Citations

Background Sleep fragmentation induced by repetitive arousals is a hallmark of obstructive sleep apnea (OSA). Sleep fragmentation has been linked to hypertension in community‐based studies, but it is unclear if this association is manifest in OSA. We aimed to explore whether frequent arousals from sleep modify the relationship between OSA and prevalent hypertension. Methods and Results A total of 10 102 patients with OSA and 1614 primary snorers were included in the study. Hypertension was defined on either direct blood pressure measures or diagnosis by a physician. Spontaneous, respiratory, and movement arousals were derived by polysomnography. Logistic regression models were used to estimate the associations between arousals and prevalent hypertension in patients with OSA and primary snorers. For every 10‐unit increase of total arousal index, odds of hypertension significantly increased in both the total sample (odds ratio [OR], 1.08; 95% CI, 1.03–1.14; P =0.002) and patients with OSA (OR, 1.10; 95% CI, 1.04–1.16; P <0.001), but not in the primary snoring group. Total arousal index was significantly associated with systolic blood pressure and diastolic blood pressure in the total sample (β=0.05 and β=0.06; P <0.001) and in patients with (β=0.05 and β=0.06; P <0.01), but not in primary snorers. In addition, a greater influence of respiratory events with arousals than respiratory events without arousals on blood pressure in OSA was also noted. Results were independent of confounders, including apnea‐hypopnea index and nocturnal hypoxemia. Conclusions We conclude that repetitive arousals from sleep are independently associated with prevalent hypertension in patients with OSA.

Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.

Intestinal fibrosis is considered an inevitable complication of Crohn’s disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

Background Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC). Methods A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score. Results Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts. Conclusions This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.

Significance The sorting nexin proteins are critical for endosomal trafficking and signaling. SNX17 and SNX27 are two SNX proteins displaying high similarity in domain structure, including a common FERM domain; however, they mediate distinct endocytic recycling pathways. We now solve this mystery by demonstrating that the FERM domains of SNX17 and SNX27 have different functions. Whereas the FERM domain of SNX17 recognizes the NPxY/NxxY motif, the same domain in SNX27 binds to a novel “DLF” motif within the N termini of SNX1/2. The interaction between SNX27 and SNX1/2 not only helps efficient retrieval of multiple cargoes but also promotes endosomal recruitment of SNX27. We further demonstrate that the SNX27–SNX1/2 interaction is crucial to neuronal growth and brain development in zebrafish.

AbstractObjectiveIn X‐raycomputed tomography (CT), many important clinical applications may benefit from a fast acquisition speed. The helical scan is the most widely used acquisition mode in clinical CT, where a fast helical pitch can improve the acquisition speed. However, on a typical single‐source helical CT (SSCT) system, the helical pitch p typically cannot exceed 1.5; otherwise, reconstruction artifacts will result from data insufficiency. The purpose of this work is to develop a deep convolutional neural network (CNN) to correct for artifacts caused by an ultra‐fast pitch, which can enable faster acquisition speed than what is currently achievable.MethodsA customized CNN (denoted as ultra‐fast‐pitch network (UFP‐net)) was developed to restore the underlying anatomical structure from the artifact‐corrupted post‐reconstruction data acquired from SSCT with ultra‐fast pitch (i.e., p ≥ 2). UFP‐net employed residual learning to capture the features of image artifacts. UFP‐net further deployed in‐house‐customized functional blocks with spatial‐domain local operators and frequency‐domain non‐local operators, to explore multi‐scale feature representation. Images of contrast‐enhanced patient exams (n = 83) with routine pitch setting (i.e., p < 1) were retrospectively collected, which were used as training and testing datasets. This patient cohort involved CT exams over different scan ranges of anatomy (chest, abdomen, and pelvis) and CT systems (Siemens Definition, Definition Flash, Definition AS+, Siemens Healthcare, Inc.), and the corresponding base CT scanning protocols used consistent settings of major scan parameters (e.g., collimation and pitch). Forward projection of the original images was calculated to synthesize helical CT scans with one regular pitch setting (p = 1) and two ultra‐fast‐pitch setting (p = 2 and 3). All patient images were reconstructed using the standard filtered‐back‐projection (FBP) algorithm. A customized multi‐stage training scheme was developed to incrementally optimize the parameters of UFP‐net, using ultra‐fast‐pitch images as network inputs and regular pitch images as labels. Visual inspection was conducted to evaluate image quality. Structural similarity index (SSIM) and relative root‐mean‐square error (rRMSE) were used as quantitative quality metrics.ResultsThe UFP‐net dramatically improved image quality over standard FBP at both ultra‐fast‐pitch settings. At p = 2, UFP‐net yielded higher mean SSIM (> 0.98) with lower mean rRMSE (< 2.9%), compared to FBP (mean SSIM < 0.93; mean rRMSE > 9.1%). Quantitative metrics at p = 3: UFP‐net—mean SSIM [0.86, 0.94] and mean rRMSE [5.0%, 8.2%]; FBP—mean SSIM [0.36, 0.61] and mean rRMSE [36.0%, 58.6%].ConclusionThe proposed UFP‐net has the potential to enable ultra‐fast data acquisition in clinical CT without sacrificing image quality. This method has demonstrated reasonable generalizability over different body parts when the corresponding CT exams involved consistent base scan parameters.

Background and Aims Sirtuin 1 (SIRT1) is a complex NAD+‐dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1‐induced destabilization of primary cilia in cholangiocarcinoma (CCA). Approach and Results A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)‐mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD ‐producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1‐overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α‐tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma‐associated oncogene 1, phosphorylated extracellular signal‐regulated kinase, and IL‐6) expression. Conclusions In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.

Pancreatic ductal adenocarcinoma is a recalcitrant tumor with minimal response to conventional chemotherapeutic approaches. Oncogenic signaling by activated tyrosine kinases has been implicated in cancers resulting in activation of diverse effector signaling pathways. Thus, the discovery of aberrantly activated tyrosine kinases is of great interest in developing novel therapeutic strategies in the treatment and management of pancreatic cancer. Patient-derived tumor xenografts (PDXs) in mice serve as potentially valuable preclinical models as they maintain the histological and molecular heterogeneity of the original human tumor. Here, we employed high-resolution mass spectrometry combined with immunoaffinity purification using anti-phosphotyrosine antibodies to profile tyrosine phosphoproteome across 13 pancreatic ductal adenocarcinoma PDX models. This analysis resulted in the identification of 1199 tyrosine-phosphorylated sites mapping to 704 proteins. The mass spectrometric analysis revealed widespread and heterogeneous activation of both receptor and non-receptor tyrosine kinases. Preclinical studies confirmed ephrin type-B receptor 4 (EphB4) as a potential therapeutic target based on the efficacy of human serum albumin-conjugated soluble EphB4 in mice bearing orthotopic xenografts. Immunohistochemistry-based validation using tissue microarrays from 346 patients with PDAC showed significant expression of EphB4 in >70% of patients. In summary, we present a comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma.