ß-carbolines with varying ΔGrot, from which a strong structure-activity relationship was observed for 2-substituted-1-naphthyl substituents. We then synthesized two of these atropisomers, 1d and 1f, by a four-step racemic synthesis and resolved the enantiomers via chiral chromatography. Racemization studies revealed experimental ΔGrot values of 39.5 and 33.0 kcal/mol for 1d and 1f, respectively, which were consistent with our computational results. These atropisomers exhibited long half-lives, which allowed for their physicochemical characterization and stereochemical assignment via UV-vis spectroscopy, fluorescence spectroscopy, electronic circular dichroism, and vibrational circular dichroism.

Violated expectations for spatial and feature attributes of visual trajectories modulate event-related potential amplitudes across the visual processing hierarchy.

During visual perception, the brain must combine its predictions about what is to be perceived with incoming relevant information. The present study investigated how this process interacts with attention by using event-related potentials that index these cognitive mechanisms. Specifically, this study focused on examining how the amplitudes of the N170, N2pc, and N300 would be modulated by violations of expectations for spatial and featural attributes of visual stimuli. Participants viewed a series of shape stimuli in which a salient shape moved across a set of circular locations so that the trajectory of the shape implied the final position and shape of the stimulus. The final salient stimuli occurred in one of four possible outcomes: predictable position and shape, predictable position but unpredictable shape, unpredictable position but predictable shape, and unpredictable position and shape. The N170 was enhanced by unpredictable positions and shapes, whereas the N300 was enlarged only by unpredictable positions. The N2pc was not modulated by violations of expectations for shapes or positions. Additionally, it was observed post-hoc that the P1pc amplitude was increased by unpredictable shapes. These findings revealed that incorrect prediction increases neural activity. Furthermore, they suggest that prediction and attention interact differently in different stages of visual perception, depending on the type of attention being engaged: The N170 indexes initial prediction error signalling irrespective of the type of information (spatial or featural) in which error occurs, followed by the N300 as a marker of prediction updating involving reorientation of spatial attention.

Picture this: Photographers no better than controls for recognizing unfamiliar faces.

With the exception of super recognizers and forensic examiners, people make a surprising number of errors when deciding whether photographs of unfamiliar faces belong to the same person or different people. Training protocols designed to improve professionals' (e.g., passport officers) performance often include photography. We evaluated the influence of life-time photography experience on the ability to distinguish matched versus mismatched face pairs. Expert photographers were not more sensitive to identity than hobbyists or novices-despite specializing in human subjects; Hobbyists were more liberal (more same responses) than Experts. We conclude that photography experience is not a route to expertise.

What happens to our representation of identity as familiar faces age? Evidence from priming and identity aftereffects.

Matching identity in images of unfamiliar faces is error prone, but we can easily recognize highly variable images of familiar faces - even images taken decades apart. Recent theoretical development based on computational modelling can account for how we recognize extremely variable instances of the same identity. We provide complementary behavioural data by examining older adults' representation of older celebrities who were also famous when young. In Experiment 1, participants completed a long-lag repetition priming task in which primes and test stimuli were the same age or different ages. In Experiment 2, participants completed an identity after effects task in which the adapting stimulus was an older or young photograph of one celebrity and the test stimulus was a morph between the adapting identity and a different celebrity; the adapting stimulus was the same age as the test stimulus on some trials (e.g., both old) or a different age (e.g., adapter young, test stimulus old). The magnitude of priming and identity after effects were not influenced by whether the prime and adapting stimulus were the same age or different age as the test face. Collectively, our findings suggest that humans have one common mental representation for a familiar face (e.g., Paul McCartney) that incorporates visual changes across decades, rather than multiple age-specific representations. These findings make novel predictions for state-of-the-art algorithms (e.g., Deep Convolutional Neural Networks).

Vaping Prevention in a Middle School Population Using CATCH My Breath.

INTRODUCTION: The number of teens using electronic cigarettes in the United States has reached epidemic proportions. One in 20 middle school youth currently vapes regularly (Wang et al., 2020), supporting the need for e-cigarette education and prevention programs in this vulnerable population. METHOD: The evidence-based youth vaping prevention program, CATCH My Breath, was implemented and evaluated in a small, private, parochial middle school using a quasi-experimental, within-subjects, longitudinal design. RESULTS: Students' e-cigarette knowledge significantly improved postintervention (p < .001) and was sustained at 3 months follow-up. Attitudes about vaping remained stable after postintervention and at 3 months follow-up (p > .05). Susceptibility toward vaping increased or remained consistent despite increased knowledge (p = .096). DISCUSSION: CATCH My Breath is an effective school-based resource to educate middle school youth about the dangers of vaping. Additional research is needed to evaluate the intervention's impact on e-cigarette attitudes and the measurement of susceptibility in teens.

