bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction Model of Shrinkage Crack Propagation in Cross-Section of Timber Components
Authors: Tian Panpan , Qiu Hongxing , Han Jianhong , Li Hongmin , Han Xia
Published: October 2023

Shrinkage cracks severely affect the safety of wood structures. Therefore, the moisture stress distribution of shrinkage cracks should be analyzed, and the interface crack depth of wood components predicted. In this paper, the equilibrium conditions, physical conditions, geometric conditions, and coordination equations of the disk humidity stress under a moisture content gradient Δw are deduced by referring to the elastic analytical solution model of temperature stress. Moreover, the humidity stress distribution equation is established, which is verified via the finite element method. The critical water content and shrinkage crack depth prediction models are further deduced based on the humidity stress distribution. The usability of the model is further verified using the test data of actual engineered wood components. The results demonstrate that the moisture stress is not determined by the initial moisture content Wi, equilibrium moisture content We, or member size but by moisture content gradient Δw. The shrinkage crack prediction model of wood components in cross-section can be applied to actual engineering prediction to provide a theoretical basis for the reinforcement measures and safety evaluation of wood structures.
Genomic Biomarker Discovery in Disease Progression and Therapy Response in Bladder Cancer Utilizing Machine Learning
Authors: Liosis Konstantinos Christos , Marouf Ahmed Al , Rokne Jon G. , Ghosh Sunita , Bismar Tarek A. , Alhajj Reda
Published: October 2023

Cancer in all its forms of expression is a major cause of death. To identify the genomic reason behind cancer, discovery of biomarkers is needed. In this paper, genomic data of bladder cancer are examined for the purpose of biomarker discovery. Genomic biomarkers are indicators stemming from the study of the genome, either at a very low level based on the genome sequence itself, or more abstractly such as measuring the level of gene expression for different disease groups. The latter method is pivotal for this work, since the available datasets consist of RNA sequencing data, transformed to gene expression levels, as well as data on a multitude of clinical indicators. Based on this, various methods are utilized such as statistical modeling via logistic regression and regularization techniques (elastic-net), clustering, survival analysis through Kaplan–Meier curves, and heatmaps for the experiments leading to biomarker discovery. The experiments have led to the discovery of two gene signatures capable of predicting therapy response and disease progression with considerable accuracy for bladder cancer patients which correlates well with clinical indicators such as Therapy Response and T-Stage at surgery with Disease Progression in a time-to-event manner.
Effect of Dimeric Disintegrins Isolated from Vipera lebetina obtusa Venom on Glioblastoma Cellular Responses
Authors: Galicka Anna , Szoka Łukasz , Radziejewska Iwona , Marcinkiewicz Cezary
Published: October 2023

Integrins play a fundamental role in the migration and invasiveness of glioblastoma (GBM) cells, making them suitable targets for innovative cancer therapy. The aim of this study was to evaluate the effect of the RGD homodimeric disintegrin VLO4, isolated from Vipera lebetina obtusa venom, on the adhesion, spreading, migration, and survival of LBC3, LN18, and LN229 cell lines. This disintegrin, as a potent antagonist for α5β1 integrin, showed pro-adhesive properties for these cell lines, the highest for LN229 and the lowest for LBC3. Glioblastoma cells displayed significant differences in the spreading on the immobilized VLO4 and the natural α5β1 integrin ligand, fibronectin. Solubilized VLO4 showed different cytotoxicity and pro-apoptotic properties among tested cell lines, with the highest against LN18 and none against LN229. Moreover, VLO4 revealed an inhibitory effect on the migration of LBC3 and LN18 cell lines, in contrast to LN229 cells, which were not sensitive to this disintegrin. However, LN229 migration was impaired by VLO5, a disintegrin antagonistic to integrin α9β1, used in combination with VLO4. A possible mechanism of action of VLO4 may be related to the downregulation of α5β1 integrin subunit expression, as revealed by Western blot. VLO4 also inhibited cell proliferation and induced caspase-dependent apoptosis in LBC3 and LN18 cell lines. These results indicate that targeting α5β1 integrin by related VLO4 compounds may be useful in the development of integrin-targeted therapy for glioblastoma.
Aging, Inflammation, and Comorbidity in Cancers—A General In Silico Study Exemplified by Myeloproliferative Malignancies
Authors: Ottesen Johnny T. , Andersen Morten
Published: October 2023

(1) Background: We consider dormant, pre-cancerous states prevented from developing into cancer by the immune system. Inflammatory morbidity may compromise the immune system and cause the pre-cancer to escape into an actual cancerous development. The immune deficiency described is general, but the results may vary across specific cancers due to different variances (2) Methods: We formulate a general conceptual model to perform rigorous in silico consequence analysis. Relevant existing data for myeloproliferative malignancies from the literature are used to calibrate the in silico computations. (3) Results and conclusions: The hypothesis suggests a common physiological origin for many clinical and epidemiological observations in relation to cancers in general. Examples are the observed age-dependent prevalence for hematopoietic cancers, a general mechanism-based explanation for why the risk of cancer increases with age, and how somatic mutations in general, and specifically seen in screenings of citizens, sometimes are non-increased or even decrease when followed over time. The conceptual model is used to characterize different groups of citizens and patients, describing different treatment responses and development scenarios.
Oncological Outcomes of Patients with High-Volume mCRPC: Results from a Longitudinal Real-Life Multicenter Cohort
Authors: Ferriero Mariaconsiglia , Prata Francesco , Anceschi Umberto , Astore Serena , Bove Alfredo Maria , Brassetti Aldo , Calabrò Fabio , Chiellino Silvia , De Nunzio Cosimo , Facchini Gaetano , Franzese Elisena , Izzo Michela , Mastroianni Riccardo , Misuraca Leonardo , Naspro Richard , Papalia Rocco , Pappalardo Annalisa , Tema Giorgia , Tuderti Gabriele , Turchi Beatrice , Tubaro Andrea , Simone Giuseppe
Published: October 2023

