bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Realization of MEMS Heart Sound Sensor with Concave, Racket-Shaped Cilium
Authors: Yang Yuhua , Wang Bo , Cui Jiangong , Zhang Guojun , Wang Renxin , Zhang Wendong , He Changde , Li Yirui , Shi Pengcheng , Wang Shuotong
Published: July 2022

The biomedical acoustic signal plays an important role in clinical non-invasive diagnosis. In view of the deficiencies in early diagnosis of cardiovascular diseases, acoustic properties of S1 and S2 heart sounds are utilized. In this paper, we propose an integrated concave cilium MEMS heart sound sensor. The concave structure enlarges the area for receiving sound waves to improve the low-frequency sensitivity, and realizes the low-frequency and high-sensitivity characteristics of an MEMS heart sound sensor by adopting a reasonable acoustic package design, reducing the loss of heart sound distortion and faint heart murmurs, and improving the auscultation effect. Finally, experimental results show that the integrated concave ciliated MEMS heart sound sensor’s sensitivity reaches −180.6 dB@500 Hz, as compared with the traditional bionic ciliated MEMS heart sound sensor; the sensitivity is 8.9 dB higher. The sensor has a signal-to-noise ratio of 27.05 dB, and has good heart sound detection ability, improving the accuracy of clinical detection methods.
QTLs Controlling Physiological and Morphological Traits of Barley (Hordeum vulgare L.) Seedlings under Salinity, Drought, and Normal Conditions
Authors: Makhtoum Somayyeh , Sabouri Hossein , Gholizadeh Abdollatif , Ahangar Leila , Katouzi Mahnaz
Published: July 2022

To identify the genomic regions for the physiological and morphological traits of barley genotypes under normal salinity and drought, a set of 103 recombinant inbred line (RIL) populations, developed between Badia and Kavir crosses, was evaluated under phytotron conditions in a completely randomized design in 2019. Linkage maps were prepared using 152 SSR markers, 72 ISSR, 7 IRAP, 29 CAAT, 27 SCoT, and 15 iPBS alleles. The markers were assigned to seven barley chromosomes and covered 999.29 centimorgans (cM) of the barley genome. In addition, composite interval mapping showed 8, 9, and 26 quantitative trait loci (QTLs) under normal, drought, and salinity stress conditions, respectively. Our results indicate the importance of chromosomes 1, 4, 5, and 7 in salinity stress. These regions were involved in genes controlling stomata length (LR), leaf number (LN), leaf weight (LW), and genetic score (SCR). Three major stable pleiotropic QTLs (i.e., qSCS-1, qRLS-1, and qLNN-1) were associated with SCR, root length (RL), and root number (RN) in both treatments (i.e., normal and salinity), and two major stable pleiotropic QTLs (i.e., qSNN-3 and qLWS-3) associated with the stomata number (SN) and LW appeared to be promising for marker-assisted selection (MAS). Two major-effect QTLs (i.e., SCot8-B-CAAT5-D and HVM54-Bmag0571) on chromosomes 1 and 2 were characterized for their positive allele effect, which can be used to develop barley varieties concerning drought conditions. The new alleles (i.e., qLWS-4a, qSLS-4, qLNS-7b, qSCS-7, and qLNS-7a) identified in this study are useful in pyramiding elite alleles for molecular breeding and marker assisted selection for improving salinity tolerance in barley.
Native Listeners’ Use of Information in Parsing Ambiguous Casual Speech
Authors: Warner Natasha , Brenner Dan , Tucker Benjamin V. , Ernestus Mirjam
Published: July 2022

In conversational speech, phones and entire syllables are often missing. This can make “he’s” and “he was” homophonous, realized for example as [ɨz]. Similarly, “you’re” and “you were” can both be realized as [jɚ], [ɨ], etc. We investigated what types of information native listeners use to perceive such verb tenses. Possible types included acoustic cues in the phrase (e.g., in “he was”), the rate of the surrounding speech, and syntactic and semantic information in the utterance, such as the presence of time adverbs such as “yesterday” or other tensed verbs. We extracted utterances such as “So they’re gonna have like a random roommate” and “And he was like, ‘What’s wrong?!’” from recordings of spontaneous conversations. We presented parts of these utterances to listeners, in either a written or auditory modality, to determine which types of information facilitated listeners’ comprehension. Listeners rely primarily on acoustic cues in or near the target words rather than meaning and syntactic information in the context. While that information also improves comprehension in some conditions, the acoustic cues in the target itself are strong enough to reverse the percept that listeners gain from all other information together. Acoustic cues override other information in comprehending reduced productions in conversational speech.
Application of the RDoC Framework to Predict Alcohol Use and Suicidal Thoughts and Behaviors among Early Adolescents in the Adolescent Brain and Cognitive Development (ABCD) Study
Authors: Aguinaldo Laika D. , Coronado Clarisa , Gomes Diego A. , Courtney Kelly E. , Jacobus Joanna
Published: July 2022