Attention and prediction modulations in expected and unexpected visuospatial trajectories.

Humans are constantly exposed to a rich tapestry of visual information in a potentially changing environment. To cope with the computational burden this engenders, our perceptual system must use prior context to simultaneously prioritise stimuli of importance and suppress irrelevant surroundings. This study investigated the influence of prediction and attention in visual perception by investigating event-related potentials (ERPs) often associated with these processes, N170 and N2pc for prediction and attention, respectively. A contextual trajectory paradigm was used which violated visual predictions and neglected to predetermine areas of spatial interest, to account for the potentially unpredictable nature of a real-life visual scene. Participants (N = 36) viewed a visual display of cued and non-cued shapes rotating in a five-step predictable trajectory, with the fifth and final position of either the cued or non-cued shape occurring in a predictable or unpredictable spatial location. To investigate the predictive coding theory of attention we used factors of attention and prediction, whereby attention was manipulated as either cued or non-cued conditions, and prediction manipulated in either predictable or unpredictable conditions. Results showed both enhanced N170 and N2pc amplitudes to unpredictable compared to predictable stimuli. Stimulus cueing status also increased N170 amplitude, but this did not interact with stimulus predictability. The N2pc amplitude was not affected by stimulus cueing status. In accordance with previous research these results suggest the N170 is in part a visual prediction error response with respect to higher-level visual processes, and furthermore the N2pc may index attention reorientation. The results demonstrate prior context influences the sensitivity of the N170 and N2pc electrophysiological responses. These findings add further support to the role of N170 as a prediction error signal and suggest that the N2pc may reflect attentional reorientation in response to unpredicted stimulus locations.

α-Chiral Amines via Thermally Promoted Deaminative Addition of Alkylpyridinium Salts to Sulfinimines.

A deaminative reaction of Katritzky alkylpyridinium salts and sulfinimines has been developed to deliver enantiopure α-chiral amines. The success of this method relied on the discovery of a thermally promoted deamination via single-electron transfer of an anion-π complex of the alkylpyridinium cation with potassium carbonate. This method boasts excellent diastereoselectivity over the α-stereocenter as well as broad functional group and heterocycle tolerance.

Engaging Alkenes and Alkynes in Deaminative Alkyl-Alkyl and Alkyl-Vinyl Cross-Couplings of Alkylpyridinium Salts.

An alkyl-alkyl cross-coupling of Katritzky alkylpyridinium salts and organoboranes, formed in situ via hydroboration of alkenes, has been developed. This method utilizes the abundance of both alkyl amine precursors and alkenes to form C(sp3)-C(sp3) bonds. This strategy is also effective with alkynes, enabling a C(sp3)-C(sp2) cross-coupling. Under these mild conditions, a broad range of functional groups, including protic groups, is tolerated. As seen with previous alkylpyridinium cross-couplings, mechanistic studies support an alkyl radical intermediate.

Deaminative Arylation of Amino Acid-derived Pyridinium Salts.

A Suzuki-Miyaura cross-coupling of α-pyridinium esters and arylboroxines has been developed. Combined with formation of the pyridinium salts from amino acid derivatives, this method enables amino acid derivatives to be efficiently transformed into α-aryl esters and amides. Under the mild conditions, broad functional group tolerance on both the amino acid derivatives and the arylboroxine are observed, including protic functional groups. Mechanistic studies support an alkyl radical intermediate, similar to other cross-couplings of alkylpyridinium salts.

Becoming Familiar With a Newly Encountered Face: Evidence of an Own-Race Advantage.

Adults' ability to match identity in images of unfamiliar faces is impaired for other- compared with own-race faces; their ability to match identity in images of familiar faces is independent of face race. Exposure to within-person variability in appearance plays a key role in face learning. Past research suggests that children need exposure to higher levels of variability than adults to learn a new face-a difference that has been attributed to experience. We predicted that adults' limited experience with other-race faces would result in their needing exposure to higher levels of variability when learning other- compared with own-race faces. We introduced adults to four new identities (two own-race; two other-race) in one of the three conditions: a single image, a low-variability video (filmed on 1 day), or a high-variability video (filmed across 3 days). Adults' ability to recognize new instances of learned identities improved in the low-variability condition for own-race faces but only in the high-variability condition for other-race faces. We discuss learning mechanisms that might drive this difference-a difference we attribute to experience.