Registrative trials recommended the use of upfront chemotherapy in high-volume metastatic prostate cancer. We reported survival outcomes of patients with high-volume mCRPC treated with ARTA in a chemo-naïve setting compared to patients treated with chemotherapy as first-line from a longitudinal real-life multicenter series. We retrospectively collected data on mCRPC patients treated at six centers. The dataset was queried for high-volume disease (defined as more than 6 bone lesions or bulky nodes ≥ 5 cm). We compared the main clinical features of chemo-naïve versus chemo-treated patients. The Mann–Whitney U test and Chi-squared test were used to compare continuous and categorial variables, respectively. The Kaplan–Meier method was used to compare differences in terms of progression-free survival (PFS), cancer specific survival (CSS) and overall survival (OS) in an upfront ARTA or chemo-treated setting. Survival probabilities were computed at 12, 24, 48, and 60 months. Out of 216 patients, 88 cases with high-volume disease were selected. Sixty-nine patients (78.4%) received upfront ARTA, while 19 patients received chemotherapy as the first-line treatment option. Forty-eight patients received Abiraterone (AA), 21 patients received Enzalutamide (EZ) as the first-line treatment. The ARTA population was older (p = 0.007) and less likely to receive further lines of treatment (p = 0.001) than the chemo-treated cohort. The five-year PFS, CSS and OS were 60%, 73.3%, and 72.9%, respectively. Overall, 28 patients (31.8%) shifted after their first-line therapy to a second-line therapy: EZ was prescribed in 17 cases, AA in seven cases and radiometabolic therapy in four patients. Sixteen cases (18.2%) developed significant progression and were treated with chemotherapy. At Kaplan–Meyer analysis PFS, CSS and OS were comparable for upfront ARTA vs chemo-treated patients (log rank p = 0.10, p = 0.64 and p = 0.36, respectively). We reported comparable survival probabilities in a real-life series of high-volume mCRPC patients who either received upfront ARTA or chemotherapy. Patients primarily treated with chemotherapy were younger and more likely to receive further treatment lines than the upfront ARTA cohort. Our data support the use of novel antiandrogens as first line treatment regardless tumor burden, delaying the beginning of a more toxic chemotherapy in case of significant disease progression.
The Role of Non-Coding RNAs in Myelodysplastic Neoplasms
Authors: Georgoulis Vasileios , Koumpis Epameinondas , Hatzimichael Eleftheria
Published: October 2023

Myelodysplastic syndromes or neoplasms (MDS) are a heterogeneous group of myeloid clonal disorders characterized by peripheral blood cytopenias, blood and marrow cell dysplasia, and increased risk of evolution to acute myeloid leukemia (AML). Non-coding RNAs, especially microRNAs and long non-coding RNAs, serve as regulators of normal and malignant hematopoiesis and have been implicated in carcinogenesis. This review presents a comprehensive summary of the biology and role of non-coding RNAs, including the less studied circRNA, siRNA, piRNA, and snoRNA as potential prognostic and/or predictive biomarkers or therapeutic targets in MDS.
Overview, Diagnosis, and Perioperative Systemic Therapy of Upper Tract Urothelial Carcinoma
Authors: Kolawa Adam , D’Souza Anishka , Tulpule Varsha
Published: October 2023

Upper tract urothelial carcinoma comprises 5–10% of all urothelial carcinoma cases. This disease tends to have a more aggressive course than its lower urinary tract counterpart, with 60% of patients presenting with invasive disease and 30% of patients presenting with metastatic disease at diagnosis. The diagnostic workup of UTUC involves imaging with CT urogram, urine cytology, and direct visualization and biopsy of suspected lesions via ureteroscopy. Standard treatment of high-grade UTUC involves radical nephroureterectomy (RNU) and excision of the ipsilateral bladder cuff. Both the NCCN and EAU Guidelines include neoadjuvant chemotherapy as a treatment option for select patients with UTUC; however, there are no strict guidelines. Much of the rationale for neoadjuvant chemotherapy is based on extrapolation from data from muscle-invasive bladder cancer, which has demonstrated a 5-year OS benefit of 5–8%. Retrospective studies evaluating the use of NACT in urothelial carcinoma have yielded pathologic objective response rates of 48% in UTUC cohorts. The randomized Phase III POUT study noted a DFS advantage with adjuvant platinum-based chemotherapy, compared with surveillance in UTUC, of 70% vs. 51% at 2 years. Though not the standard of care, multiple studies have explored the use of perioperative immunotherapy or chemoimmunotherapy in the management of invasive urothelial carcinoma. The PURE-02 study explored the use of neoadjuvant pembrolizumab in patients with high-risk UTUC. A small study of 10 patients, it showed no significant signals of activity with neoadjuvant pembrolizumab. Another Phase II study of neoadjuvant ipilimumab and nivolumab in cisplatin-ineligible UTUC yielded more promising findings, with 3/9 patients attaining a pathologic CR and the remaining six pathologically downstaged. The ABACUS trial found a 31% pathologic complete response rate amongst cisplatin-ineligible MIBC patients treated with neoadjuvant atezolizumab. The use of adjuvant immunotherapy has been explored over three phase III trials. The CheckMate-274 trial found a DFS benefit with the addition of one year of adjuvant nivolumab in patients with high-risk urothelial carcinoma. The IMvigor-010 study of adjuvant atezolizumab was a negative study. The AMBASSADOR trial of adjuvant pembrolizumab is pending results. With the FDA approval of erdafitinib in metastatic urothelial carcinoma, similar targets have been explored for use in perioperative use in invasive urothelial carcinoma, as with adjuvant infigratinib in the PROOF-302 trial. As the treatment paradigm for urothelial carcinoma evolves, further prospective studies are needed to expand the perioperative treatment landscape of UTUC.
TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited
Authors: Shin Dong-Yeop
Published: October 2023

Introduction: TP53 is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in the TP53 gene occur at various genetic locations and exhibit significant heterogeneity among patients. Mutations occurring primarily within the DNA-binding domain of TP53 result in the loss of the p53 protein’s DNA-binding capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses a significant challenge in developing an effective treatment strategy, which eradicates TP53-mutated cancer clones. This review summarizes the current understanding of TP53 mutations in AML and their implications. TP53 mutation in AML: In patients with acute myeloid leukemia (AML), six hotspot mutations (R175H, G245S, R248Q/W, R249S, R273H/S, and R282W) within the DNA-binding domain are common. TP53 mutations are frequently associated with a complex karyotype and subgroups of therapy-related or secondary AML. The presence of TP53 mutation is considered as a poor prognostic factor. TP53-mutated AML is even classified as a distinct subgroup of AML by itself, as TP53-mutated AML exhibits a significantly distinct landscape in terms of co-mutation and gene expression profiles compared with wildtype (WT)-TP53 AML. Clinical Implications: To better predict the prognosis in cancer patients with different TP53 mutations, several predictive scoring systems have been proposed based on screening experiments, to assess the aggressiveness of TP53-mutated cancer cells. Among those scoring systems, a relative fitness score (RFS) could be applied to AML patients with TP53 mutations in terms of overall survival (OS) and event-free survival (EFS). The current standard treatment, which includes cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation, is largely ineffective for patients with TP53-mutated AML. Consequently, most patients with TP53-mutated AML succumb to leukemia within several months, despite active anticancer treatment. Decitabine, a hypomethylating agent, is known to be relatively effective in patients with AML. Numerous trials are ongoing to investigate the effects of novel drugs combined with hypomethylating agents, TP53-targeting agents or immunologic agents. Conclusions: Developing an effective treatment strategy for TP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated TP53 holds promise as an approach to combating TP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field.
Unraveling the Role of Molecular Profiling in Predicting Treatment Response in Stage III Colorectal Cancer Patients: Insights from the IDEA International Study
Authors: Messaritakis Ippokratis , Psaroudaki Eleni , Vogiatzoglou Konstantinos , Sfakianaki Maria , Topalis Pantelis , Iliopoulos Ioannis , Mavroudis Dimitrios , Tsiaoussis John , Gouvas Nikolaos , Tzardi Maria , Souglakos John
Published: October 2023

Background: This study aimed to investigate the molecular profiles of 237 stage III CRC patients from the international IDEA study. It also sought to correlate these profiles with Toll-like and vitamin D receptor polymorphisms, clinicopathological and epidemiological characteristics, and patient outcomes. Methods: Whole Exome Sequencing and PCR-RFLP on surgical specimens and blood samples, respectively, were performed to identify molecular profiling and the presence of Toll-like and vitamin D polymorphisms. Bioinformatic analysis revealed mutational status. Results: Among the enrolled patients, 63.7% were male, 66.7% had left-sided tumors, and 55.7% received CAPOX as adjuvant chemotherapy. Whole exome sequencing identified 59 mutated genes in 11 different signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) CRC panel. On average, patients had 8 mutated genes (range, 2–21 genes). Mutations in ARAF and MAPK10 emerged as independent prognostic factors for reduced DFS (p = 0.027 and p < 0.001, respectively), while RAC3 and RHOA genes emerged as independent prognostic factors for reduced OS (p = 0.029 and p = 0.006, respectively). Right-sided tumors were also identified as independent prognostic factors for reduced DFS (p = 0.019) and OS (p = 0.043). Additionally, patients with tumors in the transverse colon had mutations in genes related to apoptosis, PIK3-Akt, Wnt, and MAPK signaling pathways. Conclusions: Molecular characterization of tumor cells can enhance our understanding of the disease course. Mutations may serve as promising prognostic biomarkers, offering improved treatment options. Confirming these findings will require larger patient cohorts and international collaborations to establish correlations between molecular profiling, clinicopathological and epidemiological characteristics and clinical outcomes.
Differential Expression of NEK Kinase Family Members in Esophageal Adenocarcinoma and Barrett’s Esophagus
Authors: Chen Lei , Ballout Farah , Lu Heng , Hu Tianling , Zhu Shoumin , Chen Zheng , Peng Dunfa
Published: October 2023