Alcohol use confers risk for suicidal thoughts and behaviors (ideation, attempt) in early adolescents. The Research Domain Criteria provides a framework for examination of multidimensional and modifiable risk factors. We examined distinct latent profiles based on patterns of positive valence (reward responsivity) and cognitive systems (neurocognition) from the ABCD Study (age 9–10, N = 10,414) at baseline enrollment. Longitudinal associations were determined between baseline positive valence and cognitive profiles and group classification (alcohol use, suicidal thoughts and behaviors, or their co-occurrence) two-years after initial assessment (ages 11–12). Three unique profiles of positive valence, cognition, alcohol use, and suicidal thoughts and behaviors were identified. Two baseline profiles predicted alcohol use and suicidal thoughts and behaviors, two-years after initial assessment. Low positive valence with high cognition (but low impulsivity) predicted alcohol use (OR = 1.414, p< 0.001), while high positive valence with low cognition (but high impulsivity) predicted suicidal thoughts and behaviors (OR = 1.25, p = 0.038), compared to average positive valence and cognition. Unique profiles of positive valence and cognitive systems among 9–12-year-olds may be predictive of alcohol use and suicidal thoughts and behaviors over a two-year period. Findings underscore the potential for trajectory research on positive valence and cognitive profiles to enhance prevention for early-adolescents.
Schools’ Capitalization into Housing Values in a Context of Free School Choices
Authors: Ismail Mohammad , Warsame Abukar , Wilhelmsson Mats
Published: July 2022

The issue of schools and their capitalization in property values has been analyzed extensively. Our contribution is to analyze this effect in an alternative institutional context. In this case study, we analyzed the housing market in Stockholm, Sweden. What distinguishes the Swedish school system is that we have a free choice of schools, which means that a family does not necessarily have to live in a school district to access the schools in that area. This means that families do not have to move to the district to which they intend to send their children but can apply to send them there regardless of whether they live there or not. Nevertheless, families might be interested in living close to good schools to be within walking distance of these schools. This is especially true at the primary school level. Therefore, we analyzed schools’ capitalization in property values in the context of free school choice. We used data on transaction prices for condominiums in Stockholm’s inner city. The results indicate a capitalization of living close to good schools, but this capitalization is limited. We can show that schools’ capitalization depends partly on the quality of the schools and partly on whether or not they are co-located with other externalities, such as green areas. The results also indicate that capitalization is affected by income differences within the city.
Experimental and Numerical Studies on Repaired Wooden Beam of Traditional Buildings in Huizhou Region, China
Authors: Jiang Yunpeng , Sun Qiang
Published: July 2022

In this study, three different repair methods are proposed for the common broken parts of traditional wooden beams. Four wooden beams without initial damage and six repaired beams in a planar wooden frame are tested and numerical simulated. The test phenomena, bearing capacity, and stiffness of all the wooden beams are analyzed. Compared with the wooden beams without initial damage, the bearing capacity of the beams with upper inlay repair, upper core repair, partial tenon repair, and lower core repair increases by 38.93%, 13.06%, 5.08%, and 3.94%, respectively. Furthermore, the experimental and numerical results indicate that the upper and lower parts of the wooden beam with initial damage can be more effectively repaired by the inlay and core methods, respectively. When the tenon is partially damaged, the mechanical properties of the wooden beam are improved after repair. The simulation of lower inlay repair shows that the bearing capacity of the wooden beam is inversely proportional to the repair height and the distance between the repair position and the span. Based on the experimental results, a dovetail form of inlay repair is proposed, and it is numerically verified that this method can effectively reduce the stress concentration.
Defect Repair Cost and Home Warranty Deposit, Korea
Authors: Park Junmo , Seo Deokseok
Published: July 2022

Defects in the home cause inconvenience to homeowners and loss to the developer or builder due to cost and damage to reputation. A home warranty deposit exists to protect consumers from home defects. However, it is unclear how much it costs to repair a defect and whether the standard for calculating the warranty deposit is reasonable. This study analyzed the litigation details of 290 home complexes in Korea to investigate defect repair costs and factors affecting them. According to the analysis results, the defect repair cost was 0.538% of the construction cost on average. This is far below 3% of the construction cost, the prevailing standard in the relevant acts. Additionally, there was no case where the defect repair cost ratio exceeded 3%. The actual repair cost for defects was considerably lower than the warranty deposit standard stipulated by the Act. Therefore, this study proposes a method to adjust the warranty deposit collectively and a means to apply it differentially according to the size of the construction cost. This proposal benefits everyone because it protects homeowners and keeps the costs affordable. In addition, it is expected that the warranty deposit can be used as a standard for home construction and post-quality improvement. After analyzing the factors affecting the repair cost, it was found that there was a difference in the repair cost according to the home construction implementor and the construction purchase order method. The warranty deposit system prepares for the possibility that a project owner or builder, who is the project implementor, becomes insolvent. It was found that there was no difference in the repair cost for defects depending on whether the project owner was insolvent. Nonetheless, the possibility of insolvency in the case of a developer was far higher than in the case of a builder.
Seismic Retrofit Technique Using Plywood and Common Nails for Connections of Low-Rise Timber Frame Construction
Authors: Hirakawa Hideki , Uematsu Takeyoshi , Fukushima Akira , Adachi Yusuke , Kikuta Koki
Published: July 2022

