Transdifferentiation of diffuse large B-cell lymphoma to a poorly differentiated neoplasm following CAR T-cell therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy is a recent advancement in precision medicine with promising results for patients with relapsed or refractory B-cell malignancies. However, rare post-therapy morphologic, immunophenotypic, and genomic alterations can occur. This study is to present a case of a patient with diffuse large B-cell lymphoma (DLBCL) who underwent anti-CD19 CAR-T therapy with disease in the uterus that showed transdifferentiation to a poorly differentiated malignant neoplasm that failed to express any lineage specific markers. In immunohistochemistry, fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS) were utilized to fully characterize the diagnostic DLBCL sample in comparison to the poorly differentiated neoplasm of the uterus. Analysis of the diagnostic DLBCL and the poorly differentiated neoplasm demonstrated evidence of a clonal relationship as well as revealing acquisition of mutations associated with CAR-T resistance. Furthermore, downregulation of B-cell associated antigens was observed, underscoring a mechanistic link to CAR-T evasion as well as demonstrating diagnostic confusion. This case illustrates the utility of employing multiple diagnostic modalities in elucidating a pathologic link between a B-cell lymphoma and poorly differentiated neoplasm following targeted therapy.

Speaker-turn aware diarization for speech-based cognitive assessments.

Introduction: Speaker diarization is an essential preprocessing step for diagnosing cognitive impairments from speech-based Montreal cognitive assessments (MoCA). Methods: This paper proposes three enhancements to the conventional speaker diarization methods for such assessments. The enhancements tackle the challenges of diarizing MoCA recordings on two fronts. First, multi-scale channel interdependence speaker embedding is used as the front-end speaker representation for overcoming the acoustic mismatch caused by far-field microphones. Specifically, a squeeze-and-excitation (SE) unit and channel-dependent attention are added to Res2Net blocks for multi-scale feature aggregation. Second, a sequence comparison approach with a holistic view of the whole conversation is applied to measure the similarity of short speech segments in the conversation, which results in a speaker-turn aware scoring matrix for the subsequent clustering step. Third, to further enhance the diarization performance, we propose incorporating a pairwise similarity measure so that the speaker-turn aware scoring matrix contains both local and global information across the segments. Results: Evaluations on an interactive MoCA dataset show that the proposed enhancements lead to a diarization system that outperforms the conventional x-vector/PLDA systems under language-, age-, and microphone-mismatch scenarios. Discussion: The results also show that the proposed enhancements can help hypothesize the speaker-turn timestamps, making the diarization method amendable to datasets without timestamp information.

Inhibition of APE1/Ref-1 Redox Signaling Alleviates Intestinal Dysfunction and Damage to Myenteric Neurons in a Mouse Model of Spontaneous Chronic Colitis.

BACKGROUND: Inflammatory bowel disease (IBD) associates with damage to the enteric nervous system (ENS), leading to gastrointestinal (GI) dysfunction. Oxidative stress is important for the pathophysiology of inflammation-induced enteric neuropathy and GI dysfunction. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a dual functioning protein that is an essential regulator of the cellular response to oxidative stress. In this study, we aimed to determine whether an APE1/Ref-1 redox domain inhibitor, APX3330, alleviates inflammation-induced oxidative stress that leads to enteric neuropathy in the Winnie murine model of spontaneous chronic colitis. METHODS: Winnie mice received APX3330 or vehicle via intraperitoneal injections over 2 weeks and were compared with C57BL/6 controls. In vivo disease activity and GI transit were evaluated. Ex vivo experiments were performed to assess functional parameters of colonic motility, immune cell infiltration, and changes to the ENS. RESULTS: Targeting APE1/Ref-1 redox activity with APX3330 improved disease severity, reduced immune cell infiltration, restored GI function ,and provided neuroprotective effects to the enteric nervous system. Inhibition of APE1/Ref-1 redox signaling leading to reduced mitochondrial superoxide production, oxidative DNA damage, and translocation of high mobility group box 1 protein (HMGB1) was involved in neuroprotective effects of APX3330 in enteric neurons. CONCLUSIONS: This study is the first to investigate inhibition of APE1/Ref-1's redox activity via APX3330 in an animal model of chronic intestinal inflammation. Inhibition of the redox function of APE1/Ref-1 is a novel strategy that might lead to a possible application of APX3330 for the treatment of IBD.

I-Vector-Based Patient Adaptation of Deep Neural Networks for Automatic Heartbeat Classification.

Automatic classification of electrocardiogram (ECG) signals is important for diagnosing heart arrhythmias. A big challenge in automatic ECG classification is the variation in the waveforms and characteristics of ECG signals among different patients. To address this issue, this paper proposes adapting a patient-independent deep neural network (DNN) using the information in the patient-dependent identity vectors (i-vectors). The adapted networks, namely i-vector adapted patient-specific DNNs (iAP-DNNs), are tuned toward the ECG characteristics of individual patients. For each patient, his/her ECG waveforms are compressed into an i-vector using a factor analysis model. Then, this i-vector is injected into the middle hidden layer of the patient-independent DNN. Stochastic gradient descent is then applied to fine-tune the whole network to form a patient-specific classifier. As a result, the adaptation makes use of not only the raw ECG waveforms from the specific patient but also the compact representation of his/her ECG characteristics through the i-vector. Analysis on the hidden-layer activations shows that by leveraging the information in the i-vectors, the iAP-DNNs are more capable of discriminating normal heartbeats against arrhythmic heartbeats than the networks that use the patient-specific ECG only for the adaptation. Experimental results based on the MIT-BIH database suggest that the iAP-DNNs perform better than existing patient-specific classifiers in terms of various performance measures. In particular, the sensitivity and specificity of the existing methods are all under the receiver operating characteristic curves of the iAP-DNNs.

Towards End-to-End ECG Classification With Raw Signal Extraction and Deep Neural Networks.

This paper proposes deep learning methods with signal alignment that facilitate the end-to-end classification of raw electrocardiogram (ECG) signals into heartbeat types, i.e., normal beat or different types of arrhythmias. Time-domain sample points are extracted from raw ECG signals, and consecutive vectors are extracted from a sliding time-window covering these sample points. Each of these vectors comprises the consecutive sample points of a complete heartbeat cycle, which includes not only the QRS complex but also the P and T waves. Unlike existing heartbeat classification methods in which medical doctors extract handcrafted features from raw ECG signals, the proposed end-to-end method leverages a deep neural network for both feature extraction and classification based on aligned heartbeats. This strategy not only obviates the need to handcraft the features but also produces optimized ECG representation for heartbeat classification. Evaluations on the MIT-BIH arrhythmia database show that at the same specificity, the proposed patient-independent classifier can detect supraventricular- and ventricular-ectopic beats at a sensitivity that is at least 10% higher than current state-of-the-art methods. More importantly, there is a wide range of operating points in which both the sensitivity and specificity of the proposed classifier are higher than those achieved by state-of-the-art classifiers. The proposed classifier can also perform comparable to patient-specific classifiers, but at the same time enjoys the advantage of patient independence.