The incidence of esophageal adenocarcinoma (EAC) has risen rapidly during the past four decades, making it the most common type of esophageal cancer in the USA and Western countries. The NEK (Never in mitosis A (NIMA) related kinase) gene family is a group of serine/threonine kinases with 11 members. Aberrant expression of NEKs has been recently found in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEKs in EAC and its precancerous condition (Barrett’s esophagus, BE) has not been investigated. In the present study, we first analyzed the TCGA and 9 GEO databases (a total of 10 databases in which 8 contain EAC and 6 contain BE) using bioinformatic approaches for NEKs expression in EAC and BE. We identified that several NEK members, such as NEK2 (7/8), NEK3 (6/8), and NEK6 (6/8), were significantly upregulated in EAC as compared to normal esophagus samples. Alternatively, NEK1 was downregulated in EAC as compared to the normal esophagus. On the contrary, genomic alterations of these NEKs are not frequent in EAC. We validated the above findings using qRT-PCR and the protein expression of NEKs in EAC cell lines using Western blotting and in primary EAC tissues using immunohistochemistry and immunofluorescence. Our data suggest that frequent upregulation of NEK2, NEK3, and NEK7 may be important in EAC.
Automated Cellular-Level Dual Global Fusion of Whole-Slide Imaging for Lung Adenocarcinoma Prognosis
Authors: Diao Songhui , Chen Pingjun , Showkatian Eman , Bandyopadhyay Rukhmini , Rojas Frank R. , Zhu Bo , Hong Lingzhi , Aminu Muhammad , Saad Maliazurina B. , Salehjahromi Morteza , Muneer Amgad , Sujit Sheeba J. , Behrens Carmen , Gibbons Don L. , Heymach John V. , Kalhor Neda , Wistuba Ignacio I. , Solis Soto Luisa M. , Zhang Jianjun , Qin Wenjian , Wu Jia
Published: October 2023

Histopathologic whole-slide images (WSI) are generally considered the gold standard for cancer diagnosis and prognosis. Survival prediction based on WSI has recently attracted substantial attention. Nevertheless, it remains a central challenge owing to the inherent difficulties of predicting patient prognosis and effectively extracting informative survival-specific representations from WSI with highly compounded gigapixels. In this study, we present a fully automated cellular-level dual global fusion pipeline for survival prediction. Specifically, the proposed method first describes the composition of different cell populations on WSI. Then, it generates dimension-reduced WSI-embedded maps, allowing for efficient investigation of the tumor microenvironment. In addition, we introduce a novel dual global fusion network to incorporate global and inter-patch features of cell distribution, which enables the sufficient fusion of different types and locations of cells. We further validate the proposed pipeline using The Cancer Genome Atlas lung adenocarcinoma dataset. Our model achieves a C-index of 0.675 (±0.05) in the five-fold cross-validation setting and surpasses comparable methods. Further, we extensively analyze embedded map features and survival probabilities. These experimental results manifest the potential of our proposed pipeline for applications using WSI in lung adenocarcinoma and other malignancies.
Pancreatic Cancer-Secreted Proteins: Targeting Their Functions in Tumor Microenvironment
Authors: Cammarota Anna Lisa , Falco Antonia , Basile Anna , Molino Carlo , Chetta Massimiliano , D’Angelo Gianni , Marzullo Liberato , De Marco Margot , Turco Maria Caterina , Rosati Alessandra
Published: October 2023

Pancreatic Ductal Adenocarcinoma (PDAC) is a ravaging disease with a poor prognosis, requiring a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggest a shift in focus towards the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer-secreted proteins in the complex TME tumor-stroma crosstalk, shedding lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.
Evaluating Stacked Methylation Markers for Blood-Based Multicancer Detection
Authors: Funderburk Karen , Bang-Christensen Sara R. , Miller Brendan F. , Tan Hua , Margolin Gennady , Petrykowska Hanna M. , Baugher Catherine , Farney S. Katie , Grimm Sara A. , Jameel Nader , Holland David O. , Altman Naomi S. , Elnitski Laura
Published: October 2023

The ability to detect several types of cancer using a non-invasive, blood-based test holds the potential to revolutionize oncology screening. We mined tumor methylation array data from the Cancer Genome Atlas (TCGA) covering 14 cancer types and identified two novel, broadly-occurring methylation markers at TLX1 and GALR1. To evaluate their performance as a generalized blood-based screening approach, along with our previously reported methylation biomarker, ZNF154, we rigorously assessed each marker individually or combined. Utilizing TCGA methylation data and applying logistic regression models within each individual cancer type, we found that the three-marker combination significantly increased the average area under the ROC curve (AUC) across the 14 tumor types compared to single markers (p = 1.158 × 10−10; Friedman test). Furthermore, we simulated dilutions of tumor DNA into healthy blood cell DNA and demonstrated increased AUC of combined markers across all dilution levels. Finally, we evaluated assay performance in bisulfite sequenced DNA from patient tumors and plasma, including early-stage samples. When combining all three markers, the assay correctly identified nine out of nine lung cancer plasma samples. In patient plasma from hepatocellular carcinoma, ZNF154 alone yielded the highest combined sensitivity and specificity values averaging 68% and 72%, whereas multiple markers could achieve higher sensitivity or specificity, but not both. Altogether, this study presents a comprehensive pipeline for the identification, testing, and validation of multi-cancer methylation biomarkers with a considerable potential for detecting a broad range of cancer types in patient blood samples.
Deep Learning for Automatic Diagnosis and Morphologic Characterization of Malignant Biliary Strictures Using Digital Cholangioscopy: A Multicentric Study
Authors: Saraiva Miguel Mascarenhas , Ribeiro Tiago , González-Haba Mariano , Agudo Castillo Belén , Ferreira João P. S. , Vilas Boas Filipe , Afonso João , Mendes Francisco , Martins Miguel , Cardoso Pedro , Pereira Pedro , Macedo Guilherme
Published: October 2023