Since the Japanese Building Standards Act was revised in 2000, the installation of steel timber connectors (STCs) to reinforce timber frame (TF) connections has been mandated for new-build TF houses in Japan. However, for the TF houses built before then, more than 40% do not have sufficient STCs and are considered earthquake-prone. This study proposed a simple and easy seismic retrofit technique for such earthquake-prone existing houses. The proposed technique can reinforce TF connections using only plywood and common nails and achieve equivalent performance to the benchmark STCs used in Japanese TF houses, such as the “CP-T type” or the combination of “VP type” and “BP type” STCs. Experiments were performed to compare the proposed technique with the STCs using pullout and full-scale in-plane cyclic tests. The experimental results showed that the proposed technique had a higher seismic performance than the STCs, which was particularly excellent in displacement ductility to prevent a collapse of the TF house without damaging the timbers. The proposed technique will be accepted by many carpenters when retrofitting earthquake-prone existing houses because simple and easy.
Integrated Smart-Home Architecture for Supporting Monitoring and Scheduling Strategies in Residential Clusters
Authors: Stroia Nicoleta , Moga Daniel , Petreus Dorin , Lodin Alexandru , Muresan Vlad , Danubianu Mirela
Published: July 2022

The monitoring of power consumption and the forecasting of load profiles for residential appliances are essential aspects of the control of energy savings/exchanges at multiple hierarchical levels: house, house cluster, neighborhood, and city. External environmental factors (weather conditions) and inhabitants’ behavior influence power consumption, and their usage as part of forecasting activity may lead to added value in the estimation of daily-load profiles. This paper proposes a distributed sensing infrastructure for supporting the following tasks: the monitoring of appliances’ power consumption, the monitoring of environmental parameters, the generation of records for a database that can be used for both identifying load models and testing load-scheduling algorithms, and the real-time acquisition of consumption data. The hardware/software codesign of an integrated architecture that can combine the typical distributed sensing and control networks present in modern buildings (targeting user comfort) with energy-monitoring and management systems is presented. Methods for generating simplified piecewise linear (PWL) representations of the load profiles based on these records are introduced and their benefits compared with classic averaged representations are demonstrated for the case of peak-shaving strategies. The proposed approach is validated through implementing and testing a smart-meter node with wireless communication and other wired/wireless embedded modules, enabling the tight integration of the energy-monitoring system into smart-home/building-automation systems. The ability of this node to process power measurements with a programable granularity level (seconds/minutes/hours) at the edge level and stream the processed measurement results at the selected granularity to the cloud is identified as a valuable feature for a large range of applications (model identification, power saving, prediction).
An Open-Source AI Framework for the Analysis of Single Cells in Whole-Slide Images with a Note on CD276 in Glioblastoma
Authors: Alzoubi Islam , Bao Guoqing , Zhang Rong , Loh Christina , Zheng Yuqi , Cherepanoff Svetlana , Gracie Gary , Lee Maggie , Kuligowski Michael , Alexander Kimberley L. , Buckland Michael E. , Wang Xiuying , Graeber Manuel B.
Published: July 2022

Routine examination of entire histological slides at cellular resolution poses a significant if not insurmountable challenge to human observers. However, high-resolution data such as the cellular distribution of proteins in tissues, e.g., those obtained following immunochemical staining, are highly desirable. Our present study extends the applicability of the PathoFusion framework to the cellular level. We illustrate our approach using the detection of CD276 immunoreactive cells in glioblastoma as an example. Following automatic identification by means of PathoFusion’s bifocal convolutional neural network (BCNN) model, individual cells are automatically profiled and counted. Only discriminable cells selected through data filtering and thresholding were segmented for cell-level analysis. Subsequently, we converted the detection signals into the corresponding heatmaps visualizing the distribution of the detected cells in entire whole-slide images of adjacent H&E-stained sections using the Discrete Wavelet Transform (DWT). Our results demonstrate that PathoFusion is capable of autonomously detecting and counting individual immunochemically labelled cells with a high prediction performance of 0.992 AUC and 97.7% accuracy. The data can be used for whole-slide cross-modality analyses, e.g., relationships between immunochemical signals and anaplastic histological features. PathoFusion has the potential to be applied to additional problems that seek to correlate heterogeneous data streams and to serve as a clinically applicable, weakly supervised system for histological image analyses in (neuro)pathology.
Fatty Acid Signaling Impacts Prostate Cancer Lineage Plasticity in an Autocrine and Paracrine Manner
Authors: Zhang Le , Billet Sandrine , Gonzales Gabrielle , Rohena-Rivera Krizia , Muranaka Hayato , Chu Gina , Yang Qian , Kim Hyung , Bhowmick Neil , Smith Bethany
Published: July 2022

Prostate cancer (PCa) affects an estimated 250,000 men every year and causes 34,000 deaths annually. A high-fat diet and obesity are associated with PCa progression and mortality. This study’s premise was the novel observation of crosstalk between PCa epithelia and cancer-associated fibroblasts (CAF) in response to palmitate-mediated lineage plasticity. We found that cholesterol activated canonical Hedgehog (Hh) signaling by increasing cilium Gli activity in PCa cells, while palmitate activated Hh independent of Gli. Exogenous palmitate activated SOX2, a known mediator of lineage plasticity, in PCa cells cocultured with CAF. Stroma-derived Wnt5a was upregulated in CAF while cocultured with PCa cells and treated with palmitate. Wnt5a knockdown in CAF inhibited Hh and SOX2 expression in PCa cells from cocultures. These findings supported our proposed mechanism of a high-fat diet promoting Hh signaling-mediated transformation within the tumor microenvironment. SOX2 and Wnt5a expression were limited by the CD36 neutralizing antibody. Mice xenografted with PCa epithelia and CAF tumors were fed a high-fat diet, leading to elevated SOX2 expression and lineage plasticity reprogramming compared to mice fed an isocaloric rodent diet. CD36 inhibition with enzalutamide elevated apoptosis by TUNEL, but limited proliferation and SOX2 expression compared to enzalutamide alone. This study revealed a mechanism for a high-fat diet to affect prostate cancer progression. We found that saturated fat induced lineage plasticity reprogramming of PCa by interaction with CAF through Wnt5a and Hh signaling.
Lung Nodules Missed in Initial Staging of Breast Cancer Patients in PET/MRI—Clinically Relevant?
Authors: Jannusch Kai , Bruckmann Nils Martin , Geuting Charlotte Johanna , Morawitz Janna , Dietzel Frederic , Rischpler Christoph , Herrmann Ken , Bittner Ann-Kathrin , Hoffmann Oliver , Mohrmann Svjetlana , Quick Harald H. , Umutlu Lale , Antoch Gerald , Kirchner Julian
Published: July 2022

