bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Polymorphisms of ACE1 Rs4646994 Associated with Lung Cancer in Patients with Pulmonary Nodules: A Case–Control Study
Authors: Qiao Rong , Sang Siyao , Teng Jiajun , Zhong Hua , Li Hui , Han Baohui
Published: May 2023

Background: Currently, many detection methods have high sensitivity to the diagnosis of lung cancer. However, some postoperative patients with pulmonary nodules are eventually diagnosed as having benign nodules. The ideal evaluation of an individual with a pulmonary nodule would expedite therapy for a malignant nodule and minimize testing for those with a benign nodule. Methods: This case–control study is designed to explore the relationship between ACE1 rs4646994 polymorphism and the risk of lung cancer in patients with pulmonary nodules, for which 400 individuals with lung cancer and benign pulmonary nodules were included. A DNA extraction kit was used to extract DNA from peripheral blood. The relationship between ACE1 rs4646994 and the risk of lung cancer in patients with pulmonary nodules was determined by the chi-square test, logistic regression analysis and cross analysis. Results: The results showed that after adjusting for age and gender confounding factors, the risk of lung cancer in patients with pulmonary nodules carrying the DD genotype was more than three times that of the I carriers (II + ID) genotype (OR = 3.035, 95% CI, 1.252–7.356, p = 0.014). There was no significant difference between lung squamous cell carcinoma and lung adenocarcinoma in the polymorphism of ACE1 rs4646994 (p > 0.05). We also found that the ACE1 rs4646994 DD genotype frequency was inversely correlated with the risk of EGFR mutation in lung adenocarcinoma patients. Conclusions: Our study indicated that ACE1 rs4646994 polymorphism increases the risk of lung cancer in patients with pulmonary nodules from China.
Advances in the Therapeutic Applications of Plant-Derived Exosomes in the Treatment of Inflammatory Diseases
Authors: Wei Xiaofang , Li Xiuyu , Zhang Yuejun , Wang Jian , Shen Shuibao
Published: May 2023

Plant-derived exosomes (PLDEs) are small extracellular vesicles that encapsulate proteins, nucleic acids and lipids, and they are usually involved in intercellular communication and molecular transport in plants. PLDEs are widely used in the therapy of diseases due to their abundance and easy availability. The diverse roles of PLDEs, which include transportation of drugs, acting as biomarkers for diagnosis of diseases and their roles in different therapies, suggest that there is a need to fully understand all the mechanisms involved in order to provide the optimum conditions for their therapeutic use. This review summarizes the biogenesis, components and functions of PLDEs and focuses on their use as therapeutic agents in the treatment of inflammatory diseases. It also explores new ideas for novel approaches in which PLDEs could potentially help patients with inflammatory diseases in the future.
Elevated Serum Urea-to-Creatinine Ratio and In-Hospital Death in Patients with Hyponatremia Hospitalized for COVID-19
Authors: Regolisti Giuseppe , Rebora Paola , Occhino Giuseppe , Lieti Giulia , Molon Giulio , Maloberti Alessandro , Algeri Michela , Giannattasio Cristina , Valsecchi Maria Grazia , Genovesi Simonetta
Published: May 2023

Hyponatremia is associated with adverse outcomes in hospitalized patients. An elevated value of the serum urea-to-creatinine ratio (UCR) has been proposed as a proxy of hypovolemia. The aim of this study was to investigate the relationship between the UCR and in-hospital death in patients hospitalized with COVID-19 and hyponatremia. We studied 258 patients admitted for COVID-19 between January 2020 and May 2021 with serum sodium at < 135 mmol/L. The primary end-point was all-cause mortality. A 5-unit increase in the serum UCR during hospital stays was associated with an 8% increase in the hazard of all-cause death (HR = 1.08, 95% CI: 1.03–1.14, p = 0.001) after adjusting for potential confounders. In patients with a UCR > 40 at baseline, a > 10 mmol/L increase in serum sodium values within the first week of hospitalization was associated with higher odds of in-hospital death (OR = 2.93, 95% CI: 1.03–8.36, p = 0.044) compared to patients who experienced a < 10 mmol/L change. This was not observed in patients with a UCR < 40. Hypovolemia developing during hospital stays in COVID-19 patients with hyponatremia detected at hospital admission bears an adverse prognostic impact. Moreover, in hypovolemic patients, a > 10 mmol/L increase in serum sodium within the first week of hospital stays may further worsen the in-hospital prognosis.
Beyond the Microbiota: Understanding the Role of the Enteric Nervous System in Parkinson’s Disease from Mice to Human
Authors: Montanari Martina , Imbriani Paola , Bonsi Paola , Martella Giuseppina , Peppe Antonella
Published: May 2023

The enteric nervous system (ENS) is a nerve network composed of neurons and glial cells that regulates the motor and secretory functions of the gastrointestinal (GI) tract. There is abundant evidence of mutual communication between the brain and the GI tract. Dysfunction of these connections appears to be involved in the pathophysiology of Parkinson’s disease (PD). Alterations in the ENS have been shown to occur very early in PD, even before central nervous system (CNS) involvement. Post-mortem studies of PD patients have shown aggregation of α-synuclein (αS) in specific subtypes of neurons in the ENS. Subsequently, αS spreads retrogradely in the CNS through preganglionic vagal fibers to this nerve’s dorsal motor nucleus (DMV) and other central nervous structures. Here, we highlight the role of the ENS in PD pathogenesis based on evidence observed in animal models and using a translational perspective. While acknowledging the putative role of the microbiome in the gut–brain axis (GBA), this review provides a comprehensive view of the ENS not only as a “second brain”, but also as a window into the “first brain”, a potentially crucial element in the search for new therapeutic approaches that can delay and even cure the disease.
Suppressing Inflammation for the Treatment of Diabetic Retinopathy and Age-Related Macular Degeneration: Dazdotuftide as a Potential New Multitarget Therapeutic Candidate
Authors: Vofo Brice Nguedia , Chowers Itay
Published: May 2023

