bluuebunny/crossref_metadata_2025 huggingface dataset:
Urokinase-Type Plasminogen Activator Receptor (uPAR) Cooperates with Mutated KRAS in Regulating Cellular Plasticity and Gemcitabine Response in Pancreatic Adenocarcinomas
Authors: Peng Luogen , Li Yuchan , Yao Sha , Gaedcke Jochen , Baart Victor M. , Sier Cornelis F. M. , Neesse Albrecht , Ellenrieder Volker , Bohnenberger Hanibal , Fuchs Frieder , Kitz Julia , Ströbel Philipp , Küffer Stefan
Published: March 2023

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Given the currently limited therapeutic options, the definition of molecular subgroups with the development of tailored therapies remains the most promising strategy. Patients with high-level gene amplification of urokinase plasminogen activator receptor (uPAR/PLAUR) have an inferior prognosis. We analyzed the uPAR function in PDAC to understand this understudied PDAC subgroup’s biology better. Methods: A total of 67 PDAC samples with clinical follow-up and TCGA gene expression data from 316 patients were used for prognostic correlations. Gene silencing by CRISPR/Cas9, as well as transfection of uPAR and mutated KRAS, were used in PDAC cell lines (AsPC-1, PANC-1, BxPC3) treated with gemcitabine to study the impact of these two molecules on cellular function and chemoresponse. HNF1A and KRT81 were surrogate markers for the exocrine-like and quasi-mesenchymal subgroup of PDAC, respectively. Results: High levels of uPAR were correlated with significantly shorter survival in PDAC, especially in the subgroup of HNF1A-positive exocrine-like tumors. uPAR knockout by CRISPR/Cas9 resulted in activation of FAK, CDC42, and p38, upregulation of epithelial makers, decreased cell growth and motility, and resistance against gemcitabine that could be reversed by re-expression of uPAR. Silencing of KRAS in AsPC1 using siRNAs reduced uPAR levels significantly, and transfection of mutated KRAS in BxPC-3 cells rendered the cell more mesenchymal and increased sensitivity towards gemcitabine. Conclusions: Activation of uPAR is a potent negative prognostic factor in PDAC. uPAR and KRAS cooperate in switching the tumor from a dormant epithelial to an active mesenchymal state, which likely explains the poor prognosis of PDAC with high uPAR. At the same time, the active mesenchymal state is more vulnerable to gemcitabine. Strategies targeting either KRAS or uPAR should consider this potential tumor-escape mechanism.
The Impact of Gut Microbiota-Derived Metabolites on the Tumor Immune Microenvironment
Authors: Luu Maik , Schütz Burkhard , Lauth Matthias , Visekruna Alexander
Published: March 2023

Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way.
GBE1 Promotes Glioma Progression by Enhancing Aerobic Glycolysis through Inhibition of FBP1
Authors: Chen Zhen , Bao Han , Long Jingfang , Zhao Peiqi , Hu Xiaowei , Wang Hao , Zhang Ying , Yang Jianjing , Zhuge Qichuan , Xia Lei
Published: March 2023

Tumor metabolism characterized by aerobic glycolysis makes the Warburg effect a unique target for tumor therapy. Recent studies have found that glycogen branching enzyme 1 (GBE1) is involved in cancer progression. However, the study of GBE1 in gliomas is limited. We determined by bioinformatics analysis that GBE1 expression is elevated in gliomas and correlates with poor prognoses. In vitro experiments showed that GBE1 knockdown slows glioma cell proliferation, inhibits multiple biological behaviors, and alters glioma cell glycolytic capacity. Furthermore, GBE1 knockdown resulted in the inhibition of the NF-κB pathway as well as elevated expression of fructose-bisphosphatase 1 (FBP1). Further knockdown of elevated FBP1 reversed the inhibitory effect of GBE1 knockdown, restoring glycolytic reserve capacity. Furthermore, GBE1 knockdown suppressed xenograft tumor formation in vivo and conferred a significant survival benefit. Collectively, GBE1 reduces FBP1 expression through the NF-κB pathway, shifting the glucose metabolism pattern of glioma cells to glycolysis and enhancing the Warburg effect to drive glioma progression. These results suggest that GBE1 can be a novel target for glioma in metabolic therapy.
Assessment of Barriers and Challenges to Screening, Diagnosis, and Biomarker Testing in Early-Stage Lung Cancer
Authors: Zarinshenas Reza , Amini Arya , Mambetsariev Isa , Abuali Tariq , Fricke Jeremy , Ladbury Colton , Salgia Ravi
Published: March 2023