Purpose: The evaluation of the clinical relevance of missed lung nodules at initial staging of breast cancer patients in [18F]FDG-PET/MRI compared with CT. Methods: A total of 152 patients underwent an initial whole-body [18F]FDG-PET/MRI and a thoracoabdominal CT for staging. Presence, size, shape and location for each lung nodule in [18F]FDG-PET/MRI was noted. The reference standard was established by taking initial CT and follow-up imaging into account (a two-step approach) to identify clinically-relevant lung nodules. Patient-based and lesion-based data analysis was performed. Results: No patient with clinically-relevant lung nodules was missed on a patient-based analysis with MRI VIBE, while 1/84 females was missed with MRI HASTE (1%). Lesion-based analysis revealed 4/96 (4%, VIBE) and 8/138 (6%, HASTE) missed clinically-relevant lung nodules. The average size of missed lung nodules was 3.2 mm ± 1.2 mm (VIBE) and 3.6 mm ± 1.4 mm (HASTE) and the predominant location was in the left lower quadrant and close to the hilum. Conclusion: All patients with newly-diagnosed breast cancer and clinically-relevant lung nodules were detected at initial [18F]FDG-PET/MRI staging. However, due to the lower sensitivity in detecting lung nodules, a small proportion of clinically-relevant lung nodules were missed. Thus, supplemental low-dose chest CT after neoadjuvant therapy should be considered for backup.
Neuropilin-1 as a Potential Biomarker of Prognosis and Invasive-Related Parameters in Liver and Colorectal Cancer: A Systematic Review and Meta-Analysis of Human Studies
Authors: Fernández-Palanca Paula , Payo-Serafín Tania , Fondevila Flavia , Méndez-Blanco Carolina , San-Miguel Beatriz , Romero Marta R. , Tuñón María J. , Marin Jose J. G. , González-Gallego Javier , Mauriz José L.
Published: July 2022

Neuropilin-1 (NRP1) is a transmembrane protein involved in numerous cellular functions which has had increasing interest from cancer researchers. Liver cancer and colorectal cancer (CRC) are two of the most frequent and deadly tumors with a complex pharmacological framework. Here, we assessed the prognostic, diagnostic and clinicopathological value of NRP1 in liver cancer and CRC patients. We searched PubMed, Scopus, Web of Science, Embase and Cochrane Library databases for articles evaluating the NRP1 correlation with survival parameters, tumor development or clinicopathological features. Hazard ratios and odds ratios with 95% confidence intervals were extracted or estimated by Parmar method and pooled to evaluate the overall effect size with STATA 16 software. Heterogeneity was analyzed by chi-square-based Q test and I2 statistic, along with meta-regression and subgroup analysis, and publication bias was assessed by funnel plot asymmetry and Egger’s test. The study protocol was registered in PROSPERO (CRD42022307062). NRP1 overexpression was significantly correlated with lower survival in liver cancer patients and with tumor development in hepatocarcinoma patients, and was strongly correlated with an increased risk of vascular invasion in liver cancer and metastasis in CRC and liver tumors. These results support the role of NRP1 as a potential and useful biomarker in both types of cancer.
Core-Clock Genes Regulate Proliferation and Invasion via a Reciprocal Interplay with MACC1 in Colorectal Cancer Cells
Authors: Basti Alireza , Malhan Deeksha , Dumbani Malti , Dahlmann Mathias , Stein Ulrike , Relógio Angela
Published: July 2022

The circadian clock coordinates the timing of several cellular processes including transcription, the cell cycle, and metabolism. Disruptions in the clock machinery trigger the abnormal regulation of cancer hallmarks, impair cellular homeostasis, and stimulate tumourigenesis. Here we investigated the role of a disrupted clock by knocking out or knocking down the core-clock (CC) genes ARNTL, PER2 or NR1D1 in cancer progression (e.g., cell proliferation and invasion) using colorectal cancer (CRC) cell lines HCT116, SW480 and SW620, from different progression stages with distinct clock phenotypes, and identified mechanistic links from the clock to altered cancer-promoting cellular properties. We identified MACC1 (metastasis-associated in colon cancer 1), a known driver for metastasis and an EMT (epithelial-to-mesenchymal transition)-related gene, to be significantly differentially expressed in CC manipulated cells and analysed the effect of MACC1 manipulation (knockout or overexpression) in terms of circadian clock phenotype as well as cancer progression. Our data points to a bi-directional MACC1-circadian clock interplay in CRC, via CC genes. In particular, knocking out MACC1 reduced the period of oscillations, while its overexpression increased it. Interestingly, we found the MACC1 protein to be circadian expressed in HCT116 WT cells, which was disrupted after the knockout of CC genes, and identified a MACC1-NR1D1 protein–protein interaction. In addition, MACC1 manipulation and CC knockout altered cell invasion properties of HCT116 cells, pointing to a regulation of clock and cancer progression in CRC, possibly via the interaction of MACC1 with core-clock genes.
Autophagy-Related Gene Signature Highlights Metabolic and Immunogenic Status of Malignant Cells in Non-Small Cell Lung Cancer Adenocarcinoma
Authors: Leonardi Lucas , Siberil Sophie , Alifano Marco , Cremer Isabelle , Joubert Pierre-Emmanuel
Published: July 2022