Digital single-operator cholangioscopy (D-SOC) has enhanced the ability to diagnose indeterminate biliary strictures (BSs). Pilot studies using artificial intelligence (AI) models in D-SOC demonstrated promising results. Our group aimed to develop a convolutional neural network (CNN) for the identification and morphological characterization of malignant BSs in D-SOC. A total of 84,994 images from 129 D-SOC exams in two centers (Portugal and Spain) were used for developing the CNN. Each image was categorized as either a normal/benign finding or as malignant lesion (the latter dependent on histopathological results). Additionally, the CNN was evaluated for the detection of morphologic features, including tumor vessels and papillary projections. The complete dataset was divided into training and validation datasets. The model was evaluated through its sensitivity, specificity, positive and negative predictive values, accuracy and area under the receiver-operating characteristic and precision-recall curves (AUROC and AUPRC, respectively). The model achieved a 82.9% overall accuracy, 83.5% sensitivity and 82.4% specificity, with an AUROC and AUPRC of 0.92 and 0.93, respectively. The developed CNN successfully distinguished benign findings from malignant BSs. The development and application of AI tools to D-SOC has the potential to significantly augment the diagnostic yield of this exam for identifying malignant strictures.
Trefoil Family Factor Peptide 1—A New Biomarker in Liquid Biopsies of Retinoblastoma under Therapy
Authors: Busch Maike Anna , Haase André , Alefeld Emily , Biewald Eva , Jabbarli Leyla , Dünker Nicole
Published: October 2023

Effective management of retinoblastoma (RB), the most prevalent childhood eye cancer, depends on reliable monitoring and diagnosis. A promising candidate in this context is the secreted trefoil family factor peptide 1 (TFF1), recently discovered as a promising new biomarker in patients with a more advanced subtype of retinoblastoma. The present study investigated TFF1 expression within aqueous humor (AH) of enucleated eyes and compared TFF1 levels in AH and corresponding blood serum samples from RB patients undergoing intravitreal chemotherapy (IVC). TFF1 was consistently detectable in AH, confirming its potential as a biomarker. Crucially, our data confirmed that TFF1-secreting cells within the tumor mass originate from RB tumor cells, not from surrounding stromal cells. IVC-therapy-responsive patients exhibited remarkably reduced TFF1 levels post-therapy. By contrast, RB patients’ blood serum displayed low-to-undetectable levels of TFF1 even after sample concentration and no therapy-dependent changes were observed. Our findings suggest that compared with blood serum, AH represents the more reliable source of TFF1 if used for liquid biopsy RB marker analysis in RB patients. Thus, analysis of TFF1 in AH of RB patients potentially provides a minimally invasive tool for monitoring RB therapy efficacy, suggesting its importance for effective treatment regimens.
Deep Learning for Fully Automatic Tumor Segmentation on Serially Acquired Dynamic Contrast-Enhanced MRI Images of Triple-Negative Breast Cancer
Authors: Xu Zhan , Rauch David E. , Mohamed Rania M. , Pashapoor Sanaz , Zhou Zijian , Panthi Bikash , Son Jong Bum , Hwang Ken-Pin , Musall Benjamin C. , Adrada Beatriz E. , Candelaria Rosalind P. , Leung Jessica W. T. , Le-Petross Huong T. C. , Lane Deanna L. , Perez Frances , White Jason , Clayborn Alyson , Reed Brandy , Chen Huiqin , Sun Jia , Wei Peng , Thompson Alastair , Korkut Anil , Huo Lei , Hunt Kelly K. , Litton Jennifer K. , Valero Vicente , Tripathy Debu , Yang Wei , Yam Clinton , Ma Jingfei
Published: October 2023

Accurate tumor segmentation is required for quantitative image analyses, which are increasingly used for evaluation of tumors. We developed a fully automated and high-performance segmentation model of triple-negative breast cancer using a self-configurable deep learning framework and a large set of dynamic contrast-enhanced MRI images acquired serially over the patients’ treatment course. Among all models, the top-performing one that was trained with the images across different time points of a treatment course yielded a Dice similarity coefficient of 93% and a sensitivity of 96% on baseline images. The top-performing model also produced accurate tumor size measurements, which is valuable for practical clinical applications.
Differential Expression and Diagnostic Value of MUC5AC Glycoforms in Pancreatic Ductal Adenocarcinoma
Authors: Manne Ashish , Yu Lianbo , Hart Phil A , Tsung Allan , Esnakula Ashwini
Published: October 2023