Management of lung cancer has transformed over the past decade and is no longer considered a singular disease as it now has multiple sub-classifications based on molecular markers. The current treatment paradigm requires a multidisciplinary approach. One of the most important facets of lung cancer outcomes however relies on early detection. Early detection has become crucial, and recent effects have shown success in lung cancer screening programs and early detection. In this narrative review, we evaluate low-dose computed tomography (LDCT) screening and how this screening modality may be underutilized. The barriers to broader implementation of LDCT screening is also explored as well as approaches to address these barriers. Current developments in diagnosis, biomarkers, and molecular testing in early-stage lung cancer are evaluated as well. Improving approaches to screening and early detection can ultimately lead to improved outcomes for patients with lung cancer.
Transcriptional Basis of Ca2+ Remodeling Reversal Induced by Polyamine Synthesis Inhibition in Colorectal Cancer Cells
Authors: Pérez-Riesgo Enrique , Hernando-Pérez Elena , Feijóo Verónica , Tajada Sendoa , Núñez Lucía , Villalobos Carlos
Published: March 2023

Colorectal cancer (CRC) is associated with mutations in APC/Wnt leading to c-myc activation and the overexpression of ODC1, the limiting step in polyamine synthesis. CRC cells also display a remodeling of intracellular Ca2+ homeostasis that contributes to cancer hallmarks. As polyamines may modulate Ca2+ homeostasis during epithelial tissue repair, we investigated whether polyamine synthesis inhibition may reverse Ca2+ remodeling in CRC cells and, if so, the molecular basis for this reversal. To this end, we used calcium imaging and transcriptomic analysis in normal and CRC cells treated with DFMO, an ODC1 suicide inhibitor. We found that polyamine synthesis inhibition partially reversed changes in Ca2+ homeostasis associated with CRC, including a decrease in resting Ca2+ and SOCE along with an increased Ca2+ store content. We also found that polyamine synthesis inhibition reversed transcriptomic changes in CRC cells without affecting normal cells. Specifically, DFMO treatment enhanced the transcription of SOCE modulators CRACR2A; ORMDL3; and SEPTINS 6, 7, 8, 9, and 11, whereas it decreased SPCA2, involved in store-independent Orai1 activation. Therefore, DFMO treatment probably decreased store-independent Ca2+ entry and enhanced SOCE control. Conversely, DFMO treatment decreased the transcription of the TRP channels TRPC1 and 5, TRPV6, and TRPP1 while increasing TRPP2, thus probably decreasing Ca2+ entry through TRP channels. Finally, DFMO treatment enhanced the transcription of the PMCA4 Ca2+ pump and mitochondrial channels MCU and VDAC3 for enhanced Ca2+ extrusion through the plasma membrane and mitochondria. Collectively, these findings suggested the critical role of polyamines in Ca2+ remodeling in colorectal cancer.
A Biterm Topic Model for Sparse Mutation Data
Authors: Sason Itay , Chen Yuexi , Leiserson Mark D. M. , Sharan Roded
Published: March 2023

Mutational signature analysis promises to reveal the processes that shape cancer genomes for applications in diagnosis and therapy. However, most current methods are geared toward rich mutation data that has been extracted from whole-genome or whole-exome sequencing. Methods that process sparse mutation data typically found in practice are only in the earliest stages of development. In particular, we previously developed the Mix model that clusters samples to handle data sparsity. However, the Mix model had two hyper-parameters, including the number of signatures and the number of clusters, that were very costly to learn. Therefore, we devised a new method that was several orders-of-magnitude more efficient for handling sparse data, was based on mutation co-occurrences, and imitated word co-occurrence analyses of Twitter texts. We showed that the model produced significantly improved hyper-parameter estimates that led to higher likelihoods of discovering overlooked data and had better correspondence with known signatures.
Lenalidomide Maintenance and Measurable Residual Disease in a Real-World Multiple Myeloma Transplanted Population Receiving Different Treatment Strategies Guided by Access to Novel Drugs in Brazil
Authors: Salgado Anna Beatriz dos Santos , Magalhães Roberto Jose Pessoa , Pontes Robéria M. , Barbosa Eduarda da Silva , Flores-Montero Juan , Sanoja-Flores Luzalba , Land Marcelo Gerardin Poirot , Pimenta Glicinia , Dutra Hélio dos Santos , Costa Elaine S. , Orfao Alberto , Maiolino Angelo
Published: March 2023