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are major causes of blindness globally. The primary treatment option for DME and neovascular AMD (nAMD) is anti-vascular endothelial growth factor (VEGF) compounds, but this treatment modality often yields insufficient results, and monthly injections can place a burden on the health system and patients. Although various inflammatory pathways and mediators have been recognized as key players in the development of DR and AMD, there are limited treatment options targeting these pathways. Molecular pathways that are interlinked, or triggers of multiple inflammatory pathways, could be promising targets for drug development. This review focuses on the role of inflammation in the pathogenesis of DME and AMD and presents current anti-inflammatory compounds, as well as a potential multitarget anti-inflammatory compound (dazdotuftide) that could be a candidate treatment option for the management of DME and AMD.
Topical Application of No-Ozone Cold Plasma in Combination with Vitamin C Reduced Skin Redness and Pigmentation of UV-Irradiated Mice
Authors: Nam Seoul-Hee , Choi Jeong-Hae , Kim Gyoo-Cheon
Published: May 2023

Ultraviolet (UV) is the main cause of sunburn on the skin as it induces erythema and accelerates pigmentation. Vitamin C is one of the most frequently used compounds to reduce UV-induced skin pigmentation, but it has limitations in absorption through the skin. In this study, we tested whether a no-ozone cold plasma (NCP) treatment can improve UV-irradiated skin by helping the action of Vitamin C. For this, among five groups of HRM-2 hairless mice, four groups of mice were subjected to UVB irradiation, and three groups of UVB-treated mice were treated with NCP, Vitamin C, and NCP + Vitamin C, respectively. For evaluating the effect of each treatment, the melanin and erythema index was measured during animal experiments. Histological changes were monitored by performing H&E and MTS and IHC against tyrosinase and melanin. As a result, the naturally recovered mice showed a 28-point decrease in the melanin index, whereas a decrease of around 88, 74.3, and 106 points was detected in NCP-, Vitamin C-, and NCP + vitamin C-treated mice, respectively. Likewise, only a 39-point reduction in the erythema index was monitored in naturally recovered mice, but the NCP-, vitamin C-, and NCP + vitamin C-treated mice showed a 87.3-, 77-, and 111-point reduction, respectively. Interestingly, the skin tissues of the mice treated with NCP in combination with Vitamin C mostly recovered from UVB-induced damage. Altogether, this study elucidated the beneficial effect of the treatment of NCP in combination with Vitamin C on the UVB-irradiated skin, which might be helpful for treating sunburn on the skin.
Development of a Redox-Polymer-Based Electrochemical Glucose Biosensor Suitable for Integration in Microfluidic 3D Cell Culture Systems
Authors: Navarro-Nateras L. , Diaz-Gonzalez Jancarlo , Aguas-Chantes Diana , Coria-Oriundo Lucy L. , Battaglini Fernando , Ventura-Gallegos José Luis , Zentella-Dehesa Alejandro , Oza Goldie , Arriaga L. G. , Casanova-Moreno Jannu R.
Published: May 2023

The inclusion of online, in situ biosensors in microfluidic cell cultures is important to monitor and characterize a physiologically mimicking environment. This work presents the performance of second-generation electrochemical enzymatic biosensors to detect glucose in cell culture media. Glutaraldehyde and ethylene glycol diglycidyl ether (EGDGE) were tested as cross-linkers to immobilize glucose oxidase and an osmium-modified redox polymer on the surface of carbon electrodes. Tests employing screen printed electrodes showed adequate performance in a Roswell Park Memorial Institute (RPMI-1640) media spiked with fetal bovine serum (FBS). Comparable first-generation sensors were shown to be heavily affected by complex biological media. This difference is explained in terms of the respective charge transfer mechanisms. Under the tested conditions, electron hopping between Os redox centers was less vulnerable than H2O2 diffusion to biofouling by the substances present in the cell culture matrix. By employing pencil leads as electrodes, the incorporation of these electrodes in a polydimethylsiloxane (PDMS) microfluidic channel was achieved simply and at a low cost. Under flow conditions, electrodes fabricated using EGDGE presented the best performance with a limit of detection of 0.5 mM, a linear range up to 10 mM, and a sensitivity of 4.69 μA mM−1 cm−2.
Comorbidity and Overlaps between Autism Spectrum and Borderline Personality Disorder: State of the Art
Authors: Dell’Osso Liliana , Cremone Ivan Mirko , Nardi Benedetta , Tognini Valeria , Castellani Lucrezia , Perrone Paola , Amatori Giulia , Carpita Barbara
Published: May 2023

