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Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to contract multiple muscle groups simultaneously. Twitch contractions have been demonstrated to protect against denervation-induced muscle atrophy in rats, possibly through mitochondrial biosynthesis. This study examined whether inducing tetanus contractions with B-SES suppresses muscle atrophy and identified the underlying molecular mechanisms. We evaluated the effects of acute (60 Hz, 5 min) and chronic (60 Hz, 5 min, every alternate day for one week) B-SES on the tibialis anterior (TA) and gastrocnemius (GAS) muscles in Sprague-Dawley rats using belt electrodes attached to both ankle joints. After acute stimulation, a significant decrease in the glycogen content was observed in the left and right TA and GAS, suggesting that B-SES causes simultaneous contractions in multiple muscle groups. B-SES enhanced p70S6K phosphorylation, an indicator of the mechanistic target of rapamycin complex 1 activity. During chronic stimulations, rats were divided into control (CONT), denervation-induced atrophy (DEN), and DEN + electrically stimulated with B-SES (DEN + ES) groups. After seven days of treatment, the wet weight (n = 8-11 for each group) and muscle fiber cross-sectional area (CSA, n = 6 for each group) of the TA and GAS muscles were reduced in the DEN and DEN + ES groups compared with that in the CON group. The DEN + ES group showed significantly higher muscle weight and CSA than those in the DEN group. Although RNA-seq and pathway analysis suggested that mitochondrial biogenesis is a critical event in this phenomenon, mitochondrial content showed no difference. In contrast, ribosomal RNA 28S and 18S (n = 6) levels in the DEN + ES group were higher than those in the DEN group, even though RNA-seq showed that the ribosome biogenesis pathway was reduced by electrical stimulation. The mRNA levels of the muscle proteolytic molecules atrogin-1 and MuRF1 were significantly higher in DEN than those in CONT. However, they were more suppressed in DEN + ES than those in DEN. In conclusion, tetanic electrical stimulation of both ankles using belt electrodes effectively reduced denervation-induced atrophy in multiple muscle groups. Furthermore, ribosomal biosynthesis plays a vital role in this phenomenon., (© 2024. The Author(s).)

Belt electrode skeletal muscle electrical stimulation (B-SES) can simultaneously contract multiple muscle groups. Although the beneficial effects of B-SES in clinical situations have been elucidated, its molecular mechanism remains unknown. In this study, we developed a novel rodent B-SES ankle stimulation system to test whether low-frequency stimulation prevents denervation-induced muscle atrophy. Electrical stimulations (7‒8 Hz, 30 min) with ankle belt electrodes were applied to Sprague-Dawley rats daily for one week. All animals were assigned to the control (CONT), denervation-induced atrophy (DEN), and DEN + electrical stimulation (ES) groups. The tibialis anterior (TA) and gastrocnemius (GAS) muscles were used to examine the effect of ES treatment. After seven daily sessions of continuous stimulation, muscle wet weight (n = 8-11), and muscle fiber cross-sectional area (CSA, n = 4-6) of TA and GAS muscles were lower in DEN and DEN + ES than in CON. However, it was significantly higher in DEN than DEN + ES, showing that ES partially prevented muscle atrophy. PGC-1α, COX-IV, and citrate synthase activities (n = 6) were significantly higher in DEN + ES than in DEN. The mRNA levels of muscle proteolytic molecules, Atrogin-1 and Murf1, were significantly higher in DEN than in CONT, while B-SES significantly suppressed their expression (p < 0.05). In conclusion, low-frequency electrical stimulation of the bilateral ankles using belt electrodes (but not the pad electrodes) is effective in preventing denervation-induced atrophy in multiple muscles, which has not been observed with pad electrodes. Maintaining the mitochondrial quantity and enzyme activity by low-frequency electrical stimulation is key to suppressing muscle protein degradation., (© 2022. The Author(s).)

The role of cell membrane dynamics in cell migration is unclear. To examine whether total cell surface area changes are required for cell migration, Dictyostelium cells were flattened by agar-overlay. Scanning electron microscopy demonstrated that flattened migrating cells have no membrane reservoirs such as projections and membrane folds. Similarly, optical sectioning fluorescence microscopy showed that the cell surface area does not change during migration. Interestingly, staining of the cell membrane with a fluorescent lipid analogue demonstrated that the turnover rate of cell membrane is closely related to the cell migration velocity. Next, to clarify the mechanism of cell membrane circulation, local photobleaching was separately performed on the dorsal and ventral cell membranes of rapidly moving cells. The bleached zones on both sides moved rearward relative to the cell. Thus, the cell membrane moves in a fountain-like fashion, accompanied by a high membrane turnover rate and actively contributing to cell migration.

Recent studies have linked elevated tumor aneuploidy to anti-tumor immune suppression and adverse survival following immunotherapy. Herein, we provide supportive evidence for tumor aneuploidy as a biomarker of response to immunotherapy in patients with non-small cell lung cancer (NSCLC). We identify a dose–response relationship between aneuploidy score and patient outcomes. In two independent NSCLC cohorts (n = 659 patients), we demonstrate a novel association between elevated aneuploidy and non-smoking-associated oncogenic driver mutations. Lastly, we report enrichment of TERT amplification and immune-suppressive phenotypes of highly aneuploid NSCLC. Taken together, our findings emphasize a potentially critical role for tumor aneuploidy in guiding immunotherapy treatment strategies. [ABSTRACT FROM AUTHOR]

Activating antibody-dependent cellular cytotoxicity (ADCC) by targeting claudin-18 isoform 2 (CLDN18.2) using zolbetuximab, a monoclonal antibody against CLDN18.2, has been considered a promising novel therapeutic strategy for gastric cancer (GC). However, the impact of CLDN18.2 expression on natural killer (NK) cells and monocytes/macrophages—crucial effector cells of ADCC—in GC has not been fully investigated. In the present study, we assessed the impact of CLDN18.2 expression on clinical outcomes, molecular features, and the frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, in GC by analyzing our own GC cohorts. The expression of CLDN18.2 did not significantly impact clinical outcomes of GC patients, while it was significantly and positively associated with Epstein–Barr virus (EBV) status and PD-L1 expression. The frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, were comparable between CLDN18.2-positive and CLDN18.2-negative GCs. Importantly, both CLDN18.2 expression and the number of tumor-infiltrating NK cells were significantly higher in EBV-associated GC compared to other molecular subtypes. Our findings support the effectiveness of zolbetuximab in CLDN18.2-positive GC, and offer a novel insight into the treatment of this cancer type, highlighting its potential effectiveness for CLDN18.2-positive/EBV-associated GC. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a unique radiotherapy of selectively eradicating tumor cells using boron compounds (e.g., 4-borono-l-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. Such heterogenicity potentially reduces the curative efficiency. However, the effects of temporospatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector and biophysical simulations, this study revealed the cell cycle-dependent heterogenicity of BPA uptake and subsequent biological effects of BNCT on HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators, as well as the modification effects of polyvinyl alcohol (PVA). The results showed that the BPA concentration in the S/G2/M phase was higher than that in the G1/S phase and that PVA enhances the biological effects both by improving the uptake and by canceling the heterogenicity. These findings might contribute to a maximization of therapeutic efficacy when BNCT is combined with PVA and/or cell cycle-specific anticancer agents. [ABSTRACT FROM AUTHOR]