Despite recent advances in multiple myeloma (MM), the incorporation of novel agents and measurable residual disease (MRD) monitoring in low-income countries remains a challenge. Although lenalidomide maintenance (M-Len) after autologous stem cell transplantation (ASCT) has been associated with improved outcomes and MRD has refined the prognosis of complete response (CR) cases, until now, there have been no data on the benefits of these approaches in Latin America. Here, we evaluate the benefits of M-Len and MRD using next-generation flow cytometry (NGF-MRD) at Day + 100 post-ASCT (n = 53). After ASCT, responses were evaluated based on the International Myeloma Working Group criteria and NGF-MRD. MRD was positive in 60% of patients with a median progression-free survival (PFS) of 31 months vs. not reached (NR) for MRD-negative cases (p = 0.05). The patients who received M-Len continuously had a significantly better PFS and overall survival (OS) than those without M-Len (median PFS: NR vs. 29 months, p = 0.007), with progression in 11% vs. 54% of cases after a median follow-up of 34 months, respectively. In a multivariate analysis, MRD status and M-Len therapy emerged as independent predictors of PFS (median PFS of M-Len/MRD− vs. no M-Len/MRD+ of NR vs. 35 months, respectively; p = 0.01). In summary, M-Len was associated with improved survival outcomes in our real-world MM cohort in Brazil, with MRD emerging as a useful reproducible tool to identify patients at an earlier risk of relapse. The inequity in drug access remains a hurdle in countries with financial constraints, with a negative impact on MM survival.
Clinical-Radiomics Nomogram Based on Contrast-Enhanced Ultrasound for Preoperative Prediction of Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma
Authors: Jiang Liqing , Zhang Zijian , Guo Shiyan , Zhao Yongfeng , Zhou Ping
Published: March 2023

This study aimed to establish a new clinical-radiomics nomogram based on ultrasound (US) for cervical lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). We collected 211 patients with PTC between June 2018 and April 2020, then we randomly divided these patients into the training set (n = 148) and the validation set (n = 63). 837 radiomics features were extracted from B-mode ultrasound (BMUS) images and contrast-enhanced ultrasound (CEUS) images. The maximum relevance minimum redundancy (mRMR) algorithm, least absolute shrinkage and selection operator (LASSO) algorithm, and backward stepwise logistic regression (LR) were applied to select key features and establish a radiomics score (Radscore), including BMUS Radscore and CEUS Radscore. The clinical model and clinical-radiomics model were established using the univariate analysis and multivariate backward stepwise LR. The clinical-radiomics model was finally presented as a clinical-radiomics nomogram, the performance of which was evaluated by the receiver operating characteristic curves, Hosmer–Lemeshow test, calibration curves, and decision curve analysis (DCA). The results show that the clinical-radiomics nomogram was constructed by four predictors, including gender, age, US-reported LNM, and CEUS Radscore. The clinical-radiomics nomogram performed well in both the training set (AUC = 0.820) and the validation set (AUC = 0.814). The Hosmer–Lemeshow test and the calibration curves demonstrated good calibration. The DCA showed that the clinical-radiomics nomogram had satisfactory clinical utility. The clinical-radiomics nomogram constructed by CEUS Radscore and key clinical features can be used as an effective tool for individualized prediction of cervical LNM in PTC.
Sodium New Houttuyfonate Induces Apoptosis of Breast Cancer Cells via ROS/PDK1/AKT/GSK3β Axis
Authors: He Lixin , Feng Huili , Yin Baoyi , Li Wenxuan , Wang Xiao , Umar Talha , Gao Hongbo , Zhou Ning , Qiu Changwei
Published: March 2023