Despite the relationship between Autism spectrum disorder (ASD) and personality disorders (PD) still being scarcely understood, recent investigations increased awareness about significant overlaps between some PD and autism spectrum conditions. In this framework, several studies suggested the presence of similarities between BPD and ASD symptoms and traits, based on the recent literature that increasingly reported increased comorbidity rates and significant symptomatologic overlaps between the two conditions. The aim of this review is to describe the available studies about the prevalence of the association between different forms of autism spectrum (full-fledged clinical conditions as well as subthreshold autistic traits) and BPD. Despite some controversial results and lack of homogeneity in the methods used for the diagnostic assessment, the reviewed literature highlighted how subjects with BPD reported higher scores on tests evaluating the presence of AT compared to a non-clinical population and hypothesized the presence of unrecognized ASD in some BPD patients or vice versa, while also describing a shared vulnerability towards traumatic events, and a greater risk of suicidality in BPD subjects with high autistic traits. However, the specific measure and nature of this association remain to be explored in more depth.
Inducible Knockout of 14-3-3β Attenuates Proliferation and Spheroid Formation in a Human Glioblastoma Cell Line U87MG
Authors: Gallo Kellie , Srinageshwar Bhairavi , Ward Avery , Diola Carlos , Dunbar Gary , Rossignol Julien , Bakke Jesse
Published: May 2023

Glioblastomas (GBs) are the most common and malignant brain tumors in adults. A protein encoded by the gene YWHAB, 14-3-3β, is commonly found to be upregulated throughout the initiation and progression of GB. The 14-3-3β has oncogenic roles in several different types of cancer cells through interactions with proteins such as Bad, FBI1, Raf-1, Cdc25b, and others. Previous RNA interference studies have shown that 14-3-3β promotes proliferation, cell cycle progression, and migration and invasion of GB cells. However, despite the many oncogenic functions of 14-3-3β, a CRISPR/Cas9 knockout model of 14-3-3β has not been investigated. This study confirmed previous findings and showed that siRNA inhibition of 14-3-3β results in reduced cellular proliferation in a human glioblastoma cell line, U87MG. We also used a YWHAB Tet-On CRISPR/Cas9 U87MG cell line that, upon doxycycline induction, leads to robust Cas9 expression and subsequent knockout of 14-3-3β. Using this model, we show that loss of 14-3-3β significantly reduces cellular proliferation and spheroid formation of U87MG cells.
Analysis of Typical Layout of Apartment Buildings in Indonesia
Authors: Prasetya Andhika , Ho Anh Dung , Kubota Tetsu
Published: May 2023

It is important to determine typical layouts of residential buildings, even in developing countries for standardization towards a zero-carbon society. In Indonesia, housing development in cities continues rising in parallel with high urbanization rates. This study aims to determine the typical layouts of apartments in Indonesia through qualitative and quantitative building typological analyses. A hierarchical cluster analysis was conducted using the building drawing information constructed across Indonesia from 1986 to 2021. A total of 268 public apartments and 268 private apartments from several major cities were included in the datasets, respectively. As a result, six typical layouts for public apartments and thirteen typical layouts for private apartments were determined for both 1BR and 2BR units. Furthermore, four typical unit layouts from public and private apartments associated with building-scale classifications were proposed, respectively, as the base models for the current typical apartments in Indonesia. The results showed that Indonesian public apartments tended to sacrifice semi-open spaces, such as a wide corridor and an internal void space, to increase the size of units and the number of rooms. Meanwhile, most private apartments were constructed with double-loaded corridor systems without internal voids, which potentially cause poor natural ventilation. The proposed typical layouts will be useful for further building simulations as standard testing models, such as to determine the appropriate cooling techniques for low-carbon apartments.
Development, Calibration, and Validation of a Simulation Model for Indoor Temperature Prediction and HVAC System Fault Detection
Authors: Palaić Darko , Štajduhar Ivan , Ljubic Sandi , Wolf Igor
Published: May 2023

An effective approach to increasing energy efficiency in buildings without compromising thermal comfort is to optimize heating, ventilation, and air conditioning (HVAC) systems through the use of advanced building-management system features, such as fault detection and diagnosis. Such functions are usually developed based on simulation models that must be calibrated and validated to achieve an appropriate level of accuracy and reliability. The objective of this study was to develop and calibrate a room-level simulation model of a hotel building and its HVAC system using TRNSYS 18 software and real data collected from the smart room system installed in the building. The calibration process was performed with 100 rooms using 5-min samples of room temperatures in selected 1-month periods during the summer and winter seasons by minimizing the root mean squared error (RMSE) in the average of the observed rooms using a genetic algorithm. The calibrated model was able to predict room temperatures with an RMSE of 0.79 ± 0.14 °C and a coefficient of variation in the root mean squared error (cvRMSE) of 3.58 ± 0.7%, which is well below the limits prescribed by international guidelines. The model was then applied to detect faults in the operation of fan coil units in the rooms based on the residual analysis and defined if–then rules. The results obtained show that the model can track the trends of temperature changes in real conditions and successfully detect major anomalies in a system.
Application of Minnan Folk Light and Shadow Animation in Built Environment in Object Detection Algorithm
Authors: Wu Sichao , Huang Xiaoyu , Xiong Yiqi , Wu Shengzhen , Li Enlong , Pan Chen
Published: May 2023