Engineering rockmass classifications are an integral part of design, support and excavation procedures of tunnels, mines, and other underground structures. These classifications are directly linked to ground reaction and support requirements. Various classification systems are in practice and are still evolving. As different classifications serve different purposes, it is imperative to establish inter-correlatability between them. The rating systems and engineering judgements influence the assignment of ratings owing to cognition. To understand the existing correlation between different classification systems, the existing correlations were evaluated with the help of data of 34 locations along a 618-m-long railway tunnel in the Garhwal Himalaya of India and new correlations were developed between different rock classifications. The analysis indicates that certain correlations, such as RMR-Q, RMR-RMi, RMi-Q, and RSR-Q, are comparable to the previously established relationships, while others, such as RSR-RMR, RCR-Qn, and GSI-RMR, show weak correlations. These deviations in published correlations may be due to individual parameters of estimation or measurement errors. Further, incompatible classification systems exhibited low correlations. Thus, the study highlights a need to revisit existing correlations, particularly for rockmass conditions that are extremely complex, and the predictability of existing correlations exhibit high variations. In addition to augmenting the existing database, new correlations for metamorphic rocks in the Himalayan region have been developed and presented that can serve as a guide for future rock engineering projects in such formations and aid in developing appropriate excavation and rock support methodologies. [ABSTRACT FROM AUTHOR]

Predicting clinical responses to tumor immunotherapy is essential to reduce side effects and the potential for sustained clinical responses. Nevertheless, preselecting patients who are likely to respond to such treatments remains highly challenging. Here, we explored the potential of microRNAs (miRNAs) as predictors of immune checkpoint blockade responses using a machine learning approach. First, we constructed random forest models to predict the response to tumor ICB therapy using miRNA expression profiles across 19 cancer types. The contribution of individual miRNAs to each prediction process was determined by employing SHapley Additive exPlanations (SHAP) for model interpretation. Remarkably, the predictive performance achieved by using a small number of miRNAs with high feature importance was similar to that achieved by using the entire miRNA set. Additionally, the genes targeted by these miRNAs were closely associated with tumor- and immune-related pathways. In conclusion, this study demonstrates the potential of miRNA expression data for assessing tumor immunotherapy responses. Furthermore, we confirmed the potential of informative miRNAs as biomarkers for the prediction of immunotherapy response, which will advance our understanding of tumor immunotherapy mechanisms. [ABSTRACT FROM AUTHOR]

The prognosis of advanced biliary tract cancer (BTC) patients remains poor due to limited efficacy of chemotherapy and difficulties in management. Thus, prediction of survival is crucial for the clinical management of advanced BTC. The aim was to develop and validate a nomogram to predict 6-month and 12-month survival in advanced BTC patients treated with chemotherapy. A multivariable Cox regression model was used to construct a nomogram in a training set (JCOG1113, a phase III trial comparing gemcitabine plus S-1 [GS] and gemcitabine plus cisplatin, n = 351). External validity of the nomogram was assessed using a test set (JCOG0805, a randomized, phase II trial comparing GS and S-1 alone, n = 100). Predictive performance was assessed in terms of discrimination and calibration. The constructed nomogram included lymph node metastasis, liver metastasis, carbohydrate antigen 19-9, carcinoembryonic antigen, albumin, and C-reactive protein. Uno's concordance index was 0.661 (95% confidence interval [CI] 0.629–0.696) in the training set and 0.640 (95% CI 0.566–0.715) in the test set. The calibration plots for 6-month and 12-month survival showed good agreement in the two analysis sets. The present nomogram can facilitate prediction of the prognosis of advanced BTC patients treated with chemotherapy and help clinicians' prognosis-based decision-making. [ABSTRACT FROM AUTHOR]

By affecting core neurobiological systems early in development, early life adversities (ELAs) might confer latent vulnerability to future psychopathologies. This coordinate-based meta-analysis aims to identify significant convergent alterations in functional connectivity of the amygdala related to ELAs across resting-state and task-based fMRI-studies. Five electronic databases were systematically searched until 22 October 2020, retrieving 49 eligible studies (n = 3162 participants). Convergent alterations in functional connectivity related to ELAs between the amygdala and the anterior cingulate cortex (ACC) and left hippocampus were found. Sub-analyses based on hemisphere and direction showed that connectivity seeded in the right amygdala was affected and, moreover, revealed that connectivity with ACC was decreased. Analyses based on paradigm and age showed that amygdala-ACC coupling was altered during resting state and that amygdala–left hippocampus connectivity was mostly affected during task-based paradigms and in adult participants. While both regions showed altered connectivity during emotion processing and following adverse social postnatal experiences such as maltreatment, amygdala-ACC coupling was mainly affected when ELAs were retrospectively assessed through self-report. We show that ELAs are associated with altered functional connectivity of the amygdala with the ACC and hippocampus. As such, ELAs may embed latent vulnerability to future psychopathologies by systematically affecting important neurocognitive systems. [ABSTRACT FROM AUTHOR]

To establish a high-quality, easy-to-use, and effective risk prediction model for hepatic encephalopathy, to help healthcare professionals with identifying people who are at high risk of getting hepatic encephalopathy, and to guide them to take early interventions to reduce the occurrence of hepatic encephalopathy. Patients (n = 1178) with decompensated cirrhosis who attended the First Affiliated Hospital of Guangxi University of Chinese Medicine between January 2016 and June 2022 were selected for the establishment and validation of a nomogram model for risk prediction of hepatic encephalopathy. In this study, we screened the risk factors for the development of hepatic encephalopathy in patients with decompensated cirrhosis by univariate analysis, LASSO regression and multifactor analysis, then established a nomogram model for predicting the risk of getting hepatic encephalopathy for patients with decompensated cirrhosis, and finally performed differentiation analysis, calibration analysis, clinical decision curve analysis and validation of the established model. A total of 1178 patients with decompensated cirrhosis who were hospitalized and treated at the First Affiliated Hospital of Guangxi University of Chinese Medicine between January 2016 and June 2022 were included for modeling and validation. Based on the results of univariate analysis, LASSO regression analysis and multifactor analysis, a final nomogram model with age, diabetes, ascites, spontaneous peritonitis, alanine transaminase, and blood potassium as predictors of hepatic encephalopathy risk prediction was created. The results of model differentiation analysis showed that the AUC of the model of the training set was 0.738 (95% CI 0.63–0.746), while the AUC of the model of the validation set was 0.667 (95% CI 0.541–0.706), and the two AUCs indicated a good discrimination of this nomogram model. According to the Cut-Off value determined by the Jorden index, when the Cut-Off value of the training set was set at 0.150, the sensitivity of the model was 72.8%, the specificity was 64.8%, the positive predictive value was 30.4%, and the negative predictive value was 91.9%; when the Cut-Off value of the validation set was set at 0.141, the sensitivity of the model was 69.7%, the specificity was 57.3%, the positive predictive value was 34.5%, and the negative predictive value was 84.7%. The calibration curve and the actual events curve largely overlap at the diagonal, indicating that the prediction with this model has less error. The Hosmer–Lemeshow test for goodness of fit was also applied, and the results showed that for the training set, χ2 = 1.237587, P = 0.998, and for the validation set, χ2 = 31.90904, P = 0.0202, indicating that there was no significant difference between the predicted and actual observed values. The results of the clinical decision curve analysis showed that the model had a good clinical benefit, compared with the two extreme clinical scenarios (all patients treated or none treated), and the model also had a good clinical benefit in the validation set. This study showed that aged over 55 years, complications of diabetes, ascites, and spontaneous bacterial peritonitis, abnormal glutamate aminotransferase and abnormal blood potassium are independent risks indicators for the development of hepatic encephalopathy in patients with decompensated cirrhosis. The nomogram model based on the indicators mentioned above can effectively and conveniently predict the risk of developing hepatic encephalopathy in patients with decompensated cirrhosis. The nomogram model established on this study can help clinical healthcare professionals to timely and early identify patients with high risk of developing hepatic encephalopathy. [ABSTRACT FROM AUTHOR]