Background: Sodium new houttuyfonate (SNH) has been reported to have anti-inflammatory, anti-fungal, and anti-cancer effects. However, few studies have investigated the effect of SNH on breast cancer. The aim of this study was to investigate whether SNH has therapeutic potential for targeting breast cancer. Methods: Immunohistochemistry and Western blot analysis were used to examine the expression of proteins, flow cytometry was used to detect cell apoptosis and ROS levels, and transmission electron microscopy was used to observe mitochondria. Results: Differentially expressed genes (DEGs) between breast cancer-related gene expression profiles (GSE139038 and GSE109169) from GEO DataSets were mainly involved in the immune signaling pathway and the apoptotic signaling pathway. According to in vitro experiments, SNH significantly inhibited the proliferation, migration, and invasiveness of MCF-7 (human cells) and CMT-1211 (canine cells) and promoted apoptosis. To explore the reason for the above cellular changes, it was found that SNH induced the excessive production of ROS, resulting in mitochondrial impairment, and then promoted apoptosis by inhibiting the activation of the PDK1-AKT-GSK3β pathway. Tumor growth, as well as lung and liver metastases, were suppressed under SNH treatment in a mouse breast tumor model. Conclusions: SNH significantly inhibited the proliferation and invasiveness of breast cancer cells and may have significant therapeutic potential in breast cancer.
First-Line Immunotherapy with Check-Point Inhibitors: Prospective Assessment of Cognitive Function
Authors: Myers Jamie S. , Parks Adam C. , Mahnken Jonathan D. , Young Kate J. , Pathak Harsh B. , Puri Rajni V. , Unrein Amber , Switzer Phyllis , Abdulateef Yazan , Sullivan Samantha , Walker John F. , Streeter David , Burns Jeffrey M.
Published: March 2023

Approximately 40% of patients with cancer are eligible for check-point inhibitor (CPI) therapy. Little research has examined the potential cognitive impact of CPIs. First-line CPI therapy offers a unique research opportunity without chemotherapy-related confounders. The purpose of this prospective, observational pilot was to (1) demonstrate the feasibility of prospective recruitment, retention, and neurocognitive assessment for older adults receiving first-line CPI(s) and (2) provide preliminary evidence of changes in cognitive function associated with CPI(s). Patients receiving first-line CPI(s) (CPI Group) were assessed at baseline (n = 20) and 6 months (n = 13) for self-report of cognitive function and neurocognitive test performance. Results were compared to age-matched controls without cognitive impairment assessed annually by the Alzheimer’s Disease Research Center (ADRC). Plasma biomarkers were measured at baseline and 6 months for the CPI Group. Estimated differences for CPI Group scores prior to initiating CPIs (baseline) trended to lower performance on the Montreal Cognitive Assessment-Blind (MOCA-Blind) test compared to the ADRC controls (p = 0.066). Controlling for age, the CPI Group’s 6-months MOCA-Blind performance was lower than the ADRC control group’s 12-months performance (p = 0.011). No significant differences in biomarkers were detected between baseline and 6 months, although significant correlations were noted for biomarker change and cognitive performance at 6 months. IFNγ, IL-1β, IL-2, FGF2, and VEGF were inversely associated with Craft Story Recall performance (p < 0.05), e.g., higher levels correlated with poorer memory performance. Higher IGF-1 and VEGF correlated with better letter-number sequencing and digit-span backwards performance, respectively. Unexpected inverse correlation was noted between IL-1α and Oral Trail-Making Test B completion time. CPI(s) may have a negative impact on some neurocognitive domains and warrant further investigation. A multi-site study design may be crucial to fully powering prospective investigation of the cognitive impact of CPIs. Establishment of a multi-site observational registry from collaborating cancer centers and ADRCs is recommended.
Temperature Distribution and Thermal Criticality of Kinetics Exothermic Reactant in Concentric Cylinders Subject to Various Boundary Conditions
Authors: Salawu Sulyman Olakunle , Okoya Samuel Segun
Published: March 2023

A study of the high-heat distribution of reacting species with approximation kinetics is essential in practical applications, for example, chemical synthesis, explosion safety and propulsion denotatives. As such, the temperature distribution and thermal criticality of an exothermic kinetics species in a concentric cylinder is the focus of this study. The chemistry of the pre-exponential factor, termination step, initiation rate and branch chain of the combustible reactant is investigated to study the system’s critical behaviour. The temperature is assumed not to be large; as such, the consumption of reactant species is ignored. A partition weighted residual semi-analytical approximate solution to heat propagation under boundary conditions, thermal ignition and branch chain for varying activation energies and chemical kinetics is discussed. The solution validation criteria for the approximate semi-analytical method and numerical method are established. This study ascertained the impact of boundary conditions on the explosion, and the effect of certain parameter changes on the heat distribution and thermal criticality was shown to be significant. Hence, the outcomes offer an understanding into the homogeneous species behaviour in a cylindrical geometry.
Design of Peptide Ligand for Lactoferrin and Study of Its Binding Specificity
Authors: Zimina Tatiana , Sitkov Nikita , Karasev Vladimir , Skorik Yury , Kolobov Alexey , Kolobov Alexander , Bunenkov Nikolay , Luchinin Viktor
Published: March 2023