To resolve the problems of deep convolutional neural network models with many parameters and high memory resource consumption, a lightweight network-based algorithm for building detection of Minnan folk light synthetic aperture radar (SAR) images is proposed. Firstly, based on the rotating target detection algorithm R-centernet, the Ghost ResNet network is constructed to reduce the number of model parameters by replacing the traditional convolution in the backbone network with Ghost convolution. Secondly, a channel attention module integrating width and height information is proposed to enhance the network’s ability to accurately locate salient regions in folk light images. Content-aware reassembly of features (CARAFE) up-sampling is used to replace the deconvolution module in the network to fully incorporate feature map information during up-sampling to improve target detection. Finally, the constructed dataset of rotated and annotated light and shadow SAR images is trained and tested using the improved R-centernet algorithm. The experimental results show that the improved algorithm improves the accuracy by 3.8%, the recall by 1.2% and the detection speed by 12 frames/second compared with the original R-centernet algorithm.
Early Prediction of Response Focused on Tumor Markers in Atezolizumab plus Bevacizumab Therapy for Hepatocellular Carcinoma
Authors: Tanabe Norikazu , Saeki Issei , Aibe Yuki , Matsuda Takashi , Hanazono Tadasuke , Nishi Maiko , Hidaka Isao , Kuwashiro Shinya , Shiratsuki Shogo , Matsuura Keiji , Egusa Maho , Nishiyama Natsuko , Fujioka Tsuyoshi , Kawamoto Daiki , Sasaki Ryo , Nishimura Tatsuro , Oono Takashi , Hisanaga Takuro , Matsumoto Toshihiko , Ishikawa Tsuyoshi , Yamasaki Takahiro , Takami Taro
Published: May 2023

Despite the promising efficacy of atezolizumab plus bevacizumab (atezo/bev), some patients with unresectable hepatocellular carcinoma (HCC) experience disease progression. This retrospective study, which included 154 patients, aimed to evaluate predictors of treatment efficacy of atezo/bev for unresectable HCC. Factors associated with treatment response were examined, focusing on tumor markers. In the high-alpha-fetoprotein (AFP) group (baseline AFP ≥ 20 ng/mL), a decrease in AFP level > 30% was an independent predictor of objective response (odds ratio, 5.517; p = 0.0032). In the low-AFP group (baseline AFP < 20 ng/mL), baseline des-gamma-carboxy prothrombin (DCP) level < 40 mAU/mL was an independent predictor of objective response (odds ratio, 3.978; p = 0.0206). The independent predictors of early progressive disease were an increase in AFP level ≥ 30% at 3 weeks (odds ratio, 4.077; p = 0.0264) and the presence of extrahepatic spread (odds ratio, 3.682; p = 0.0337) in the high-AFP group and up-to-seven criteria, OUT (odds ratio, 15.756; p = 0.0257) in the low-AFP group. In atezo/bev therapy, focusing on early AFP changes, baseline DCP, and tumor burden of up-to-seven criteria are useful in predicting response to treatment.
The Role of Artificial Intelligence in the Detection and Implementation of Biomarkers for Hepatocellular Carcinoma: Outlook and Opportunities
Authors: Mansur Arian , Vrionis Andrea , Charles Jonathan P. , Hancel Kayesha , Panagides John C. , Moloudi Farzad , Iqbal Shams , Daye Dania
Published: May 2023

Liver cancer is a leading cause of cancer-related death worldwide, and its early detection and treatment are crucial for improving morbidity and mortality. Biomarkers have the potential to facilitate the early diagnosis and management of liver cancer, but identifying and implementing effective biomarkers remains a major challenge. In recent years, artificial intelligence has emerged as a promising tool in the cancer sphere, and recent literature suggests that it is very promising in facilitating biomarker use in liver cancer. This review provides an overview of the status of AI-based biomarker research in liver cancer, with a focus on the detection and implementation of biomarkers for risk prediction, diagnosis, staging, prognostication, prediction of treatment response, and recurrence of liver cancers.
Screening of Breast Cancer from Sweat Samples Analyzed by 2-Dimensional Gas Chromatography-Mass Spectrometry: A Preliminary Study
Authors: Leemans Michelle , Cuzuel Vincent , Bauër Pierre , Baba Aissa Hind , Cournelle Gabriel , Baelde Aurélien , Thuleau Aurélie , Cognon Guillaume , Pouget Nicolas , Guillot Eugénie , Fromantin Isabelle , Audureau Etienne
Published: May 2023

Breast cancer (BC) remains one of the most commonly diagnosed malignancies in women. There is increasing interest in the development of non-invasive screening methods. Volatile organic compounds (VOCs) emitted through the metabolism of cancer cells are possible novel cancer biomarkers. This study aims to identify the existence of BC-specific VOCs in the sweat of BC patients. Sweat samples from the breast and hand area were collected from 21 BC participants before and after breast tumor ablation. Thermal desorption coupled with two-dimensional gas chromatography and mass spectrometry was used to analyze VOCs. A total of 761 volatiles from a homemade human odor library were screened on each chromatogram. From those 761 VOCs, a minimum of 77 VOCs were detected within the BC samples. Principal component analysis showed that VOCs differ between the pre- and post-surgery status of the BC patients. The Tree-based Pipeline Optimization Tool identified logistic regression as the best-performing machine learning model. Logistic regression modeling identified VOCs that distinguish the pre-and post-surgery state in BC patients on both the breast and hand area with sensitivities close to 1. Further, Shapley additive explanations and the probe variable method identified the most important and pertinent VOCs distinguishing pre- and post-operative status which are mostly of distinct origin for the hand and breast region. Results suggest the possibility to identify endogenous metabolites linked to BC, hence proposing this innovative pipeline as a stepstone to discovering potential BC biomarkers. Large-scale studies in a multi-centered VOC analysis setting must be carried out to validate obtained findings.
Folic Acid Supplementation Promotes Hypomethylation in Both the Inflamed Colonic Mucosa and Colitis-Associated Dysplasia
Authors: Chang Wen-Chi L. , Ghosh Jayashri , Cooper Harry S. , Vanderveer Lisa , Schultz Bryant , Zhou Yan , Harvey Kristen N. , Kaunga Esther , Devarajan Karthik , Li Yuesheng , Jelinek Jaroslav , Fragoso Mariana F. , Sapienza Carmen , Clapper Margie L.
Published: May 2023

Purpose: The purpose of this study was to assess the effect of folic acid (FA) supplementation on colitis-associated colorectal cancer (CRC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model. Methods: Mice were fed a chow containing 2 mg/kg FA at baseline and randomized after the first DSS treatment to receive 0, 2, or 8 mg/kg FA chow for 16 weeks. Colon tissue was collected for histopathological evaluation, genome-wide methylation analyses (Digital Restriction Enzyme Assay of Methylation), and gene expression profiling (RNA-Seq). Results: A dose-dependent increase in the multiplicity of colonic dysplasias was observed, with the multiplicity of total and polypoid dysplasias higher (64% and 225%, respectively) in the 8 mg FA vs. the 0 mg FA group (p < 0.001). Polypoid dysplasias were hypomethylated, as compared to the non-neoplastic colonic mucosa (p < 0.05), irrespective of FA treatment. The colonic mucosa of the 8 mg FA group was markedly hypomethylated as compared to the 0 mg FA group. Differential methylation of genes involved in Wnt/β-catenin and MAPK signaling resulted in corresponding alterations in gene expression within the colonic mucosa. Conclusions: High-dose FA created an altered epigenetic field effect within the non-neoplastic colonic mucosa. The observed decrease in site-specific DNA methylation altered oncogenic pathways and promoted colitis-associated CRC.
Clinical Outcomes of Cabozantinib in Patients Previously Treated with Atezolizumab/Bevacizumab for Advanced Hepatocellular Carcinoma—Importance of Good Liver Function and Good Performance Status
Authors: Kuzuya Teiji , Kawabe Naoto , Ariga Mizuki , Ohno Eizaburo , Funasaka Kohei , Nagasaka Mitsuo , Nakagawa Yoshihito , Miyahara Ryoji , Shibata Tomoyuki , Takahara Takeshi , Kato Yutaro , Hirooka Yoshiki
Published: May 2023

(1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular carcinoma (HCC) previously treated with atezolizumab plus bevacizumab (Atz/Bev), with a focus on whether patients met criteria of Child–Pugh Class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0/1 at baseline. (2) Methods: Eleven patients (57.9%) met the criteria of both Child–Pugh class A and ECOG-PS score 0/1 (CP-A+PS-0/1 group) and eight patients (42.1%) did not (Non-CP-A+PS-0/1 group); efficacy and safety were retrospectively evaluated. (3) Results: Disease control rate was significantly higher in the CP-A+PS-0/1 group (81.1%) than in the non-CP-A+PS-0/1 group (12.5%). Median progression-free survival, overall survival and duration of cabozantinib treatment were significantly longer in the CP-A+PS-0/1 group (3.9 months, 13.4 months, and 8.3 months, respectively) than in the Non-CP-A+PS-0/1 group (1.2 months, 1.7 months, and 0.8 months, respectively). Median daily dose of cabozantinib was significantly higher in the CP-A+PS-0/1 group (22.9 mg/day) than in the non-CP-A+PS-0/1 group (16.9 mg/day). (4) Conclusions: Cabozantinib in patients previously treated with Atz/Bev has potential therapeutic efficacy and safety if patients have good liver function (Child–Pugh A) and are in good general condition (ECOG-PS 0/1).
Pancreatic Cancer: BRCA Targeted Therapy and Beyond
Authors: Keane Fergus , O’Connor Catherine A. , Park Wungki , Seufferlein Thomas , O’Reilly Eileen M.
Published: May 2023

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.
Polygenic Risk Score Predicts Modified Risk in BRCA1 Pathogenic Variant c.4035del and c.5266dup Carriers in Breast Cancer Patients
Authors: Berga-Švītiņa Egija , Maksimenko Jeļena , Miklaševičs Edvīns , Fischer Krista , Vilne Baiba , Mägi Reedik
Published: May 2023

The aim of this study was to assess the power of the polygenic risk score (PRS) in estimating the overall genetic risk of women carrying germline BRCA1 pathogenic variants (PVs) c.4035del or c.5266dup to develop breast (BC) or ovarian cancer (OC) due to additional genetic variations. In this study, PRSs previously developed from two joint models using summary statistics of age-at-onset (BayesW model) and case–control data (BayesRR-RC model) from a genome-wide association analysis (GWAS) were applied to 406 germline BRCA1 PV (c.4035del or c.5266dup) carriers affected by BC or OC, compared with unaffected individuals. A binomial logistic regression model was used to assess the association of PRS with BC or OC development risk. We observed that the best-fitting BayesW PRS model effectively predicted the individual’s BC risk (OR = 1.37; 95% CI = 1.03–1.81, p = 0.02905 with AUC = 0.759). However, none of the applied PRS models was a good predictor of OC risk. The best-fitted PRS model (BayesW) contributed to assessing the risk of developing BC for germline BRCA1 PV (c.4035del or c.5266dup) carriers and may facilitate more precise and timely patient stratification and decision-making to improve the current BC treatment or even prevention strategies.
Astrocytic CD44 Deficiency Reduces the Severity of Kainate-Induced Epilepsy
Authors: Kruk Patrycja K. , Nader Karolina , Skupien-Jaroszek Anna , Wójtowicz Tomasz , Buszka Anna , Olech-Kochańczyk Gabriela , Wilczynski Grzegorz M. , Worch Remigiusz , Kalita Katarzyna , Włodarczyk Jakub , Dzwonek Joanna
Published: May 2023

Background: Epilepsy affects millions of people worldwide, yet we still lack a successful treatment for all epileptic patients. Most of the available drugs modulate neuronal activity. Astrocytes, the most abundant cells in the brain, may constitute alternative drug targets. A robust expansion of astrocytic cell bodies and processes occurs after seizures. Highly expressed in astrocytes, CD44 adhesion protein is upregulated during injury and is suggested to be one of the most important proteins associated with epilepsy. It connects the astrocytic cytoskeleton to hyaluronan in the extracellular matrix, influencing both structural and functional aspects of brain plasticity. Methods: Herein, we used transgenic mice with an astrocyte CD44 knockout to evaluate the impact of the hippocampal CD44 absence on the development of epileptogenesis and ultrastructural changes at the tripartite synapse. Results: We demonstrated that local, virally-induced CD44 deficiency in hippocampal astrocytes reduces reactive astrogliosis and decreases the progression of kainic acid-induced epileptogenesis. We also observed that CD44 deficiency resulted in structural changes evident in a higher dendritic spine number along with a lower percentage of astrocyte-synapse contacts, and decreased post-synaptic density size in the hippocampal molecular layer of the dentate gyrus. Conclusions: Overall, our study indicates that CD44 signaling may be important for astrocytic coverage of synapses in the hippocampus and that alterations of astrocytes translate to functional changes in the pathology of epilepsy.
scViewer: An Interactive Single-Cell Gene Expression Visualization Tool
Authors: Patil Abhijeet R. , Kumar Gaurav , Zhou Huanyu , Warren Liling
Published: May 2023

Single-cell RNA sequencing (scRNA-seq) is an attractive technology for researchers to gain valuable insights into the cellular processes and cell type diversity present in all tissues. The data generated by the scRNA-seq experiment are high-dimensional and complex in nature. Several tools are now available to analyze the raw scRNA-seq data from public databases; however, simple and easy-to-explore single-cell gene expression visualization tools focusing on differential expression and co-expression are lacking. Here, we present scViewer, an interactive graphical user interface (GUI) R/Shiny application designed to facilitate the visualization of scRNA-seq gene expression data. With the processed Seurat RDS object as input, scViewer utilizes several statistical approaches to provide detailed information on the loaded scRNA-seq experiment and generates publication-ready plots. The major functionalities of scViewer include exploring cell-type-specific gene expression, co-expression analysis of two genes, and differential expression analysis with different biological conditions considering both cell-level and subject-level variations using negative binomial mixed modeling. We utilized a publicly available dataset (brain cells from a study of Alzheimer’s disease to demonstrate the utility of our tool. scViewer can be downloaded from GitHub as a Shiny app with local installation. Overall, scViewer is a user-friendly application that will allow researchers to visualize and interpret the scRNA-seq data efficiently for multi-condition comparison by performing gene-level differential expression and co-expression analysis on the fly. Considering the functionalities of this Shiny app, scViewer can be a great resource for collaboration between bioinformaticians and wet lab scientists for faster data visualizations.
Targeting BET Proteins Decreases Hyaluronidase-1 in Pancreatic Cancer
Authors: Kumar Krishan , Kanojia Deepak , Bentrem David J. , Hwang Rosa F. , Butchar Jonathan P. , Tridandapani Susheela , Munshi Hidayatullah G.
Published: May 2023

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of dense stroma that is enriched in hyaluronan (HA), with increased HA levels associated with more aggressive disease. Increased levels of the HA-degrading enzymes hyaluronidases (HYALs) are also associated with tumor progression. In this study, we evaluate the regulation of HYALs in PDAC. Methods: Using siRNA and small molecule inhibitors, we evaluated the regulation of HYALs using quantitative real-time PCR (qRT-PCR), Western blot analysis, and ELISA. The binding of BRD2 protein on the HYAL1 promoter was evaluated by chromatin immunoprecipitation (ChIP) assay. Proliferation was evaluated by WST-1 assay. Mice with xenograft tumors were treated with BET inhibitors. The expression of HYALs in tumors was analyzed by immunohistochemistry and by qRT-PCR. Results: We show that HYAL1, HYAL2, and HYAL3 are expressed in PDAC tumors and in PDAC and pancreatic stellate cell lines. We demonstrate that inhibitors targeting bromodomain and extra-terminal domain (BET) proteins, which are readers of histone acetylation marks, primarily decrease HYAL1 expression. We show that the BET family protein BRD2 regulates HYAL1 expression by binding to its promoter region and that HYAL1 downregulation decreases proliferation and enhances apoptosis of PDAC and stellate cell lines. Notably, BET inhibitors decrease the levels of HYAL1 expression in vivo without affecting the levels of HYAL2 or HYAL3. Conclusions: Our results demonstrate the pro-tumorigenic role of HYAL1 and identify the role of BRD2 in the regulation of HYAL1 in PDAC. Overall, these data enhance our understanding of the role and regulation of HYAL1 and provide the rationale for targeting HYAL1 in PDAC.
Study on the Influence of Regular Physical Activity on Children’s Oral Health
Authors: Popa Paul Șerban , Onișor Daniela , Nechita Aurel , Earar Kamel , Matei Mădălina Nicoleta
Published: May 2023

The benefits of physical activities conducted systematically on the harmonious development, intellectual performance, and general health of children are unanimously accepted. This study’s aim is to determine whether differences in oral health between young athletes and children not engaged in competitive sports are present. A total of 173 children aged between 6 and 17 years, 58 hockey players, 55 football players, and 60 in the control group were divided into groups according to their activity, age, and biological sex and examined for oral hygiene and dental and periodontal health, using clinically determined indices. Statistical analysis showed significant differences between the groups, with lower (better) values for athletes, regardless of age, sex, or activity. Oral hygiene showed the most relevant differences for males aged 14 to 17, as did the index for dental health. Periodontal health, on the other hand, was significantly better for females aged 6 to 13. Based on this data, the beneficial influence of regular physical activity also has an impact on oral health. Identifying the mechanisms behind this needs to be explored in depth and may be a topic for further research.
Parent-Integrated Interventions to Improve Language Development in Children Born Very Preterm
Authors: Synnes Anne , Luu Thuy Mai , Afifi Jehier , Khairy May , de Cabo Cecilia , Moddemann Diane , Hendson Leonora , Reichert Amber , Coughlin Kevin , Nguyen Kim Anh , Richter Lindsay L. , Bacchini Fabiana , Aziz Khalid
Published: May 2023

Neurodevelopmental challenges in children born very preterm are common and not improving. This study tested the feasibility of using Evidence-based Practice to Improve Quality (EPIQ), a proven quality improvement technique that incorporates scientific evidence to target improving language abilities in very preterm populations in 10 Canadian neonatal follow-up programs. Feasibility was defined as at least 70% of sites completing four intervention cycles and 75% of cycles meeting targeted aims. Systematic reviews were reviewed and performed, an online quality improvement educational tool was developed, multidisciplinary teams that included parents were created and trained, and sites provided virtual support to implement and audit locally at least four intervention cycles of approximately 6 months in duration. Eight of ten sites implemented at least four intervention cycles. Of the 48 cycles completed, audits showed 41 (85%) met their aim. Though COVID-19 was a barrier, parent involvement, champions, and institutional support facilitated success. EPIQ is a feasible quality improvement methodology to implement family-integrated evidence-informed interventions to support language interventions in neonatal follow-up programs. Further studies are required to identify potential benefits of service outcomes, patients, and families and to evaluate sustainability.
A Medicago truncatula Autoregulation of Nodulation Mutant Transcriptome Analysis Reveals Disruption of the SUNN Pathway Causes Constitutive Expression Changes in Some Genes, but Overall Response to Rhizobia Resembles Wild-Type, Including Induction of TML1 and TML2
Authors: Schnabel Elise L. , Chavan Suchitra A. , Gao Yueyao , Poehlman William L. , Feltus Frank Alex , Frugoli Julia A.
Published: May 2023

Nodule number regulation in legumes is controlled by a feedback loop that integrates nutrient and rhizobia symbiont status signals to regulate nodule development. Signals from the roots are perceived by shoot receptors, including a CLV1-like receptor-like kinase known as SUNN in Medicago truncatula. In the absence of functional SUNN, the autoregulation feedback loop is disrupted, resulting in hypernodulation. To elucidate early autoregulation mechanisms disrupted in SUNN mutants, we searched for genes with altered expression in the loss-of-function sunn-4 mutant and included the rdn1-2 autoregulation mutant for comparison. We identified constitutively altered expression of small groups of genes in sunn-4 roots and in sunn-4 shoots. All genes with verified roles in nodulation that were induced in wild-type roots during the establishment of nodules were also induced in sunn-4, including autoregulation genes TML2 and TML1. Only an isoflavone-7-O-methyltransferase gene was induced in response to rhizobia in wild-type roots but not induced in sunn-4. In shoot tissues of wild-type, eight rhizobia-responsive genes were identified, including a MYB family transcription factor gene that remained at a baseline level in sunn-4; three genes were induced by rhizobia in shoots of sunn-4 but not wild-type. We cataloged the temporal induction profiles of many small secreted peptide (MtSSP) genes in nodulating root tissues, encompassing members of twenty-four peptide families, including the CLE and IRON MAN families. The discovery that expression of TML2 in roots, a key factor in inhibiting nodulation in response to autoregulation signals, is also triggered in sunn-4 in the section of roots analyzed, suggests that the mechanism of TML regulation of nodulation in M. truncatula may be more complex than published models.
Changing Water Cycle under a Warming Climate: Tendencies in the Carpathian Basin
Authors: Jánosi Imre Miklós , Bíró Tibor , Lakatos Boglárka O. , Gallas Jason A. C. , Szöllosi-Nagy András
Published: May 2023