How does a newly encountered face become familiar? The effect of within-person variability on adults' and children's perception of identity.

Adults and children aged 6years and older easily recognize multiple images of a familiar face, but often perceive two images of an unfamiliar face as belonging to different identities. Here we examined the process by which a newly encountered face becomes familiar, defined as accurate recognition of multiple images that capture natural within-person variability in appearance. In Experiment 1 we examined whether exposure to within-person variability in appearance helps children learn a new face. Children aged 6-13years watched a 10-min video of a woman reading a story; she was filmed on a single day (low variability) or over three days, across which her appearance and filming conditions (e.g., camera, lighting) varied (high variability). After familiarization, participants sorted a set of images comprising novel images of the target identity intermixed with distractors. Compared to participants who received no familiarization, children showed evidence of learning only in the high-variability condition, in contrast to adults who showed evidence of learning in both the low- and high-variability conditions. Experiment 2 highlighted the efficiency with which adults learn a new face; their accuracy was comparable across training conditions despite variability in duration (1 vs. 10min) and type (video vs. static images) of training. Collectively, our findings show that exposure to variability leads to the formation of a robust representation of facial identity, consistent with perceptual learning in other domains (e.g., language), and that the development of face learning is protracted throughout childhood. We discuss possible underlying mechanisms.

Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo.

Thyroid tumors arising from the follicular cells often harbor mutations leading to the constitutive activation of the PI3K and Ras signaling cascades. However, it is still unclear what their respective contribution to the neoplastic process is, as well as to what extent they interact. We have used mice harboring a Kras oncogenic mutation and a Pten deletion targeted to the thyroid epithelium to address in vivo these questions. Here, we show that although each of these two pathways, alone, is unable to transform thyroid follicular cells, their simultaneous activation is highly oncogenic, leading to invasive and metastatic follicular carcinomas. In particular, phosphatidylinositol-3-kinase (PI3K) activation suppressed Kras-initiated feedback signals that uncouple mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activation, thus stunting MAPK activity; in addition, PI3K and Kras cooperated to drastically up-regulate cyclin D1 mRNA levels. Finally, combined pharmacologic inhibition of PI3K and MAPK completely inhibited the growth of double-mutant cancer cell lines, providing a compelling rationale for the dual targeting of these pathways in thyroid cancer.

Mechanism of cell death induced by cis-3, 4', 5-trimethoxy-3'-aminostilbene in ovarian cancer.

OBJECTIVE: Stilbene derivative, cis-3, 4', 5-trimethoxy-3'-aminostilbene (stilbene 5c), is highly potent to induce cell death in ovarian cancer cells. This study is to investigate its mechanism to induce cell death. METHODS: UCI101 ovarian cancer cells were used for this study. Cell death was analyzed by Alamar blue staining. Cell cycle was analyzed by flow cytometry after PI staining. Mitochondrial potential and reactive oxygen species were determined by MitoTracker green and DCF-DA, respectively. Immunofluorescent staining was done with tubulin antibody following by confocal microscope examination. Cell lysates were collected after treatment with stilbene 5c for Western blotting analysis of various cell cycle regulators and signal transduction mediators. RESULTS: Stilbene-treated cells die in both cell cycle-dependent and -independent pathways. Low concentration (30 nM) induces cell death without cell cycle arrest. This process involves disruption of mitochondrial potential and production of ROS by a Bcl-2-independent pathway. Higher concentration of stilbene 5c arrests cell cycle in G(2)/M phase, which is supported by dephosphorylation of Cdc2 and Cdc25C, and transiently elevation of spindle checkpoint BubR1. Although phosphorylation of Chk1 and Chk2 both increases after treatment, loss of Chk1 suppresses, whereas loss of Chk2 enhances, stilbene 5c-induced cell death. Phosphorylation of Akt and Stat3, but not MAPK, is suppressed after stilbene 5c treatment. CONCLUSION: These studies provide a mechanistic insight in using stilbenes in ovarian cancer. Stilbenes could be potentially useful agents for ovarian cancer therapy and induce cell death through mitochondrial damage and cell cycle arrest.