Invasive species and climate change are primary factors influencing biodiversity, and examining the behavior of invasive species is essential for effective conservation management. Here, we report the global distribution of the sika deer (Cervus nippon) based on locations reported in published literature (Google Scholar), the Global Biodiversity Information Facility (GBIF) database, and the International Union for Conservation of Nature report. We used the maximum entropy (Maxent) model to examine the impact of climate change on sika deer habitats in South Korea based on GBIF occurrence data and WorldClim bioclimatic variables. Habitat suitability analysis was performed using the Maxent model under Representative Concentration Pathways (RCPs) 4.5 and 8.5 (for predicted climatic conditions in both 2050 and 2070) to project the effects of different climate change scenarios on South Korean sika deer habitats. We identified that the sika deer is distributed in 39 countries worldwide. Due to climate change effects, South Korean sika deer habitats will decline by approximately 24.98% and 20.63% (under RCP 4.5) and by 50.51% and 57.35% (under RCP 8.5) by 2050 and 2070, respectively. Our findings shed light on sika deer ecology and provide reference data for future conservation management strategies and policy design. [ABSTRACT FROM AUTHOR]

Approximately 20% of aged captive giant pandas (Ailuropoda melanoleuca) have cataracts that impair their quality of life. To identify potential biomarkers of cataract formation, we carried out a quantitative proteomics analysis of 10 giant pandas to find proteins differing in abundance between healthy and cataract-bearing animals. We identified almost 150 proteins exceeding our threshold for differential abundance, most of which were associated with GO categories related to extracellular localization. The most significant differential abundance was associated with components of the proteasome and other proteins with a role in proteolysis or its regulation, most of which were depleted in pandas with cataracts. Other modulated proteins included components of the extracellular matrix or cytoskeleton, as well as associated signaling proteins and regulators, but we did not find any differentially expressed transcription factors. These results indicate that the formation of cataracts involves a complex post-transcriptional network of signaling inside and outside lens cells to drive stress responses as a means to address the accumulation of protein aggregates triggered by oxidative damage. The modulated proteins also indicate that it should be possible to predict the onset of cataracts in captive pandas by taking blood samples and testing them for the presence or absence of specific protein markers. [ABSTRACT FROM AUTHOR]

The standard treatment for platinum-sensitive relapsed ovarian cancer (PSROC) is platinum-based chemotherapy followed by olaparib monotherapy. A retrospective study was conducted to identify factors affecting the survival of patients with PSROC undergoing olaparib monotherapy in real-world clinical settings. The study enrolled 122 patients who received olaparib monotherapy between April 2018 and December 2020 at three national centers in Japan. The study used the Kaplan–Meier method and univariable and multivariable Cox proportional hazards models to evaluate the associations between factors and progression-free survival (PFS). Patients with BRCA1/2 mutations had a significantly longer median PFS than those without these mutations. Both the BRCA1/2 mutation-positive and mutation-negative groups exhibited a prolonged PFS when the platinum-free interval (PFI) was ≥ 12 months. Cancer antigen 125 (CA-125) level within reference values was significantly linked to prolonged PFS, while a high platelet-to-lymphocyte ratio (≥ 210) was significantly associated with poor PFS in the BRCA1/2 mutation-negative group. The study suggests that a PFI of ≥ 12 months may predict survival after olaparib monotherapy in patients with PSROC, regardless of their BRCA1/2 mutation status. Additionally, a CA-125 level within reference values may be associated with extended survival in patients without BRCA1/2 mutations. A larger prospective study should confirm these findings. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) patients show brain tissue changes in mood and cognitive regulatory sites, but the nature and extent of tissue injury and their associations with symptoms are unclear. Our aim was to examine brain tissue damage in T2DM over controls using mean diffusivity (MD) computed from diffusion tensor imaging (DTI), and assess correlations with mood and cognitive symptoms in T2DM. We collected DTI series (MRI), mood, and cognitive data, from 169 subjects (68 T2DM and 101 controls). Whole-brain MD-maps were calculated, normalized, smoothed, and compared between groups, as well as correlated with mood and cognition scores in T2DM subjects. Type 2 diabetes patients showed altered cognitive and mood functions over control subjects. Multiple brain sites in T2DM patients showed elevated MD values, indicating chronic tissue changes, including the cerebellum, insula, and frontal and prefrontal cortices, cingulate, and lingual gyrus. Associations between MD values and mood and cognition scores appeared in brain sites mediating these functions. Type 2 diabetes patients show predominantly chronic brain tissue changes in areas mediating mood and cognition functions, and tissue changes from those regions correlate with mood and cognitive symptoms suggesting that the microstructural brain changes may account for the observed functional deficits. [ABSTRACT FROM AUTHOR]

As portable chest X-rays are an efficient means of triaging emergent cases, their use has raised the question as to whether imaging carries additional prognostic utility for survival among patients with COVID-19. This study assessed the importance of known risk factors on in-hospital mortality and investigated the predictive utility of radiomic texture features using various machine learning approaches. We detected incremental improvements in survival prognostication utilizing texture features derived from emergent chest X-rays, particularly among older patients or those with a higher comorbidity burden. Important features included age, oxygen saturation, blood pressure, and certain comorbid conditions, as well as image features related to the intensity and variability of pixel distribution. Thus, widely available chest X-rays, in conjunction with clinical information, may be predictive of survival outcomes of patients with COVID-19, especially older, sicker patients, and can aid in disease management by providing additional information. [ABSTRACT FROM AUTHOR]

To assess the potential clinical utility of cell-free DNA (cfDNA)-based biomarkers for identifying gastric cancer (GC) patients who benefit from nivolumab. From 31 GC patients treated with nivolumab monotherapy (240 mg/body, Bi-weekly) in 3rd or later line setting, we prospectively collected blood samples at baseline and before the 3rd dose. We compared cfDNA-based molecular findings, including microsatellite instability (MSI) status, to tissue-based biomarkers. We assessed the clinical value of blood tumor mutation burden (bTMB) and copy number alterations (CNA) as well as the cfDNA dynamics. The concordance between deficient-MMR and cfDNA-based MSI-high was 100% (3/3). Patients with bTMB ≥ 6 mut/Mb had significantly better progression-free survival (PFS) and overall survival (OS); however, such significance disappeared when excluding MSI-High cases. The combination of bTMB and CNA positivity identified patients with survival benefit regardless of MSI status (both PFS and OS, P < 0.001), with the best survival in those with bTMB≥6mut/Mb and CNAnegative. Moreover, patients with decreased bTMB during treatment had a better disease control rate (P = 0.04) and longer PFS (P = 0.04). Our results suggest that a combination of bTMB and CNA may predict nivolumab efficacy for GC patients regardless of MSI status. bTMB dynamics have a potential utility as an on-treatment biomarker. [ABSTRACT FROM AUTHOR]

Amplification of chromosome 9p24.1 targeting PD-L1, PD-L2, and JAK2 (PDJ amplicon) is present in subsets of triple negative breast cancers (TNBCs) and is associated with poor clinical outcomes. However, the prevalence of PDJ+ TNBCs varies extensively across studies applying different methods for interrogating samples of interest. To rigorously assess the prevalence of PDJ amplicons in TNBC, its prognostic value and whether it is enriched by chemotherapy, we interrogated 360 TNBC samples including 74 surgical resections from patients treated in the neoadjuvant setting, and tissue microarrays (TMAs) with 31 cases from African American women and 255 resected non-metastatic cases, with a 3 color fluorescence in situ hybridization (FISH) assay targeting the 9p24.1 PDJ amplicon, 9q24.3, and 9q34.1. Samples with mean PDJ signal of > 4.5 copies, and ratios of PDJ/9q24 ≥ 2 and/or PDJ/9q34.1 ≥ 2 were called amplified (PDJ+). Correlative analyses included the association of tumor infiltrating lymphocytes (TILs) with PDJ amplicons in TNBCs. In addition, we investigated intratumor copy number of PDJ amplicons in PDJ+ and PDJ− TNBCs. Matched pre- and post-neoadjuvant treatment biopsies were available from patients (n = 6) to evaluate the effects of therapy on PDJ status. Our study provides a rigorous analysis of the prevalence, distribution, and clinical correlatives of the PDJ amplicon in TNBC. [ABSTRACT FROM AUTHOR]