In this mini-review, we present evidence from the vast literature that one essential part of the coupled atmosphere–ocean system that makes life on Earth possible, the water cycle, is exhibiting changes along with many attributes of the global climate. Our starting point is the 6th Assessment Report of the IPCC, which appeared in 2021, where the almost monograph-size Chapter 8, with over 1800 references, is devoted entirely to the water cycle. In addition to listing the main observations on the Earth globally, we focus on Europe, particularly on the Carpathian (Pannonian) Basin. We collect plausible explanations of the possible causes behind an observably accelerating and intensifying water cycle. Some authors still suggest that changes in the natural boundary conditions, such as solar irradiance or Earth’s orbital parameters, explain the observations. In contrast, most authors attribute such changes to the increasing greenhouse gas concentrations since the industrial revolution. The hypothesis being tested, and which has already yielded convincing affirmative answers, is that the hydrological cycle intensifies due to anthropogenic impacts. The Carpathian Basin, a part of the Danube watershed, including the sub-basin of the Tisza River, is no exception to these changes. The region is experiencing multiple drivers contributing to alterations in the water cycle, including increasing temperatures, shifting precipitation regimes, and various human impacts.
A Relationship between Climate Finance and Climate Risk: Evidence from the South Asian Region
Authors: Masud Md. Abdul Kaium , Sahara Juichiro , Kabir Md. Humayun
Published: May 2023

South Asia is the most vulnerable region in the context of global warming, climate change, and climate risk. Climate finance is the most useful tool for combating climate challenges worldwide. The study explores the present picture of climate finance in South Asian (SA) countries. The study uses multilateral development bank (MDB), Green Climate Fund (GCF), and Germanwatch supplied data from 2011 to 2021. Under the theoretical lens of institutional capacity development, the study attempts to correlate climate finance and climate risk. The study indicates an increasing trend of MBDs’ and the GCF’s climate finance in many countries worldwide. The study finds that MDBs’ total global climate finance is USD 446,977 million, while the SA region has received USD 59,301 million since 2011. It also reports that MDBs provide 77% and 23% of the money to the mitigation and adaptation areas. Moreover, the study reports that, after COVID-19, MDBs substantially increased the amount of global climate financing, but this increase was not seen in the SA region. Our climate risk data indicate that most of the SA countries are highly long-term climate risky and lose, on average, 0.378% of GDP. The correlation matrix finds a negative and significant correlation between climate finance and long-term and yearly climate risk. The study identifies that the region’s climate financing flow of money is not rationally distributed based on the short-run and long-run climate risks. The study presumes that more climate finance would be the most effective mechanism to mitigate climate risk. Therefore, SA region leadership drastically requires a holistic framework to address the prevailing climate problems and to ensure regional coordination and cooperation toward climate finance and policies. The research findings have significant implications for climate policy and climate finance.
Structure and Void Connectivity in Nanocolumnar Thin Films Grown by Magnetron Sputtering at Oblique Angles
Authors: Alvarez Rafael , Regodon Guillermo , Acosta-Rivera Hiedra , Rico Victor , Alcala German , González-Elipe Agustín R. , Palmero Alberto
Published: May 2023

The morphology and void connectivity of thin films grown by a magnetron sputtering deposition technique at oblique geometries were studied in this paper. A well-tested thin film growth model was employed to assess the features of these layers along with experimental data taken from the literature. A strong variation in the film morphology and pore topology was found as a function of the growth conditions, which have been linked to the different collisional transport of sputtered species in the plasma gas. Four different characteristic film morphologies were identified, such as (i) highly dense and compact, (ii) compact with large, tilted mesopores, (iii) nanocolumns separated by large mesopores, and (iv) vertically aligned sponge-like coalescent nanostructures. Attending to the topology and connectivity of the voids in the film, the nanocolumnar morphology was shown to present a high pore volume and area connected with the outside by means of mesopores, with a diameter above 2 nm, while the sponge-like nanostructure presented a high pore volume and area, as well as a dense network connectivity by means of micropores, with a diameter below 2 nm. The obtained results describe the different features of the porous network in these films and explain the different performances as gas or liquid sensors in electrochromic applications or for infiltration with nanoparticles or large molecules.
Corrosion Rate of Steel in Liquid Zn, Zn-Bi and Zn-Sn Baths
Authors: Kania Henryk
Published: May 2023

In the hot dip galvanizing process, steel products are immersed in a liquid zinc bath. The contact of steel with liquid zinc causes the corrosion of the steel as a result of Fe dissolution processes in the liquid. If the dissolution process is carried out in a controlled manner, it results in the formation of a coating. Uncontrolled dissolution leads to the degradation of the steel surface. This article presents the results of research into the influence of Bi and Sn additions to zinc baths on the corrosion of steel in liquid zinc. Corrosion tests were carried out under conditions of kinetic dissolution using the rotating disc method. The kinetic dissolution constants of steel with different Si contents in Zn, Zn-0.5Bi and Zn-2Sn baths were determined. It was found that the addition of Bi and Sn lowers the value of the dissolution constant and may act as an inhibitor of Fe dissolution in liquid zinc. Based on the measurements and the determined value of the dissolution constant, the activation energy of kinetic dissolution was determined. It was found that in the temperature range of 440–480 °C, the addition of Bi and Sn increases the value of dissolution activation energy, which reduces the intensity of Fe transfer to the zinc bath.