The in silico modelling of peptides complementary to lactoferrin was carried out using the Protein 3D software package and replication of the natural bonding site between pneumococcal surface protein (PSP) and lactoferrin (LF). The modeling was based on analysis of the conjugated ion–hydrogen bond systems between these proteins (CIHBS). The oligopeptide EEVAPQAQAKIAELENQVHRLE was proposed via computer modelling and synthesized using the solid phase synthesis technique, purified, and analyzed with MS and HPLC methods to confirm >95% purity. The peptide was then studied by capillary electrophoresis (CE). The CE experiments demonstrated the split of peptide zone in the presence of LF, due to complex formation and subsequent mobility change of the system peptide-protein. The reference experiments with homomyeloperoxidase and myoglobin did not show binding with LETI-11.
An Accessible Yarn-Based Sensor for In-Field Detection of Succinylcholine Poisoning
Authors: Ong Victor , Cortez Nicholas R. , Xu Ziru , Amirghasemi Farbod , Abd El-Rahman Mohamed K. , Mousavi Maral P. S.
Published: March 2023

Succinylcholine (SUX) is a clinical anesthetic that induces temporary paralysis and is degraded by endogenous enzymes within the body. In high doses and without respiratory support, it results in rapid and untraceable death by asphyxiation. A potentiometric thread-based method was developed for the in-field and rapid detection of SUX for forensic use. We fabricated the first solid-contact SUX ion-selective electrodes from cotton yarn, a carbon black ink, and a polymeric ion-selective membrane. The electrodes could selectively measure SUX in a linear range of 1 mM to 4.3 μM in urine, with a Nernstian slope of 27.6 mV/decade. Our compact and portable yarn-based SUX sensors achieved 94.1% recovery at low concentrations, demonstrating feasibility in real-world applications. While other challenges remain, the development of a thread-based ion-selective electrode for SUX detection shows that it is possible to detect this poison in urine and paves the way for other low-cost, rapid forensic diagnostic devices.
Gut Leakage Markers and Cognitive Functions in Patients with Attention-Deficit/Hyperactivity Disorder
Authors: Lee Sheng-Yu , Li Sung-Chou , Yang Chia-Yu , Kuo Ho-Chang , Chou Wen-Jiun , Wang Liang-Jen
Published: March 2023

Attention-deficit/hyperactivity disorder (ADHD) is a commonly seen mental disorder in children. Intestinal permeability may be associated with the pathogenesis of ADHD. The study herein investigated the role of gut leakage biomarkers in the susceptibility of ADHD. A total of 130 children with ADHD and 73 healthy controls (HC) individuals were recruited. Serum concentrations of zonulin, occludin, and defensin (DEFA1) were determined. Visual attention was assessed with Conners’ continuous performance test (CPT). In order to rate participants’ ADHD core symptoms at home and school, their parents and teachers completed the Swanson, Nolan, and Pelham—Version IV Scale (SNAP-IV), respectively. We found significantly lower DEFA1 levels in the ADHD group compared to that in the HC group (p = 0.008), but not serum levels of zonulin and occludin. The serum levels of DEFA1 showed an inverse correlation with the inattention scores in the SNAP-IV parent form (p = 0.042) and teacher form (p = 0.010), and the hyperactivity/impulsivity scores in the SNAP-IV teacher form (p = 0.014). The serum levels of occludin showed a positive correlation with the subtest of detectability in the CPT (p = 0.020). Our study provides new reference into the relation between gut leakage markers and cognition, which may advance research of the pathophysiology of ADHD.
Crocin Attenuates NLRP3 Inflammasome Activation by Inhibiting Mitochondrial Reactive Oxygen Species and Ameliorates Monosodium Urate-Induced Mouse Peritonitis
Authors: Sangare Ruth , Madhi Iskander , Kim Ji-Hee , Kim YoungHee
Published: March 2023