Acoustic communication signals diversify even on short evolutionary time scales. To understand how the auditory system underlying acoustic communication could evolve, we conducted a systematic comparison of the early stages of the auditory neural circuit involved in song information processing between closely-related fruit-fly species. Male Drosophila melanogaster and D. simulans produce different sound signals during mating rituals, known as courtship songs. Female flies from these species selectively increase their receptivity when they hear songs with conspecific temporal patterns. Here, we firstly confirmed interspecific differences in temporal pattern preferences; D. simulans preferred pulse songs with longer intervals than D. melanogaster. Primary and secondary song-relay neurons, JO neurons and AMMC-B1 neurons, shared similar morphology and neurotransmitters between species. The temporal pattern preferences of AMMC-B1 neurons were also relatively similar between species, with slight but significant differences in their band-pass properties. Although the shift direction of the response property matched that of the behavior, these differences are not large enough to explain behavioral differences in song preferences. This study enhances our understanding of the conservation and diversification of the architecture of the early-stage neural circuit which processes acoustic communication signals. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) and diminished myocardial perfusion increase the risk of heart failure (HF) and/or all-cause mortality during 6-year follow up following primary percutaneous coronary intervention (pPCI) for ST elevation myocardial infarction (STEMI). The aim of the present study was to evaluate the impact of myocardial perfusion on infarct size and left ventricular ejection fraction (LVEF) in patients with T2DM and STEMI treated with pPCI. This is an ancillary analysis of an observational cohort study of T2DM patients with STEMI. We enrolled 406 patients with STEMI, including 104 with T2DM. Myocardial perfusion was assessed with the Quantitative Myocardial Blush Evaluator (QUBE) and infarct size with the creatine kinase myocardial band (CK-MB) maximal activity and troponin area under the curve. LVEF was measured with biplane echocardiography using Simpson's method at admission and hospital discharge. Analysis of covariance was used for modeling the association between myocardial perfusion, infarct size and left ventricular systolic function. Patients with T2DM and diminished perfusion (QUBE below median) had the highest CK-MB maximal activity (252.7 ± 307.2 IU/L, P < 0.01) along with the lowest LVEF (40.6 ± 10.0, P < 0.001). Older age (p = 0.001), QuBE below median (p = 0.026), and maximal CK-MB activity (p < 0.001) were independent predictors of LVEF. Diminished myocardial perfusion assessed by QuBE predicts significantly larger enzymatic infarct size and lower LVEF among patients with STEMI treated with pPCI, regardless of diabetes status. [ABSTRACT FROM AUTHOR]

Yaku sika deer (Cervus nippon yakushimae) are endemic to Yakushima Island, whose landscape covered with primary evergreen forest is recognized as a World Heritage Site. In this study, the rumen bacterial microbiota (RBM) of wild Yaku sika was characterized using high throughput sequencing of bacterial 16S rRNA genes combined with targeted cultivation and functional analyses. Comparative analyses of RBM datasets from other ruminant animals revealed distinct community structure among domesticated and wild ruminants. Wild Yaku sika RBM exhibited higher species richness than other sika deer (i.e. wild Ezo sika and domesticated sika deer), likely reflecting their dietary variations associated with unique ecosystem in the island. The Yaku sika RBM of high deer population density samples exhibited higher diversity and contained higher proportion of Firmicutes than those of lower density samples. Moreover, the highest abundance of tannase gene were observed in individuals from the highest population density area, consistent with the previous observation that Yaku sika in the high density areas expanded their feed to include tannin-rich unpalatable plants. This study indicated that RBM of unique wild Yaku sika contribute to the flexibility of dietary shift and thus maintaining nutritional status of Yaku sika under high density conditions. [ABSTRACT FROM AUTHOR]

Our study investigates the effects of heterogeneity in image parameters on the reproducibility of prognostic performance of models built using radiomic biomarkers. We compare the prognostic performance of models derived from the heterogeneity-mitigated features with that of models obtained from raw features, to assess whether reproducibility of prognostic scores improves upon application of our methods. We used two datasets: The Breast I-SPY1 dataset—Baseline DCE-MRI scans of 156 women with locally advanced breast cancer, treated with neoadjuvant chemotherapy, publicly available via The Cancer Imaging Archive (TCIA); The NSCLC IO dataset—Baseline CT scans of 107 patients with stage 4 non-small cell lung cancer (NSCLC), treated with pembrolizumab immunotherapy at our institution. Radiomic features (n = 102) are extracted from the tumor ROIs. We use a variety of resampling and harmonization scenarios to mitigate the heterogeneity in image parameters. The patients were divided into groups based on batch variables. For each group, the radiomic phenotypes are combined with the clinical covariates into a prognostic model. The performance of the groups is assessed using the c-statistic, derived from a Cox proportional hazards model fitted on all patients within a group. The heterogeneity-mitigation scenario (radiomic features, derived from images that have been resampled to minimum voxel spacing, are harmonized using the image acquisition parameters as batch variables) gave models with highest prognostic scores (for e.g., IO dataset; batch variable: high kernel resolution—c-score: 0.66). The prognostic performance of patient groups is not comparable in case of models built using non-heterogeneity mitigated features (for e.g., I-SPY1 dataset; batch variable: small pixel spacing—c-score: 0.54, large pixel spacing—c-score: 0.65). The prognostic performance of patient groups is closer in case of heterogeneity-mitigated scenarios (for e.g., scenario—harmonize by voxel spacing parameters: IO dataset; thin slice—c-score: 0.62, thick slice—c-score: 0.60). Our results indicate that accounting for heterogeneity in image parameters is important to obtain more reproducible prognostic scores, irrespective of image site or modality. For non-heterogeneity mitigated models, the prognostic scores are not comparable across patient groups divided based on batch variables. This study can be a step in the direction of constructing reproducible radiomic biomarkers, thus increasing their application in clinical decision making. [ABSTRACT FROM AUTHOR]

Dentitions of the sympatric herbivorous dinosaurs Hungarosaurus (Ankylosauria, Nodosauridae) and Mochlodon (Ornithopoda, Rhabdodontidae) (Santonian, Hungary) were analysed to investigate their dietary ecology, using several complementary methods—orientation patch count, tooth replacement rate, macrowear, tooth wear rate, traditional microwear, and dental microwear texture analysis (DMTA). Tooth formation time is similar in Hungarosaurus and Mochlodon, and traditional and DMTA microwear features suggest low-browsing habits for both taxa, consistent with their inferred stances and body sizes. However, Mochlodon possesses a novel adaptation for increasing dental durability: the dentine on the working side of the crown is double the thickness of that on the balancing side. Moreover, crown morphology, enamel thickness, macrowear orientation, and wear rate differ greatly between the two taxa. Consequently, these sympatric herbivores probably exploited plants of different toughness, implying dietary selectivity and niche partitioning. Hungarosaurus is inferred to have eaten softer vegetation, whereas Mochlodon likely fed on tougher material. Compared to the much heavier, quadrupedal Hungarosaurus, the bipedal Mochlodon wore down more than twice as much of its crown volume during the functional life of the tooth. This heavy tooth wear might correlate with more intensive food processing and, in turn, could reflect differences in the metabolic requirements of these animals. [ABSTRACT FROM AUTHOR]