Autophagy is a self-degradative mechanism involved in many biological processes, including cell death, survival, proliferation or migration. In tumors, autophagy plays an important role in tumorigenesis as well as cancer progression and resistance to therapies. Usually, a high level of autophagy in malignant cells has been associated with tumor progression and poor prognostic for patients. However, the investigation of autophagy levels in patients remains difficult, especially because quantification of autophagy proteins is challenging in the tumor microenvironment. In this study, we analyzed the expression of autophagy genes in non-small cell lung (NSCLC) cancer patients using public datasets and revealed an autophagy gene signature for proliferative and immune-checkpoint-expressed malignant cells in lung adenocarcinoma (LUAD). Analysis of autophagy-related gene expression profiles in tumor and adjacent tissues revealed differential signatures, namely signature A (23 genes) and signature B (12 genes). Signature B correlated with a bad prognosis and poor overall and disease-specific survival. Univariate and multivariate analyses revealed that this signature was an independent factor for prognosis. Moreover, patients with high expression of signature B exhibited more genes related to proliferation and fewer genes related to immune cells or immune response. The analysis of datasets from sorted fresh tumor cells or single cells revealed that signature B is predominantly represented in malignant cells, with poor expression in pan-immune population or in fibroblast or endothelial cells. Interestingly, autophagy was increased in malignant cells exhibiting high levels of signature B, which correlated with an elevated expression of genes involved in cell proliferation and immune checkpoint signaling. Taken together, our analysis reveals a novel autophagy-based signature to define the metabolic and immunogenic status of malignant cells in LUAD.
Brain Gliomas and Ollier Disease: Molecular Findings as Predictive Risk Factors?
Authors: Corvino Sergio , Mariniello Giuseppe , Corazzelli Giuseppe , Franca Raduan Ahmed , Del Basso De Caro Marialaura , Della Monica Rosa , Chiariotti Lorenzo , Maiuri Francesco
Published: July 2022

Background: Ollier disease (OD) is a rare nonhereditary type of dyschondroplasia characterized by multiple enchondromas, with typical onset in the first decade of life. Surgery is the only curative treatment for primary disease and its complications. Patients with OD are at risk of malignant transformation of enchondromas and of occurrence of other neoplasms. Methods: A wide literature review disclosed thirty cases of glioma associated with OD, most of them belonging to the pre-molecular era. Our own case was also included. Demographic, clinical, pathologic, molecular, management, and outcome data were analyzed and compared to those of sporadic gliomas. Results: Gliomas associated with OD more frequently occur at younger age, present higher rates of multicentric lesions (49%), brainstem localizations (29%), and significantly lower rates of glioblastomas (7%) histotype. The IDH1 R132H mutation was detected in 80% of gliomas of OD patients and simultaneously in enchondromas and gliomas in 100% of cases. Conclusions: The molecular data suggest a higher risk of occurrence of glioma in patients with enchondromas harboring the IDH1 R132H mutation than those with the IDH1 R132C mutation. Thus, we suggest considering the IDH1 R132H mutation in enchondromas of patients with OD as a predictive risk factor of occurrence of glioma.
Prognostic Impact of Lymphatic Invasion in Patients with High-Risk Prostate Cancer after Robot-Assisted Radical Prostatectomy and Extended Lymph Node Dissection: A Single-Institution Prospective Cohort Study
Authors: Yamashita Shimpei , Muraoka Satoshi , Wakamiya Takahito , Kikkawa Kazuro , Kohjimoto Yasuo , Hara Isao
Published: July 2022

The prognostic impact of lymphatic invasion in patients with high-risk prostate cancer (PC) remains unclear. The aim of our single-institution prospective cohort study was to examine the impact of lymphatic invasion on biochemical recurrence (BCR) in patients with high-risk PC according to National Comprehensive Cancer Network (NCCN) criteria who underwent robot-assisted radical prostatectomy (RARP) and extended lymph node dissection (eLND). A total of 183 patients were included who underwent RARP and eLND for NCCN high-risk PC between June 2014 and August 2019. Lymphatic invasion in resected specimens was observed in 47 patients (26%), whereas lymph node metastasis was observed in 17 patients (9%). During follow-up, BCR was observed in 48 patients (26%). The BCR rate in patients with lymphatic invasion was significantly higher than that in patients without lymphatic invasion (p < 0.01). According to multivariable Cox proportional hazards regression analyses, lymphatic invasion was a significant independent predictor of BCR in the overall patient group and was independently associated with BCR, even in patients without lymph node metastasis. In conclusion, evaluation of lymphatic invasion could be useful in predicting BCR in patients undergoing RARP and eLND for high-risk PC.
Association between Metabolic Disorders and Cholangiocarcinoma: Impact of a Postulated Risk Factor with Rising Incidence
Authors: Da Fonseca Leonardo G. , Hashizume Pedro H. , de Oliveira Irai Santana , Izquierdo-Sanchez Laura , Saud Lisa Rodrigues da Cunha , Xerfan Mariana Pinheiro , Alves Venancio Avancini Ferreira , de Mello Evandro Sobroza , Herman Paulo , Banales Jesus M. , Oliveira Claudia P. , Carrilho Flair J.
Published: July 2022

