Purpose Pan-class histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform selective HDAC inhibitors are emerging as potentially more targeted agents. HDAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for degradation. We investigated the mechanism and therapeutic impact of the selective HDAC6 inhibitor ACY-1215 alone and in combination with bortezomib in preclinical models of lymphoma. Experimental Design Concentration : effect relationships were defined for ACY-1215 across 16 lymphoma cell lines and for synergy with bortezomib. Mechanism was interrogated by immunoblot and flow cytometry. An in vivo xenograft model of DLBCL was utilized to confirm in vitro findings. A collection of primary lymphoma samples were surveyed for markers of the UPR. Results Concentration : effect relationships defined maximal cytotoxicity at 48 hours with IC50 values ranging from 0.9—4.7 μM. Strong synergy was observed in combination with bortezomib. Treatment with ACY-1215 led to inhibition of the aggresome evidenced by acetylated α-tubulin and accumulated poly-ubiquitinated proteins, and up-regulation of the UPR. All pharmacodynamic effects were enhanced with the addition of bortezomib. Findings were validated in vivo where mice treated with the combination demonstrated significant tumor growth delay and prolonged overall survival. Evaluation of a collection of primary lymphoma samples for markers of the UPR revealed increased HDAC6, GRP78 and XBP-1 expression as compared to reactive lymphoid tissue. Conclusion These data are the first results to demonstrate that dual targeting of protein degradation pathways represents an innovative and rational approach for the treatment of lymphoma.

Purpose: Several biomarkers of response to immune checkpoint inhibitors (ICI) show potential but are not yet scalable to the clinic. We developed a pipeline that integrates deep learning on histology specimens with clinical data to predict ICI response in advanced melanoma. Experimental Design: We used a training cohort from New York University (New York, NY) and a validation cohort from Vanderbilt University (Nashville, TN). We built a multivariable classifier that integrates neural network predictions with clinical data. A ROC curve was generated and the optimal threshold was used to stratify patients as high versus low risk for progression. Kaplan–Meier curves compared progression-free survival (PFS) between the groups. The classifier was validated on two slide scanners (Aperio AT2 and Leica SCN400). Results: The multivariable classifier predicted response with AUC 0.800 on images from the Aperio AT2 and AUC 0.805 on images from the Leica SCN400. The classifier accurately stratified patients into high versus low risk for disease progression. Vanderbilt patients classified as high risk for progression had significantly worse PFS than those classified as low risk (P = 0.02 for the Aperio AT2; P = 0.03 for the Leica SCN400). Conclusions: Histology slides and patients' clinicodemographic characteristics are readily available through standard of care and have the potential to predict ICI treatment outcomes. With prospective validation, we believe our approach has potential for integration into clinical practice.

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Key Points Treatment of DLBCL with the combination of sirtuin and DAC inhibitors leads to synergistic cytotoxicity and acetylation of Bcl6 and p53. The overall response rate of relapsed lymphoma patients treated with vorinostat and niacinamide was 24%, and an additional 57% achieved stable disease.

How can self-knowledge of personality be improved? What path is the most fruitful source for learning about our true selves? Previous research has noted two main avenues for learning about the self: looking inward (e.g., introspection) and looking outward (e.g., feedback). Although most of the literature on these topics does not directly measure the accuracy of self-perceptions (i.e., self-knowledge), we review these paths and their potential for improving self-knowledge. We come to the conclusion that explicit feedback, a largely unexamined path, is likely a fruitful avenue for learning about one’s own personality. Specifically, we suggest that self-knowledge might be fully realized through the use of explicit feedback from close, knowledgeable others. As such, we conclude that the road to self-knowledge likely cannot be traveled alone but must be traveled with close others who can help shed light on our blind spots.