Patients with non-small cell lung cancer (NSCLC) who have distant metastases have a poor prognosis. To determine which genomic factors of the primary tumor are associated with metastasis, we analyzed data from 759 patients originally diagnosed with stage I–III NSCLC as part of the AACR Project GENIE Biopharma Collaborative consortium. We found that TP53 mutations were significantly associated with the development of new distant metastases. TP53 mutations were also more prevalent in patients with a history of smoking, suggesting that these patients may be at increased risk for distant metastasis. Our results suggest that additional investigation of the optimal management of patients with early-stage NSCLC harboring TP53 mutations at diagnosis is warranted in light of their higher likelihood of developing new distant metastases. [ABSTRACT FROM AUTHOR]

While there exist numerous methods to identify binary phenotypes (i.e. COPD) using electronic health record (EHR) data, few exist to ascertain the timings of phenotype events (i.e. COPD onset or exacerbations). Estimating event times could enable more powerful use of EHR data for longitudinal risk modeling, including survival analysis. Here we introduce Semi-supervised Adaptive Markov Gaussian Embedding Process (SAMGEP), a semi-supervised machine learning algorithm to estimate phenotype event times using EHR data with limited observed labels, which require resource-intensive chart review to obtain. SAMGEP models latent phenotype states as a binary Markov process, and it employs an adaptive weighting strategy to map timestamped EHR features to an embedding function that it models as a state-dependent Gaussian process. SAMGEP's feature weighting achieves meaningful feature selection, and its predictions significantly improve AUCs and F1 scores over existing approaches in diverse simulations and real-world settings. It is particularly adept at predicting cumulative risk and event counting process functions, and is robust to diverse generative model parameters. Moreover, it achieves high accuracy with few (50–100) labels, efficiently leveraging unlabeled EHR data to maximize information gain from costly-to-obtain event time labels. SAMGEP can be used to estimate accurate phenotype state functions for risk modeling research. [ABSTRACT FROM AUTHOR]

Sigmoid colon cancer often has an unsatisfactory prognosis. This study explored the effect of tumor deposits (TDs) on survival, and whether their presence/absence influence individualized treatment. Data of postoperative patients with sigmoid colon cancer were extracted from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) was calculated using the Kaplan–Meier method and prognostic factors were identified using Cox regression analysis and random forest (RF). The nomogram's discrimination performance was evaluated using a concordance index (C-index), integrated discrimination improvement (IDI), calibration curves, and decision-curve analysis. The N1c group showed a worse prognosis than the N0 group. For N1c patients, a combination of surgery and chemotherapy prolonged survival, compared to surgery alone; however, the chemotherapy-surgery combination did not affect the OS of patients younger than 70 years, in stage T1–2, and/or of black race. Multivariable analysis and RF presented Age, T stage, and N stage were the most important predictors for OS. The novel nomogram had superiority to the TNM staging system with improved C-index and IDI, as well as good consistency and higher clinical benefit. TDs are associated with poor survival from sigmoid colon cancer, and considering TDs can inform the formulation of individual treatment regimens. The nomogram shows satisfactory prediction ability for OS. [ABSTRACT FROM AUTHOR]

The prognosis of non-metastatic gallbladder adenocarcinoma (NM-GBA) patients is affected by the status of metastatic lymph nodes. The purpose of this study was to explore the prognostic value of the log odds of positive lymph nodes (LODDS) and develop a novel nomogram to predict the overall survival in NM-GBA patients. A total of 1035 patients confirmed to have NM-GBA were selected from the Surveillance, Epidemiology, and End Results (SEER) database and further divided into training and validation cohorts. The discrimination and calibration of the nomogram were evaluated using the concordance index (C-index), the area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration plots. The net benefits and clinical utility of the nomogram were quantified and compared with those of the 8th edition American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging system using decision curve analysis (DCA), net reclassification index (NRI), and integrated discrimination improvement (IDI). The risk stratifications of the nomogram and the TNM-staging system were compared. LODDS showed the highest accuracy in predicting OS for NM-GBA. The C-index (0.730 for the training cohort and 0.746 for the validation cohort) and the time-dependent AUC (> 0.7) indicated the satisfactory discriminative ability of the nomogram. The calibration plots showed a high degree of consistency. The DCA, NRI, and IDI indicated that the nomogram performed significantly better than the TNM-staging (P < 0.05). A novel LODDS-included nomogram was developed and validated to assist clinicians in evaluating the prognosis of NM-GBA patients. [ABSTRACT FROM AUTHOR]

Interpretable risk assessment of SARS-CoV-2 positive patients can aid clinicians to implement precision medicine. Here we trained a machine learning model to predict mortality within 12 weeks of a first positive SARS-CoV-2 test. By leveraging data on 33,938 confirmed SARS-CoV-2 cases in eastern Denmark, we considered 2723 variables extracted from electronic health records (EHR) including demographics, diagnoses, medications, laboratory test results and vital parameters. A discrete-time framework for survival modelling enabled us to predict personalized survival curves and explain individual risk factors. Performance on the test set was measured with a weighted concordance index of 0.95 and an area under the curve for precision-recall of 0.71. Age, sex, number of medications, previous hospitalizations and lymphocyte counts were identified as top mortality risk factors. Our explainable survival model developed on EHR data also revealed temporal dynamics of the 22 selected risk factors. Upon further validation, this model may allow direct reporting of personalized survival probabilities in routine care. [ABSTRACT FROM AUTHOR]

We aim to determine whether ischemic stroke(IS)-related PRSs are also associated with and further predict 3-year all-cause mortality. 1756 IS patients with European ancestry were randomly split into training (n = 1226) and testing (n = 530) groups with 3-year post-event observations. Univariate Cox proportional hazards regression model (CoxPH) was used for primary screening of individual prognostic PRSs. Only the significantly associated PRSs and clinical risk factors with the same direction for a causal relationship with IS were used to construct a multivariate CoxPH. Feature selection was conducted by the LASSO method. After feature selection, a prediction model with 11 disease-associated pathway-specific PRSs outperformed the base model, as demonstrated by a higher concordance index (0.751, 95%CI [0.693–0.809] versus 0.729, 95%CI [0.676–0.782]) in the testing sample. A PRS derived from endothelial cell apoptosis showed independent predictability in the multivariate CoxPH (Hazard Ratio = 1.193 [1.027–1.385], p = 0.021). These PRSs fine-tuned the model by better stratifying high, intermediate, and low-risk groups. Several pathway-specific PRSs were associated with clinical risk factors in an age-dependent manner and further confirmed some known etiologies of IS and all-cause mortality. In conclusion, Pathway-specific PRSs for IS are associated with all-cause mortality, and the integrated multivariate risk model provides prognostic value in this context. [ABSTRACT FROM AUTHOR]

This retrospective observational study analyzed the postoperative outcomes of bicanalicular intubation using different diameters of tube stents for treating postsaccal nasolacrimal duct obstruction. A total of 130 patients diagnosed with postsaccal obstruction who underwent endoscopic-assisted silicone tube intubation were included in the study. Patients intubated with a 1.5-mm large-diameter tube were designated as the LD group, and those with a 1.0-mm normal-diameter tube were designated as the ND group. The patency rates of the two groups at 1 year after tube removal were compared using the Kaplan–Meier curve and restricted mean survival time (RMST) method with τ = 365 days. Results demonstrated that the recurrence rate after tube removal was significantly lower in the LD group as compared with the ND group (p = 0.001). The patency rates at 1 year after removal in the LD and ND group were 85.7% (95% confidence interval [CI]: 75.4, 91.9) and 73.9% (95% CI: 61.7, 82.8), respectively. When comparing the patency rates by the RMST method at τ = 365 days, the RMST difference, RMST ratio, and RMTL ratio were higher in the LD group at p = 0.045, 0.052, and 0.046, respectively. [ABSTRACT FROM AUTHOR]

Genomic instability (GI) in cancer facilitates cancer evolution and is an exploitable target for therapy purposes. However, specific genes involved in cancer GI remain elusive. Causal genes for GI via expressions have not been comprehensively identified in colorectal cancers (CRCs). To fill the gap in knowledge, we developed a data mining strategy (Gene Expression to Copy Number Alterations; "GE-CNA"). Here we applied the GE-CNA approach to 592 TCGA CRC datasets, and identified 500 genes whose expression levels associate with CNA. Among these, 18 were survival-critical (i.e., expression levels correlate with significant differences in patients' survival). Comparison with previous results indicated striking differences between lung adenocarcinoma and CRC: (a) less involvement of overexpression of mitotic genes in generating genomic instability in the colon and (b) the presence of CNA-suppressing pathways, including immune-surveillance, was only partly similar to those in the lung. Following 13 genes (TIGD6, TMED6, APOBEC3D, EP400NL, B3GNT4, ZNF683, FOXD4, FOXD4L1, PKIB, DDB2, MT1G, CLCN3, CAPS) were evaluated as potential drug development targets (hazard ratio [> 1.3 or < 0.5]). Identification of specific CRC genomic instability genes enables researchers to develop GI targeting approach. The new results suggest that the "targeting genomic instability and/or aneuploidy" approach must be tailored for specific organs. [ABSTRACT FROM AUTHOR]

We developed an immunohistogram representing an individual cancer-immunity cycle based on immunohistochemical analyses. We evaluated its ability to predict the efficacy of immune checkpoint inhibitors (ICI) in 11 patients with urothelial carcinoma and 7 patients with renal cell carcinoma who underwent surgery and received ICIs for disease recurrence. Immunohistochemical analyses for CD8, TIA-1, HLA class I, HLA-DR, and PD-L1 were performed and scored 0–3. T-cell infiltration pattern was classified into desert, excluded, partially inflamed, and inflamed. Tumors with an inflamed or partially inflamed pattern and positive scores (score ≥ 1) for all five immune markers were classified as "immune-hot" and others as "immune-cold." Association between the immunohistogram and ICI treatment efficacy was evaluated with objective response rate, disease control rate (DCR), progression-free survival (PFS), and cancer-specific survival (CSS). Eight (44%) and 10 (56%) patients had immune-hot and immune-cold tumors, respectively. Immune-hot tumors showed a higher DCR (100% vs. 40%, p < 0.01), longer PFS (median unreached for hot, 1.3 months for cold, p < 0.01), and longer CSS (median unreached for hot, 3.3 months for cold, p < 0.01) than immune-cold tumors. The immunohistogram could be clinically useful as an accessible biomarker for precision cancer immunotherapy in urological cancer. [ABSTRACT FROM AUTHOR]

We aim to determine the feasibility of a novel radiomic biomarker that can integrate with other established clinical prognostic factors to predict progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) undergoing first-line immunotherapy. Our study includes 107 patients with stage 4 NSCLC treated with pembrolizumab-based therapy (monotherapy: 30%, combination chemotherapy: 70%). The ITK-SNAP software was used for 3D tumor volume segmentation from pre-therapy CT scans. Radiomic features (n = 102) were extracted using the CaPTk software. Impact of heterogeneity introduced by image physical dimensions (voxel spacing parameters) and acquisition parameters (contrast enhancement and CT reconstruction kernel) was mitigated by resampling the images to the minimum voxel spacing parameters and harmonization by a nested ComBat technique. This technique was initialized with radiomic features, clinical factors of age, sex, race, PD-L1 expression, ECOG status, body mass index (BMI), smoking status, recurrence event and months of progression-free survival, and image acquisition parameters as batch variables. Two phenotypes were identified using unsupervised hierarchical clustering of harmonized features. Prognostic factors, including PDL1 expression, ECOG status, BMI and smoking status, were combined with radiomic phenotypes in Cox regression models of PFS and Kaplan Meier (KM) curve-fitting. Cox model based on clinical factors had a c-statistic of 0.57, which increased to 0.63 upon addition of phenotypes derived from harmonized features. There were statistically significant differences in survival outcomes stratified by clinical covariates, as measured by the log-rank test (p = 0.034), which improved upon addition of phenotypes (p = 0.00022). We found that mitigation of heterogeneity by image resampling and nested ComBat harmonization improves prognostic value of phenotypes, resulting in better prediction of PFS when added to other prognostic variables. [ABSTRACT FROM AUTHOR]

Understanding the tumor microenvironment (TME) and anti-tumor immune responses in gastric cancer are required for precision immune-oncology. Taking advantage of next-generation sequencing technology, the feasibility and reliability of transcriptome-based TME analysis were investigated. TME of 30 surgically resected gastric cancer tissues was analyzed by RNA-Seq, immunohistochemistry (IHC) and flow cytometry (FCM). RNA-Seq of bulk gastric cancer tissues was computationally analyzed to evaluate TME. Computationally analyzed immune cell composition was validated by comparison with cell densities established by IHC and FCM from the same tumor tissue. Immune cell infiltration and cellular function were also validated with IHC and FCM. Cell proliferation and cell death in the tumor as assessed by RNA-Seq and IHC were compared. Computational tools and gene set analysis for quantifying CD8+ T cells, regulatory T cells and B cells, T cell infiltration and functional status, and cell proliferation and cell death status yielded an excellent correlation with IHC and FCM data. Using these validated transcriptome-based analyses, the immunological status of gastric cancer could be classified into immune-rich and immune-poor subtypes. Transcriptome-based TME analysis is feasible and is valuable for further understanding the immunological status of gastric cancer. [ABSTRACT FROM AUTHOR]

Patients with heart failure (HF) and coronary artery disease (CAD) have a high risk for cardiovascular (CV) events including HF hospitalization, stroke, myocardial infarction (MI) and sudden cardiac death (SCD). The present study evaluated associations of proteomic biomarkers with CV outcome in patients with CAD and HF with reduced ejection fraction (HFrEF), shortly after a worsening HF episode. We performed a case–control study within the COMMANDER HF international, double-blind, randomized placebo-controlled trial investigating the effects of the factor-Xa inhibitor rivaroxaban. Patients with the following first clinical events: HF hospitalization, SCD and the composite of MI or stroke were matched with corresponding controls for age, sex and study drug. Plasma concentrations of 276 proteins with known associations with CV and cardiometabolic mechanisms were analyzed. Results were corrected for multiple testing using false discovery rate (FDR). In 485 cases and 455 controls, 49 proteins were significantly associated with clinical events of which seven had an adjusted FDR < 0.001 (NT-proBNP, BNP, T-cell immunoglobulin and mucin domain containing 4 (TIMD4), fibroblast growth factor 23 (FGF-23), growth differentiation factor-15 (GDF-15), pulmonary surfactant-associated protein D (PSP-D) and Spondin-1 (SPON1)). No significant interactions were identified between the type of clinical event (MI/stroke, SCD or HFH) and specific biomarkers (all interaction FDR > 0.20). When adding the biomarkers significantly associated with the above outcome to a clinical model (including NT-proBNP), the C-index increase was 0.057 (0.033–0.082), p < 0.0001 and the net reclassification index was 54.9 (42.5 to 67.3), p < 0.0001. In patients with HFrEF and CAD following HF hospitalization, we found that NT-proBNP, BNP, TIMD4, FGF-23, GDF-15, PSP-D and SPON1, biomarkers broadly associated with inflammation and remodeling mechanistic pathways, were strong but indiscriminate predictors of a variety of individual CV events. [ABSTRACT FROM AUTHOR]

Detecting microsatellite instability (MSI) in colorectal cancers (CRCs) is essential because it is the determinant of treatment strategies, including immunotherapy and chemotherapy. Yet, no attempt has been made to exploit transcriptomic profile and tumor microenvironment (TME) of it to unveil MSI status in CRC. Hence, we developed a novel TME-aware, single-transcriptome predictor of MSI for CRC, called MAP (Microsatellite instability Absolute single sample Predictor). MAP was developed utilizing recursive feature elimination-random forest with 466 CRC samples from The Cancer Genome Atlas, and its performance was validated in independent cohorts, including 1118 samples. MAP showed robustness and predictive power in predicting MSI status in CRC. Additional advantages for MAP were demonstrated through comparative analysis with existing MSI classifier and other cancer types. Our novel approach will provide access to untouched vast amounts of publicly available transcriptomic data and widen the door for MSI CRC research and be useful for gaining insights to help with translational medicine. [ABSTRACT FROM AUTHOR]

Gini's mean difference (GMD, mean absolute difference between any two distinct quantities) of the restricted mean survival times (RMSTs, expectation of life at a given time limit) has been proposed as a new metric where higher GMD indicates better prognostic value. GMD is applied to the RMSTs at 25 years time-horizon to evaluate the long-term overall survival of women with breast cancer who received neoadjuvant chemotherapy, comparing a classification based on the number (pN) versus a classification based on the ratio (LNRc) of positive nodes found at axillary surgery. A total of 233 patients treated in 1980–2009 with documented number of positive nodes (npos) and number of nodes examined (ntot) were identified. The numbers were categorized into pN0, npos = 0; pN1, npos = [1,3]; pN2, npos = [4,9]; pN3, npos ≥ 10. The ratios npnx = npos/ntot were categorized into Lnr0, npnx = 0; Lnr1, npnx = (0,0.20]; Lnr2, npnx = (0.20,0.65]; Lnr3, npnx > 0.65. The GMD for pN-classification was 5.5 (standard error: ± 0.9) years, not much improved over a simple node-negative vs. node-positive that showed a GMD of 5.0 (± 1.4) years. The GMD for LNRc-classification was larger, 6.7 (± 0.8) years. Among other conventional metrics, Cox-model LNRc's c-index was 0.668 vs. pN's c = 0.641, indicating commensurate superiority of LNRc-classification. The usability of GMD-RMSTs warrants further investigation. [ABSTRACT FROM AUTHOR]

A prognostic model to determine an association between survival outcomes and clinical risk factors, such as the Cox model, has been developed over the past decades in the medical field. Although the data size containing subjects' information gradually increases, the number of events is often relatively low as medical technology develops. Accordingly, poor discrimination and low predicted ability may occur between low- and high-risk groups. The main goal of this study was to evaluate the predicted probabilities with three existing competing risks models in variation with censoring rates. Three methods were illustrated and compared in a longitudinal study of a nationwide prospective cohort of patients with chronic kidney disease in Korea. The prediction accuracy and discrimination ability of the three methods were compared in terms of the Concordance index (C-index), Integrated Brier Score (IBS), and Calibration slope. In addition, we find that these methods have different performances when the effects are linear or nonlinear under various censoring rates., (© 2023. Springer Nature Limited.)

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm2, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care. Trial Registration ClinicalTrials.gov Identifier: NCT00930735 and ClinicalTrials.gov Identifier: NCT01755936. [ABSTRACT FROM AUTHOR]

Computed tomography (CT)-measured psoas muscle thickness standardized for height (PMTH) has emerged as a promising predictor of mortality. The study aimed to investigate whether PMTH could accurately predict mortality in patients undergoing hemodialysis. We examined 207 patients (mean age: 63.1 years; men: 66.2%) undergoing hemodialysis for more than 6 months in hospital affiliated clinic. PMTH was calculated at the L3 vertebra level using CT. Patients were divided according to the PMTH cut-off points: 8.44 mm/m in women and 8.85 mm/m in men; thereafter, they were combined into low and high PMTH groups. PMTH was independently correlated with the simplified creatinine index (β = 0.213, P = 0.021) and geriatric nutritional risk index (β = 0.295, P < 0.0001) in multivariate regression analysis. During a median follow-up of 3.7 (1.8–6.4) years, 76 patients died, including 41 from cardiovascular causes. In the multivariate Cox regression analysis, low PMTH (adjusted hazard ratio, 2.48; 95% confidence interval, 1.36–4.70) was independently associated with an increased risk of all-cause mortality. The addition of binary PMTH groups to the baseline risk model tended to improve net reclassification improvement (0.460, p = 0.060). In conclusion, PMTH may be an indicator of protein energy wasting and a useful tool for predicting mortality in patients undergoing hemodialysis. [ABSTRACT FROM AUTHOR]

The (pro)renin receptor [(P)RR)] is a multifunctional protein that is cleaved to generate the soluble (P)RR [s(P)RR], reflecting the status of the tissue renin-angiotensin system and/or activity of the (P)RR. The serum s(P)RR level is associated with arteriosclerosis, independent of other risk factors, in patients undergoing hemodialysis (HD). This study was conducted to investigate whether the s(P)RR level was associated with new-onset cardiovascular events or malignant diseases and poor prognosis in patients undergoing HD. Overall, 258 patients [70 (61–76) years, 146 males] undergoing maintenance HD were prospectively followed up for 60 months. We investigated the relationships between s(P)RR levels and new-onset cardiovascular events/ malignant diseases and mortality during the follow-up period using Cox proportional hazard analyses. The cumulative incidence of new-onset cardiovascular events (P = 0.009) and deaths (P < 0.001), but not of malignant diseases, was significantly greater in patients with higher serum s(P)RR level (≥ 29.8 ng/ml) than in those with lower s(P)RR level (< 29.8 ng/ml). A high serum s(P)RR level was independently correlated with cardiovascular mortality (95% CI 1.001–1.083, P = 0.046). The serum s(P)RR level was associated with cardiovascular events and mortality, thus qualifying as a biomarker for identifying patients requiring intensive care. [ABSTRACT FROM AUTHOR]

Immune reactions in the tumor microenvironment are an important hallmark of cancer, and emerging immune therapies have been proven effective against several types of cancers. To investigate cancer genome-immune interactions and the role of immunoediting or immune escape mechanisms in cancer development, we analyzed 2834 whole genome and RNA sequencing datasets across 31 distinct tumor types with respect to key immunogenomic aspects and provided comprehensive immunogenomic profiles of pan-cancers. We found that selective copy number changes in immune-related genes may contribute to immune escape. Furthermore, we developed an index of the immunoediting history of each tumor sample based on the information of mutations in exonic regions and pseudogenes and evaluated the immunoediting history of each tumor. Our immuno-genomic analyses of pan-cancers have the potential to identify a subset of tumors with immunogenicity and diverse backgrounds or intrinsic pathways associated with their immune status and immunoediting history. [ABSTRACT FROM AUTHOR]

Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation. [ABSTRACT FROM AUTHOR]

Several studies showed the association between non-traditional risk factors [proteinuria and estimated Glomerular Filtration Rate (eGFR)] and cardiovascular (CV) and renal outcomes. Nevertheless, the etiologic role of traditional CV risk factors in referred CKD patients is less defined. Herein, we examined the association between smoking habit and CV events, mortality and CKD progression. We undertook an observational analysis of 1306 stage III–V CKD patients. Smoking habit was modeled as a categorical (never, current or former smokers) and continuous (number of cigarettes/day) variable. Mean eGFR was 35.8 ± 12.5 mL/min/1.73 m2. Never, current and former smokers were 61.1%, 10.8% and 28.1%. During a median follow-up of 2.87 years, current and former smokers were at significant risk for CV events (HRs of 1.93 [95% CI, 1.18–3.16] and 1.44 [95% CI, 1.01–2.05]) versus never smokers. Current smokers were at increased mortality risk (HR 2.13 [95% CI, 1.10–4.11]). Interactions were found between former smokers and proteinuria (p = 0.007) and diabetes (p = 0.041) for renal risk, and between current smokers and male gender (p = 0.044) and CKD stage V (p = 0.039) for renal and mortality risk. In referred CKD patients, smoking habit is independently associated with CV events and mortality. It acts as a risk "amplifier" for the association between other risk factors and renal outcomes. [ABSTRACT FROM AUTHOR]

After a cell divides into two daughter cells, the total cell surface area of the daughter cells should increase to the original size to maintain cell size homeostasis in a single cell cycle. Previously, three models have been proposed to explain the regulation of cell size homeostasis: sizer, timer, and adder models. Here, we precisely measured the total cell surface area of Dictyostelium cells in a whole cell cycle by using the agar-overlay method, which eliminated the influence of surface membrane reservoirs, such as microvilli and membrane wrinkles. The total cell surface area exponentially increased during interphase, slightly decreased at metaphase, and then increased by approximately 20% during cytokinesis. From the analysis of the added surface area, we concluded that the cell size was regulated by the adder or near-adder model in interphase. This adder model is not caused by a simple cell membrane addition, but is more dynamic due to the rapid cell membrane turnover. We propose a 'dynamic adder model' to explain cell size homeostasis in interphase. [ABSTRACT FROM AUTHOR]

This study was designed to build models predicting early graft failure after liver transplantation. Cox regression model for predicting early graft failure after liver transplantation using post-transplantation aspartate aminotransferase, total bilirubin, and international normalized ratio of prothrombin time was constructed based on data from both living donor (n = 1153) and deceased donor (n = 359) liver transplantation performed during 2004 to 2018. The model was compared with Model for Early Allograft Function Scoring (MEAF) and early allograft dysfunction (EAD) with their C-index and time-dependent area-under-curve (AUC). The C-index of the model for living donor (0.73, CI = 0.67–0.79) was significantly higher compared to those of both MEAF (0.69, P = 0.03) and EAD (0.66, P = 0.001) while C-index for deceased donor (0.74, CI = 0.65–0.83) was only significantly higher compared to C-index of EAD. (0.66, P = 0.002) Time-dependent AUC at 2 weeks of living donor (0.96, CI = 0.91–1.00) and deceased donor (0.98, CI = 0.96–1.00) were significantly higher compared to those of EAD. (both 0.83, P < 0.001 for living donor and deceased donor) Time-dependent AUC at 4 weeks of living donor (0.93, CI = 0.86–0.99) was significantly higher compared to those of both MEAF (0.87, P = 0.02) and EAD. (0.84, P = 0.02) Time-dependent AUC at 4 weeks of deceased donor (0.94, CI = 0.89–1.00) was significantly higher compared to both MEAF (0.82, P = 0.02) and EAD. (0.81, P < 0.001). The prediction model for early graft failure after liver transplantation showed high predictability and validity with higher predictability compared to traditional models for both living donor and deceased donor liver transplantation. [ABSTRACT FROM AUTHOR]

Among non-small cell lung cancer (NSCLC) patients with therapeutically targetable tumor mutations in epidermal growth factor receptor (EGFR), not all patients respond to targeted therapy. Combining circulating-tumor DNA (ctDNA), clinical variables, and radiomic phenotypes may improve prediction of EGFR-targeted therapy outcomes for NSCLC. This single-center retrospective study included 40 EGFR-mutant advanced NSCLC patients treated with EGFR-targeted therapy. ctDNA data included number of mutations and detection of EGFR T790M. Clinical data included age, smoking status, and ECOG performance status. Baseline chest CT scans were analyzed to extract 429 radiomic features from each primary tumor. Unsupervised hierarchical clustering was used to group tumors into phenotypes. Kaplan–Meier (K–M) curves and Cox proportional hazards regression were modeled for progression-free survival (PFS) and overall survival (OS). Likelihood ratio test (LRT) was used to compare fit between models. Among 40 patients (73% women, median age 62 years), consensus clustering identified two radiomic phenotypes. For PFS, the model combining radiomic phenotypes with ctDNA and clinical variables had c-statistic of 0.77 and a better fit (LRT p = 0.01) than the model with clinical and ctDNA variables alone with a c-statistic of 0.73. For OS, adding radiomic phenotypes resulted in c-statistic of 0.83 versus 0.80 when using clinical and ctDNA variables (LRT p = 0.08). Both models showed separation of K–M curves dichotomized by median prognostic score (p < 0.005). Combining radiomic phenotypes, ctDNA, and clinical variables may enhance precision oncology approaches to managing advanced non-small cell lung cancer with EGFR mutations. [ABSTRACT FROM AUTHOR]

The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1–11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, − 0.6–6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5–44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18–28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice. [ABSTRACT FROM AUTHOR]

Diagnosing stroke in patients experiencing dizziness without neurological deficits is challenging for physicians. The aim of this study was to evaluate the prevalence of acute stroke in patients who presented with isolated dizziness without neurological deficits at the emergency department (ED), and determine the relevant stroke predictors in this population. This was an observational, retrospective record review of consecutive 2215 adult patients presenting with dizziness at the ED between August 2019 and February 2020. Multivariate analysis was performed to identify risk factors for acute stroke. 1239 patients were enrolled and analyzed. Acute stroke was identified in 55 of 1239 patients (4.5%); most cases (96.3%) presented as ischemic stroke with frequent involvement (29.1%) of the cerebellum. In the multivariate analysis, the history of cerebrovascular injury (odds ratio [OR] 3.08 [95% confidence interval {CI} 1.24 to 7.67]) and an age of > 65 years (OR 3.01 [95% CI 1.33 to 6.83]) were the independent risk factors for predicting acute stroke. The combination of these two risks showed a higher specificity (94.26%) than that of each factor alone. High-risk patients, such as those aged over 65 years or with a history of cerebrovascular injury, may require further neuroimaging workup in the ED to rule out stroke. [ABSTRACT FROM AUTHOR]

While the molecular functions of miR-200 family have been deeply investigated, a role for these miRNAs as breast cancer biomarkers remains largely unexplored. In the attempt to clarify this, we profiled the miR-200 family members expression in a large cohort of breast cancer cases with a long follow-up (H-CSS cohort) and in TCGA-BRCA cohort. Overall, miR-200 family was found upregulated in breast tumors with respect to normal breast tissues while downregulated in more aggressive breast cancer molecular subtypes (i.e. Luminal B, HER2 and triple negative), consistently with their function as repressors of the epithelial-to-mesenchymal transition (EMT). In particular miR-141-3p was found differentially expressed in breast cancer molecular subtypes in both H-CSS and TCGA-BRCA cohorts, and the combined analysis of all miR-200 family members demonstrated a slight predictive accuracy on H-CSS cancer specific survival at 12 years (survival c-statistic: 0.646; 95%CI 0.538–0.754). [ABSTRACT FROM AUTHOR]