Introduction and objectives: The incidence of cholangiocarcinoma (CCA) has been increasing globally. Although a concomitant increase in the incidence of metabolic disorders might suggest a causal relationship, the data are scarce. We aimed to describe the prevalence of metabolic disorders in patients with CCA and report the clinical features and outcomes. Patients and Methods: Retrospective study including patients with CCA. Patients were divided into: (1) past history of diabetes or/and overweight/obesity (“metabolic disorder group”) and (2) without any of these features (“non-metabolic-disorder group”). A Cox regression model was used to determine the prognostic factors. Results: 122 patients were included. In total, 36 (29.5%) had overweight/obesity, 24 (19.7%) had diabetes, and 8 (6.6%) had both. A total of 29 (23.8%) patients had resectable disease and received upfront surgery. A total of 104 (85.2%) received chemotherapy for advanced/recurrent disease. The overall survival of the cohort was 14.3 months (95% CI: 10.1–17.3). ECOG-PS 0 (p < 0.0001), resectable disease (p = 0.018) and absence of vascular invasion (p = 0.048) were independently associated with better prognosis. The “metabolic disorder group” (n = 52) had a median survival of 15.5 months (95% CI 10.9–33.9) vs. 11.5 months (95% CI 8.4–16.5) in the “non-metabolic-disorder group” (n = 70) (HR: 1.10; 95% CI 0.62–1.94). Patients with resectable disease in the “metabolic group” had longer survival than patients in the “non-metabolic group” (43.4 months (95% CI 33.9-NR) vs. 21.8 months (95% CI 8.6–26.9); HR = 0.12, 95% CI 0.03–0.59). Conclusion: Metabolic disorders are frequent among CCA patients. Underlying metabolic comorbidities may be associated with prognosis in resectable CCA. There is a need to explore the mechanism that drives CCA carcinogenesis in a metabolic background.
Identification and Characterization of Cancer-Associated Fibroblast Subpopulations in Lung Adenocarcinoma
Authors: Kim Daeseung , Kim Jeong Seon , Cheon Inyoung , Kim Seo Ree , Chun Sang Hoon , Kim Jae Jun , Lee Sieun , Yoon Jung Sook , Hong Soon Auck , Won Hye Sung , Kang Keunsoo , Ahn Young-Ho , Ko Yoon Ho
Published: July 2022

Cancer-associated fibroblasts (CAFs) reside within the tumor microenvironment, facilitating cancer progression and metastasis via direct and indirect interactions with cancer cells and other stromal cell types. CAFs are composed of heterogeneous subpopulations of activated fibroblasts, including myofibroblastic, inflammatory, and immunosuppressive CAFs. In this study, we sought to identify subpopulations of CAFs isolated from human lung adenocarcinomas and describe their transcriptomic and functional characteristics through single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatics analyses. Cell trajectory analysis of combined total and THY1 + CAFs revealed two branching points with five distinct branches. Based on Gene Ontology analysis, we denoted Branch 1 as “immunosuppressive”, Branch 2 as “neoantigen presenting”, Branch 4 as “myofibroblastic”, and Branch 5 as “proliferative” CAFs. We selected representative branch-specific markers and measured their expression levels in total and THY1 + CAFs. We also investigated the effects of these markers on CAF activity under coculture with lung cancer cells. This study describes novel subpopulations of CAFs in lung adenocarcinoma, highlighting their potential value as therapeutic targets.
N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication
Authors: Chen Danyu , Cheung Henley , Lau Harry Cheuk-Hay , Yu Jun , Wong Chi Chun
Published: July 2022

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic cell mRNA, and this modification plays a key role in regulating mRNA translation, splicing, and stability. Emerging evidence implicates aberrant m6A as a crucial player in the occurrence and development of diseases, especially GI cancers. Among m6A regulators, YTHDF1 is the most abundant m6A reader that functionally connects m6A-modified mRNA to its eventual fate, mostly notably protein translation. Here, we summarized the function, molecular mechanisms, and clinical implications of YTHDF1 in GI cancers. YTHDF1 is largely upregulated in multiple GI cancer and its high expression predicts poor patient survival. In vitro and in vivo experimental evidence largely supports the role of YTDHF1 in promoting cancer initiation, progression, and metastasis, which suggests the oncogenic function of YTHDF1 in GI cancers. Besides, YTHDF1 overexpression is associated with changes in the tumor microenvironment that are favorable to tumorigenesis. Mechanistically, YTHDF1 regulates the expression of target genes by promoting translation, thereby participating in cancer-related signaling pathways. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy. In summary, YTHDF1-mediated regulation of m6A modified mRNA is an actionable target and a prognostic factor for GI cancers.
Guanidine–Curcumin Complex-Loaded Amine-Functionalised Hollow Mesoporous Silica Nanoparticles for Breast Cancer Therapy
Authors: Viswanathan Thimma Mohan , Chitradevi Kaniraja , Zochedh Azar , Vijayabhaskar Ramakrishnan , Sukumaran Sureba , Kunjiappan Selvaraj , Kumar Nachimuthu Senthil , Sundar Krishnan , Babkiewicz Ewa , Maszczyk Piotr , Kathiresan Thandavarayan
Published: July 2022

The current study focuses on developing a tumour-targeted functionalised nanocarrier that wraps hollow mesoporous silica nanoparticles. The guanidine carbonate and curcumin are immobilised on the surface of 3-aminopropyl-triethoxy silane (APTES)-decorated hollow mesoporous silica nanoparticles (HMSNP), as confirmed through XPS and NMR analysis. XPS analysis demonstrates that the shape of the hysteresis loops is modified and that pore volume and pore diameter are consequently decreased compared to control. Guanidine (85%) and guanidine–curcumin complex (90%) were successfully encapsulated in HMSNAP and showed a 90% effective and sustained release at pH 7.4 for up to 72 h. Acridine orange/ethidium bromide dual staining determined that GuC-HMNSAP induced more late apoptosis and necrosis at 48 and 72 h compared with Gu-HMNSAP-treated cells. Molecular investigation of guanidine-mediated apoptosis was analysed using western blotting. It was found that cleaved caspases, c-PARP, and GSK-3β (Ser9) had increased activity in MCF-7 cells. GuC-HMSNAP increased the activity of phosphorylation of oncogenic proteins such as Akt (Ser473), c-Raf (Ser249), PDK1 (Ser241), PTEN (Ser380), and GSK-3β (Ser9), thus inducing cell death in MCF-7 cells. Altogether, our findings confirm that GuC-HMNSAP induces cell death by precisely associating with tumour-suppressing proteins, which may lead to new therapeutic approaches for breast cancer therapy.
Automated Pupillometry as an Assessment Tool for Intracranial Hemodynamics in Septic Patients
Authors: Crippa Ilaria Alice , Pelosi Paolo , Quispe-Cornejo Armin Alvaro , Messina Antonio , Corradi Francesco , Taccone Fabio Silvio , Robba Chiara
Published: July 2022

Impaired cerebral autoregulation (CA) may increase the risk of brain hypoperfusion in septic patients. Sepsis dysregulates the autonomic nervous system (ANS), potentially affecting CA. ANS function can be assessed through the pupillary light reflex (PLR). The aim of this prospective, observational study was to investigate the association between CA and PLR in adult septic patients. Transcranial Doppler was used to assess CA and calculate estimated cerebral perfusion pressure (eCPP) and intracranial pressure (eICP). An automated pupillometer (AP) was used to record Neurological Pupil Index (NPi), constriction (CV) and dilation (DV) velocities. The primary outcome was the relationship between AP-derived variables with CA; the secondary outcome was the association between AP-derived variables with eCPP and/or eICP. Among 40 included patients, 21 (53%) had impaired CA, 22 (55%) had low eCPP (<60 mmHg) and 15 (38%) had high eICP (>16 mmHg). DV was lower in patients with impaired CA compared to others; DV predicted impaired CA with area under the curve, AUROC= 0.78 [95% Confidence Interval, CI 0.63–0.94]; DV < 2.2 mm/s had sensitivity 85% and specificity 69% for impaired CA. Patients with low eCPP or high eICP had lower NPi values than others. NPi was correlated with eCPP (r = 0.77, p < 0.01) and eICP (r = −0.87, p < 0.01). Automated pupillometry may play a role to assess brain hemodynamics in septic patients.
Oxidative Glucose Metabolism Promotes Senescence in Vascular Endothelial Cells
Authors: Stabenow Leonie K. , Zibrova Darya , Ender Claudia , Helbing Dario L. , Spengler Katrin , Marx Christian , Wang Zhao-Qi , Heller Regine
Published: July 2022

Vascular aging is based on the development of endothelial dysfunction, which is thought to be promoted by senescent cells accumulating in aged tissues and is possibly affected by their environment via inflammatory mediators and oxidative stress. Senescence appears to be closely interlinked with changes in cell metabolism. Here, we describe an upregulation of both glycolytic and oxidative glucose metabolism in replicative senescent endothelial cells compared to young endothelial cells by employing metabolic profiling and glucose flux measurements and by analyzing the expression of key metabolic enzymes. Senescent cells exhibit higher glycolytic activity and lactate production together with an enhanced expression of lactate dehydrogenase A as well as increases in tricarboxylic acid cycle activity and mitochondrial respiration. The latter is likely due to the reduced expression of pyruvate dehydrogenase kinases (PDHKs) in senescent cells, which may lead to increased activity of the pyruvate dehydrogenase complex. Cellular and mitochondrial ATP production were elevated despite signs of mitochondrial dysfunction, such as an increased production of reactive oxygen species and extended mitochondrial mass. A shift from glycolytic to oxidative glucose metabolism induced by pharmacological inhibition of PDHKs in young endothelial cells resulted in premature senescence, suggesting that alterations in cellular glucose metabolism may act as a driving force for senescence in endothelial cells.
A Method for Bridging Population-Specific Genotypes to Detect Gene Modules Associated with Alzheimer’s Disease
Authors: Dai Yulin , Jia Peilin , Zhao Zhongming , Gottlieb Assaf
Published: July 2022

Background: Genome-wide association studies have successfully identified variants associated with multiple conditions. However, generalizing discoveries across diverse populations remains challenging due to large variations in genetic composition. Methods that perform gene expression imputation have attempted to address the transferability of gene discoveries across populations, but with limited success. Methods: Here, we introduce a pipeline that combines gene expression imputation with gene module discovery, including a dense gene module search and a gene set variation analysis, to address the transferability issue. Our method feeds association probabilities of imputed gene expression with a selected phenotype into tissue-specific gene-module discovery over protein interaction networks to create higher-level gene modules. Results: We demonstrate our method’s utility in three case-control studies of Alzheimer’s disease (AD) for three different race/ethnic populations (Whites, African descent and Hispanics). We discovered 182 AD-associated genes from gene modules shared between these populations, highlighting new gene modules associated with AD. Conclusions: Our innovative framework has the potential to identify robust discoveries across populations based on gene modules, as demonstrated in AD.
Craniofacial Sleep Medicine: The Important Role of Dental Providers in Detecting and Treating Sleep Disordered Breathing in Children
Authors: Heit Tammarie , Tablizo Bea Janine , Salud Martina , Mo Fan , Kang Mandip , Tablizo Mary Anne , Witmans Manisha
Published: July 2022

Obstructive sleep apnea (OSA) is a clinical disorder within the spectrum of sleep-related breathing disorders (SRDB) which is used to describe abnormal breathing during sleep resulting in gas exchange abnormalities and/or sleep disruption. OSA is a highly prevalent disorder with associated sequelae across multiple physical domains, overlapping with other chronic diseases, affecting development in children as well as increased health care utilization. More precise and personalized approaches are required to treat the complex constellation of symptoms with its associated comorbidities since not all children are cured by surgery (removal of the adenoids and tonsils). Given that dentists manage the teeth throughout the lifespan and have an important understanding of the anatomy and physiology involved with the airway from a dental perspective, it seems reasonable that better understanding and management from their field will give the opportunity to provide better integrated and optimized outcomes for children affected by OSA. With the emergence of therapies such as mandibular advancement devices and maxillary expansion, etc., dentists can be involved in providing care for OSA along with sleep medicine doctors. Furthermore, the evolving role of myofunctional therapy may also be indicated as adjunctive therapy in the management of children with OSA. The objective of this article is to discuss the important role of dentists and the collaborative approach between dentists, allied dental professionals such as myofunctional therapists, and sleep medicine specialists for identifying and managing children with OSA. Prevention and anticipatory guidance will also be addressed.
Impact of Quality Improvement Bundle on Neonatal Mortality in a District Hospital in Tanzania
Authors: Pietravalle Andrea , Brasili Luca , Cavallin Francesco , Piquè Margherita , Zavattero Chiara , Azzimonti Gaetano , Maziku Donald Micah , Leluko Dionis Erasto , Putoto Giovanni , Trevisanuto Daniele
Published: July 2022

Background: The poor quality of care received by mothers and neonates in many limited-resource countries represents a main determinant of newborn mortality. Small and sick hospitalized newborns are the highest-risk population, and they should be one of the prime beneficiaries of quality-of-care interventions. This study aimed to evaluate the impact on neonatal mortality of quality improvement interventions which were implemented at Tosamaganga Council Designated Hospital, Iringa, Tanzania, between 2016 and 2020. Methods: A retrospective comparison between pre- and post-intervention periods was performed using the chi-square test and Fisher’s exact test. Effect sizes were reported as odds ratios with 95% confidence intervals. Results: The analysis included 5742 neonates admitted to the Special Care Unit (2952 in the pre-intervention period and 2790 in the post-intervention period). A decrease in mortality among infants with birth weight between 1500 and 2499 g (overall: odds ratio 0.49, 95% confidence interval 0.27–0.87; inborn: odds ratio 0.50, 95% confidence interval 0.27–0.93) was found. The analysis of cause-specific mortality showed a decrease in mortality for asphyxia (odds ratio 0.33, 95% confidence interval 0.12–0.87) among inborn infants with birth weight between 1500 and 2499 g. Conclusions: A quality improvement intervention was associated with decreased mortality among infants with birth weight between 1500 and 2499 g. Further efforts are needed to improve prognosis in very-low-birth-weight infants.
Global Irradiation in Children Treated for Hydrocephalus and Its Change over Time—A Single Institutional Analysis
Authors: Schabl Lukas , Küppers Julia , Jhala Tobias , Winicker Hermann , Esslinger Peter , Lehner Markus
Published: July 2022

Radiation exposure early in life is associated with greater incidences of malignancy. Our goal was to quantify radiation exposure in shunt-treated hydrocephalus patients and study changes in the diagnostic modalities used. A single-center, retrospective analysis was performed, and 41 children treated for hydrocephalus using an adjustable ventriculoperitoneal shunt were identified. Diagnostics associated with hydrocephalus and other comorbidities were analyzed and radiation exposure was calculated. During 330.09 total shunt years, patients were exposed to a mean hydrocephalus-associated radiation dose of 3.93 mSv (range: 0–24.38 mSv), which amounted to a mean rate of 0.49 mSv per shunt year, respectively. Radiation exposure was greatest after shunt insertion in the first year of life. A continuous change from CT scans to MRIs could be seen over the study period, such that patients who underwent shunt insertion after 2017 were not exposed to additional hydrocephalus-associated radiation during their first year of life. Nevertheless, our patients, and a few individuals especially, seemed to be at higher risk for radiation sequelae. Our results suggest that CT scans should be substituted with MRIs, which decrease overall radiation exposure and can lead to zero additional radiation exposure during the first year of life after shunt insertion.