Canine as a Comparative and Translational Model for Human Mammary Tumor.

Despite the advances in research and treatment of human breast cancer, its incidence rate continues to increase by 0.5% per year, and the discovery of novel therapeutic strategies for specific subtypes of human breast cancer remains challenging. Traditional laboratory mouse models have contributed tremendously to human breast cancer research. However, mice do not develop tumors spontaneously; consequently, genetically engineered mouse models or patient-derived xenograft models are often relied upon for more sophisticated human breast cancer studies. Since human breast cancer develops spontaneously, there is a need for alternative, yet complementary, models that can better recapitulate the features of human breast cancer to better understand the molecular and clinical complexities of the disease in developing new therapeutic strategies. Canine mammary tumors are one such alternative model that share features with human breast cancer, including prevalence rate, subtype classification, treatment, and mutational profiles, all of which are described in this review

Multiple Sclerosis and Peripheral Multifocal Demyelinating Neuropathies Occurring in a Same Patient

The co-occurrence of multiple sclerosis and peripheral demyelinating neuropathy is rare. It has been disputed whether these are pathologically related or coincidental findings. We report a 36-year-old woman who presented with diplopia, right facial palsy and left-sided weakness. Brain magnetic resonance imaging showed a lesion indicative of central demyelinating disease. Nerve conduction studies revealed peripheral multifocal demyelinating neuropathies. We suggest that the central and the peripheral lesions may be continua of a demyelinating process

Encoder-decoder multimodal speaker change detection

The task of speaker change detection (SCD), which detects points where speakers change in an input, is essential for several applications. Several studies solved the SCD task using audio inputs only and have shown limited performance. Recently, multimodal SCD (MMSCD) models, which utilise text modality in addition to audio, have shown improved performance. In this study, the proposed model are built upon two main proposals, a novel mechanism for modality fusion and the adoption of a encoder-decoder architecture. Different to previous MMSCD works that extract speaker embeddings from extremely short audio segments, aligned to a single word, we use a speaker embedding extracted from 1.5s. A transformer decoder layer further improves the performance of an encoder-only MMSCD model. The proposed model achieves state-of-the-art results among studies that report SCD performance and is also on par with recent work that combines SCD with automatic speech recognition via human transcription.Comment: 5 pages, accepted for presentation at INTERSPEECH 202

An Essential Role of N-Terminal Arginylation in Cardiovascular Development

The enzymatic conjugation of arginine to the N-termini of proteins is a part of the ubiquitin-dependent N-end rule pathway of protein degradation. In mammals, three N-terminal residues—aspartate, glutamate, and cysteine—are substrates for arginylation. The mouseATE1 gene encodes a family of Arg-tRNA-protein transferases (R-transferases) that mediate N-terminal arginylation. We constructed ATE1-lacking mouse strains and found thatATE1 −/− embryos die with defects in heart development and in angiogenic remodeling of the early vascular plexus. Through biochemical analyses, we show that N-terminal cysteine, in contrast to N-terminal aspartate and glutamate, is oxidized before its arginylation by R-transferase, suggesting that the arginylation branch of the N-end rule pathway functions as an oxygen sensor

Genome-scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib-resistant lung cancer.

Erlotinib is highly effective in lung cancer patients with epidermal growth factor receptor (EGFR) mutations. However, despite initial favorable responses, most patients rapidly develop resistance to erlotinib soon after the initial treatment. This study aims to identify new genes and pathways associated with erlotinib resistance mechanisms in order to develop novel therapeutic strategies. Here, we induced knockout (KO) mutations in erlotinib-resistant human lung cancer cells (NCI-H820) using a genome-scale CRISPR-Cas9 sgRNA library to screen for genes involved in erlotinib susceptibility. The spectrum of sgRNAs incorporated among erlotinib-treated cells was substantially different to that of the untreated cells. Gene set analyses showed a significant depletion of \u27cell cycle process\u27 and \u27protein ubiquitination pathway\u27 genes among erlotinib-treated cells. Chemical inhibitors targeting genes in these two pathways, such as nutlin-3 and carfilzomib, increased cancer cell death when combined with erlotinib in both in vitro cell line and in vivo patient-derived xenograft experiments. Therefore, we propose that targeting cell cycle processes or protein ubiquitination pathways are promising treatment strategies for overcoming resistance to EGFR inhibitors in lung cancer

Direct cell-to-cell transfer in stressed tumor microenvironment aggravates tumorigenic or metastatic potential in pancreatic cancer.

Pancreatic cancer exhibits a characteristic tumor microenvironment (TME) due to enhanced fibrosis and hypoxia and is particularly resistant to conventional chemotherapy. However, the molecular mechanisms underlying TME-associated treatment resistance in pancreatic cancer are not fully understood. Here, we developed an in vitro TME mimic system comprising pancreatic cancer cells, fibroblasts and immune cells, and a stress condition, including hypoxia and gemcitabine. Cells with high viability under stress showed evidence of increased direct cell-to-cell transfer of biomolecules. The resulting derivative cells (CD4

How Does the SST Variability over the Western North Atlantic Ocean Control Arctic Warming over the Barents-Kara Seas?

Arctic warming over the BarentsKara Seas and its impacts on the mid-latitude circulations have been widely discussed. However, the specific mechanism that brings the warming still remains unclear. In this study, a possible cause of the regional Arctic warming over the BarentsKara Seas during early winter (OctoberDecember) is suggested. We found that warmer sea surface temperature anomalies over the western North Atlantic Ocean (WNAO) modulate the transient eddies overlying the oceanic frontal region. The altered transient eddy vorticity flux acts as a source for the Rossby wave straddling the western North Atlantic and the BarentsKara Seas (Scandinavian pattern), and induces a significant warm advection, increasing surface and lower-level temperature over the Eurasian sector of the Arctic Ocean. The importance of the sea surface temperature anomalies over the WNAO and subsequent transient eddy forcing over the WNAO was also supported by both specially designed simple model experiments and general circulation model experiments