We explored the differential expression and diagnostic value of two significant Mucin 5AC (MUC5AC) glycoforms, less-glycosylated immature (IM) and heavily-glycosylated mature (MM), in neoplastic diseases (NpD), including pancreatic ductal adenocarcinoma (PDA) and neuroendocrine tumors (NET), and non-neoplastic (non-NpD) diseases. Commercially available tissue microarray (TMA) was constructed from 96 patients, including 38 primary PDA (PT), 5 metastatic lesions (ML), 11 NET, and the rest being non-NpD tissues. Immunohistochemistry for MUC5AC was performed using CHL2 and 45M1 clones for IM and MM isoforms, respectively. MUC5AC (both glycoforms) are not detected in non-NpD. In MUC5AC-positive neoplastic tissues, IM was localized to the cytoplasm (Cy) while MM was identified in apical (Ap) and extracellular (Ec) regions too. One ML positive (omentum) in the TMA expressed both. For PDA vs. non-PDA, the sensitivity (SN) was higher with MM ± IM (71%) than MM (47%) or IM (65%)-alone. The specificity (SP) was 100% with MM-alone, which dropped with the addition of IM (96%) or IM-alone (93%). For NpD vs. non-NpD, the SN (MM + IM-59%, IM-55%, MM-37%) was inferior, and SP was 100% for both glycoforms (MM ± IM). The combination of MUC5AC glycoforms has high SP and reasonable SN to diagnose PDA. They have the potential to be a reliable diagnostic marker and should be investigated further in more extensive studies.
Vitamin D3 Inhibits the Viability of Breast Cancer Cells In Vitro and Ehrlich Ascites Carcinomas in Mice by Promoting Apoptosis and Cell Cycle Arrest and by Impeding Tumor Angiogenesis
Authors: Veeresh Prashanth Kumar M. , Basavaraju Chaithanya G. , Dallavalasa Siva , Anantharaju Preethi G. , Natraj Suma M. , Sukocheva Olga A. , Madhunapantula SubbaRao V.
Published: October 2023

The incidence of aggressive and resistant breast cancers is growing at alarming rates, indicating a necessity to develop better treatment strategies. Recent epidemiological and preclinical studies detected low serum levels of vitamin D in cancer patients, suggesting that vitamin D may be effective in mitigating the cancer burden. However, the molecular mechanisms of vitamin D3 (cholecalciferol, vit-D3)-induced cancer cell death are not fully elucidated. The vit-D3 efficacy of cell death activation was assessed using breast carcinoma cell lines in vitro and a widely used Ehrlich ascites carcinoma (EAC) breast cancer model in vivo in Swiss albino mice. Both estrogen receptor-positive (ER+, MCF-7) and -negative (ER-, MDA-MB-231, and MDA-MB-468) cell lines absorbed about 50% of vit-D3 in vitro over 48 h of incubation. The absorbed vit-D3 retarded the breast cancer cell proliferation in a dose-dependent manner with IC50 values ranging from 0.10 to 0.35 mM. Prolonged treatment (up to 72 h) did not enhance vit-D3 anti-proliferative efficacy. Vit-D3-induced cell growth arrest was mediated by the upregulation of p53 and the downregulation of cyclin-D1 and Bcl2 expression levels. Vit-D3 retarded cell migration and inhibited blood vessel growth in vitro as well as in a chorioallantoic membrane (CAM) assay. The intraperitoneal administration of vit-D3 inhibited solid tumor growth and reduced body weight gain, as assessed in mice using a liquid tumor model. In summary, vit-D3 cytotoxic effects in breast cancer cell lines in vitro and an EAC model in vivo were associated with growth inhibition, the induction of apoptosis, cell cycle arrest, and the impediment of angiogenic processes. The generated data warrant further studies on vit-D3 anti-cancer therapeutic applications.
The Design and Testing of a Text Message for Use as an Informational Nudge in a Novel Food Insecurity Intervention
Authors: Royer Michael F. , Wharton Christopher
Published: October 2023

Food insecurity is an ongoing problem in the U.S. with implications for health problems and social disadvantages. Past food insecurity intervention studies have targeted barriers to accessing healthy food. However, information barriers have not been adequately addressed by food insecurity interventions. This research included the first phase of a two-phase feasibility study that involved testing a text message as an informational nudge through interviews among a small, preliminary sample of adults in the southwest U.S. (n = 10). Interview questions focused on the message content, persuasiveness, relevancy, clarity, and details that participants liked and disliked. A qualitative content analysis of interview responses then highlighted any necessary modifications to the text message. Interview responses highlighted that the message conveyed details about how to access food assistance resources. The message was perceived as informative, clear, and friendly. Participants highlighted the need for better spacing in the message layout, more details about the Supplemental Nutrition Assistance Program (SNAP), and a better explanation for why SNAP is relevant. Text message readability, relevancy, and informativeness were common concerns raised during interviews. Participant-informed modifications to the text message were applied in preparation for using the message in a food insecurity intervention. This research is a novel contribution to the extant literature on nudges, as no known intervention study has used informational nudges to exclusively promote food security. Future food insecurity research efforts should similarly test novel interventions to ensure the intervention is acceptable and relevant for the target population.
Place-Based Strategies Addressing Neighborhood Environments to Improve Perinatal and Preterm Infant Outcomes
Authors: Nelin Timothy D. , Scott Kristan A. , Just Allan C. , Burris Heather H.
Published: October 2023

Preterm birth (defined as birth <37 weeks of gestation) is a significant health concern globally, with lasting implications for individuals, families, and society. In the United States, high preterm birth rates among Black and low-income populations likely result from differences in environmental exposures. Structural racism and economic disadvantage have led to unequal distribution of polluting industrial sites and roadways across society as well as differential access to health-promoting resources which contribute to preterm birth risk. Once born, preterm infants remain at risk for numerous environmentally responsive adverse health outcomes that affect growth and development throughout childhood and adulthood. In this commentary, we describe associations of neighborhood environments with pregnancy and preterm infant health outcomes and propose strategies to address harmful exposures that affect families across the lifespan.
SUMO-Activating Enzyme Subunit 1 Is Associated with Poor Prognosis, Tumor Progression, and Radio-Resistance in Colorectal Cancer
Authors: Wu Yueh-Jung , Huang Siang-Ting , Chang Ya-Hui , Lin Shih-Yi , Lin Weng-Ling , Chen Ying-Jung , Chien Shang-Tao
Published: October 2023

Concurrent chemoradiotherapy is an effective treatment option for patients with low-grade colorectal cancer (CRC) in the local disease stage. At present, the principle of the Taiwan Medical Center is to treat CRC patients with combination radiotherapy and chemotherapy (high-dose 5-FU) for a period of about five weeks prior to surgery. Radical resection of the tumor is performed at least six to eight weeks after concurrent chemoradiotherapy (CCRT). However, this approach fails to produce the desired therapeutic effect in approximately 20% to 30% of patients, and such patients are unnecessarily exposed to the risks of radiation and drug toxicity posed by this therapy. Therefore, it is crucial to explore new biomarkers to predict the prognosis of CRC. SUMO-activating enzyme subunit 1 (SAE1) plays an important role in SUMOylation, a post-translational modification involved in cellular functions, such as cell proliferation, cell cycle, and apoptosis. In our study, to explore the clinical–pathological role of SAE1 protein in CRC, we evaluated the clinical data and paraffin sections from CRC patients. The expression of SAE1 was evaluated using immunohistochemical analysis, and clinical parameters were analyzed using chi-square and Kaplan–Meier survival tests. The results of in vitro proliferation and radiosensitive assays were compared between control groups and SAE1 siRNA groups. Western blotting was also used to detect the expressions of the SAE1, PARP, cyclin D1, p-NF-κB, and NF-κB proteins. Flow cytometry and colony formation assays were used to detect the effect of SAE-1 on radiosensitivity. In vivo, we detected the growth curve in a mouse xenograft model. The results showed that SAE-1 was revealed to be an independent prognostic biomarker of CRC. SAE1 knockdown inhibited CRC proliferation in vitro and in vivo, and led to the cleavage of PARP, downregulation of cyclin D1 protein expression, and downregulation of p-NF-κB/NF-κB. Additionally, SAE1 knockdown promoted radiosensitivity in CRC cells. Therefore, it was inferred that SAE1 may be used as a potential therapeutic target in CRC treatment.
Tryptase-Positive Mast Cells Promote Adipose Fibrosis in Secondary Lymphedema through PDGF
Authors: Nuri Takashi , Jin Denan , Takai Shinji , Ueda Koichi
Published: October 2023

Lymphedema is a chronic and progressive condition that causes physical disfigurement and psychological trauma due to the accumulation of lymphatic fluid in the interstitial space. Once it develops, lymphedema is difficult to treat because it leads to the fibrosis of adipose tissue. However, the mechanism behind this remains unclear. The purpose of this study was to investigate the involvement of mast cells (MCs) in the adipose tissues of patients with lymphedema. We found that fibrosis spread through blood vessels in the adipose tissues of lymphedema patients, and the expression of the collagen I and III genes was significantly increased compared to that of those in normal adipose tissue. Immunostaining of vimentin and α-smooth muscle actin showed that fibroblasts were the main cellular components in severely fibrotic regions. Toluidine blue staining confirmed a significant increase in the number of MCs in the adipose tissues of lymphedema patients, and immunostaining of serial sections of adipose tissue showed a significant increase in the number of tryptase-positive cells in lymphedema tissues compared with those in normal adipose tissues. Linear regression analyses revealed significant positive correlations between tryptase and the expressions of the TNF-α, platelet-derived growth factor (PDGF)-A, and PDGFR-α genes. PDGF-A–positive staining was observed in both fibroblasts and granules of tryptase-positive MCs. These results suggest that MC-derived tryptase plays a role in the fibrosis of adipose tissue due to lymphedema directly or in cooperation with other mediators.
Prior Treatment with AICAR Causes the Selective Phosphorylation of mTOR Substrates in C2C12 Cells
Authors: Dedert Cass J. , Bagdady Kazimir R. , Fisher Jonathan S.
Published: October 2023

Metabolic stress in skeletal muscle cells causes sustained metabolic changes, but the mechanisms of the prolonged effects are not fully known. In this study, we tested C2C12 cells with the AMP-activated protein kinase (AMPK) stimulator AICAR and measured the changes in the metabolic pathways and signaling kinases. AICAR caused an acute increase in the phosphorylation of the AMPK target ULK1, the mTORC1 substrate S6K, and the mTORC2 target Akt. Intriguingly, prior exposure to AICAR only decreased glucose-6 phosphate dehydrogenase activity when it underwent three-hour recovery after exposure to AICAR in a bicarbonate buffer containing glucose (KHB) instead of Dulbecco’s Minimum Essential Medium (DMEM). The phosphorylation of the mTORC1 target S6K was increased after recovery in DMEM but not KHB, although this appeared to be specific to S6K, as the phosphorylation of the mTORC1 target site on ULK1 was not altered when the cells recovered in DMEM. The phosphorylation of mTORC2 target sites was also heterogenous under these conditions, with Akt increasing at serine 473 while other targets (SGK1 and PKCα) were unaffected. The exposure of cells to rapamycin (an mTORC1 inhibitor) and PP242 (an inhibitor of both mTOR complexes) revealed the differential phosphorylation of mTORC2 substrates. Taken together, the data suggest that prior exposure to AICAR causes the selective phosphorylation of mTOR substrates, even after prolonged recovery in a nutrient-replete medium.
Pomace from Oil Plants as a New Type of Raw Material for the Production of Environmentally Friendly Biocomposites
Authors: Betlej Izabela , Borysiuk Piotr , Borysiak Sławomir , Rybak Katarzyna , Nowacka Małgorzata , Barlak Marek , Andres Bogusław , Krajewski Krzysztof , Lipska Karolina , Cebulak Tomasz , Boruszewski Piotr
Published: October 2023

The production of environmentally friendly biocomposites can be based on attractive and low-cost vegetable pomace, a waste product from oil production. In the present study, biocomposites made from HDPE and pomace from black cumin, corn, and flax seeds were subjected to evaluation of structural, morphological, and thermal parameters and susceptibility to germination by filamentous fungi. Based on the characteristics of the produced biocomposites, it should be concluded that vegetable waste from oil production, applied at a 1:1 ratio as a filler for polyethylene-based biocomposites, significantly reduces the crystallinity of the produced material and decreases its thermal stability. It should also be noted that such biocomposites are more easily overgrown by fungi, which may facilitate their biodegradation. Very poor antioxidant properties, resulting from the encapsulation of the plant fraction in polyethylene, limit the functionality of this type of material as, for example, active biomaterials to prevent free radical processes. Although the structural and physical characteristics of the produced biocomposites have been shown to be inferior to polyethylene, efforts should be made to improve these characteristics. Plant waste can be a valuable raw material for the production of materials compatible with various industries.
Study on the Preparation of Nd–Doped Zinc Cobalt Oxide Porous Film and Its Electrochemical Properties
Authors: Yue Xinrui , Wang Jing , Wu Hongyu , Hao Tingting , Hao Jian , Liu Yang , Ma Tenghao , Yi Xiaolin
Published: October 2023

In this paper, ZnCo2O4(Nd–ZnCo2O4) films were prepared using a hydrothermal method and an electrodeposition method. We characterized the samples using X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The effect of Nd–ZnCo2O4 doping on the stability of the materials was studied. The results show that the Nd−ZnCo2O4 prepared in the experiment presents a porous network structure, no other impurity peaks and impurity elements exist, and the purity is high. In the experiment, the electrochemical properties of Nd−ZnCo2O4 were studied. When the current density is 3 A·g−1, the specific capacitance F·g−1 of the electrode is 1982 F·g−1. When the current density is changed 100 times, and every time it is changed back to 3 A·g−1, the specific capacitance F·g−1 is 1973 F·g−1, which is 99.5% of the initial specific capacitance F·g−1. 1982 F·g−1 indicates that Nd−ZnCo2O4 has good stability and can be reused many times. In the cycle stability performance test of Nd–ZnCo2O4//CNTs devices, when the current density is 3 A·g−1, the specific capacitance is 180 F·g−1. After 10,000 cycle charge discharge tests, the specific capacitance F·g−1 becomes 162 F·g−1, maintaining 90% of the initial specific capacitance. These results show that the electrode material has a long cycle life and good cycle stability.
Experimental Study on Cutting Force and Surface Integrity of TC4 Titanium Alloy with Longitudinal Ultrasonic-Assisted Milling
Authors: Lü Qingqing , Chai Yongbo , Yang Liquan , Liu Xiaodong , Li Guangxi , Xiang Daohui
Published: October 2023

The ultrasonic vibration-assisted milling process was used to study the difficult-to-machine aerospace material titanium alloy TC4 and explore the milling parameters that fit the processing. Based on the orthogonal experimental method, the changes in cutting force, roughness, and surface morphology under conventional and ultrasonic-assisted milling conditions were studied, and the relationship between various processing parameters and their effects was obtained. The results showed that the cutting force was most affected by the feed per tooth and cutting depth. Adding ultrasonic vibration could change the surface texture and significantly impact roughness. By adding an appropriate amplitude of ultrasonic-assisted milling, the maximum average cutting force can be reduced by more than 20.66%, and the maximum surface roughness can be reduced by 44.23%, making the workpiece surface produce regular “sine/cosine” patterns and improving the surface quality of the workpiece. Compared with conventional milling, the deformation layer of the workpiece slightly increased under ultrasonic-assisted milling. The cutting force and surface roughness of titanium alloy TC4 under ultrasonic-assisted milling were reduced. A reasonable selection of processing parameters can further improve cutting force and other parameters, providing a reference basis for the processing of aerospace materials.