Crocin is a hydrophilic carotenoid pigment found in the stigma of Crocus sativus or the fruit of Gardenia jasminoides. In this study, we investigated the effects of Crocin on the activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome in J774A.1 murine macrophage cells and monosodium urate (MSU)-induced peritonitis. Crocin significantly inhibited Nigericin-, adenosine triphosphate (ATP)-, MSU-induced interleukin (IL)-1β secretion, and caspase-1 cleavage without affecting pro-IL-1β and pro-caspase-1. Crocin also suppressed gasdermin-D cleavage and lactate dehydrogenase release and enhanced cell viability, indicating that Crocin reduces pyroptosis. Similar effects were observed in primary mouse macrophages. However, Crocin did not affect poly(dA:dT)-induced absent in melanoma 2 (AIM2) and muramyl dipeptide-induced NLRP1 inflammasomes. Crocin decreased Nigericin-induced oligimerization and the speck formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Crocin also dramatically alleviated the ATP-induced production of mitochondrial reactive oxygen species (mtROS). Finally, Crocin ameliorated the MSU-induced production of IL-1β and IL-18 and the recruitment of neutrophils during peritoneal inflammation. These results suggest that Crocin suppresses NLRP3 inflammasome activation by blocking mtROS production and ameliorates MSU-induced mouse peritonitis. Thus, Crocin may have therapeutic potential in various NLRP3 inflammasome-related inflammatory diseases.
The Landscape and Therapeutic Targeting of BRCA1, BRCA2 and Other DNA Damage Response Genes in Pancreatic Cancer
Authors: Voutsadakis Ioannis A. , Digklia Antonia
Published: March 2023

Genes participating in the cellular response to damaged DNA have an important function to protect genetic information from alterations due to extrinsic and intrinsic cellular insults. In cancer cells, alterations in these genes are a source of genetic instability, which is advantageous for cancer progression by providing background for adaptation to adverse environments and attack by the immune system. Mutations in BRCA1 and BRCA2 genes have been known for decades to predispose to familial breast and ovarian cancers, and, more recently, prostate and pancreatic cancers have been added to the constellation of cancers that show increased prevalence in these families. Cancers associated with these genetic syndromes are currently treated with PARP inhibitors based on the exquisite sensitivity of cells lacking BRCA1 or BRCA2 function to inhibition of the PARP enzyme. In contrast, the sensitivity of pancreatic cancers with somatic BRCA1 and BRCA2 mutations and with mutations in other homologous recombination (HR) repair genes to PARP inhibitors is less established and the subject of ongoing investigations. This paper reviews the prevalence of pancreatic cancers with HR gene defects and treatment of pancreatic cancer patients with defects in HR with PARP inhibitors and other drugs in development that target these molecular defects.
Identification of Dietary Bioflavonoids as Potential Inhibitors against KRAS G12D Mutant—Novel Insights from Computer-Aided Drug Discovery
Authors: Ramalingam Prasanna Srinivasan , Balakrishnan Purushothaman , Rajendran Senthilnathan , Jothi Arunachalam , Ramalingam Rajasekaran , Arumugam Sivakumar
Published: March 2023

The KRAS G12D mutation is very frequent in many cancers, such as pancreatic, colon and lung, and has remained undruggable for the past three decades, due to its smooth surface and lack of suitable pockets. Recent small pieces of evidence suggest that targeting the switch I/II of KRAS G12D mutant could be an efficient strategy. Therefore, in the present study, we targeted the switch I (residues 25–40) and switch II (residues 57–76) regions of KRAS G12D with dietary bioflavonoids in comparison with the reference KRAS SI/II inhibitor BI-2852. Initially, we screened 925 bioflavonoids based on drug-likeness properties, and ADME properties and selected 514 bioflavonoids for further studies. Molecular docking resulted in four lead bioflavonoids, namely 5-Dehydroxyparatocarpin K (L1), Carpachromene (L2), Sanggenone H (L3), and Kuwanol C (L4) with binding affinities of 8.8 Kcal/mol, 8.64 Kcal/mol, 8.62 Kcal/mol, and 8.58 Kcal/mol, respectively, in comparison with BI-2852 (−8.59 Kcal/mol). Further steered-molecular dynamics, molecular-dynamics simulation, toxicity, and in silico cancer-cell-line cytotoxicity predictions significantly support these four lead bioflavonoids as potential inhibitors of KRAS G12D SI/SII inhibitors. We finally conclude that these four bioflavonoids have potential inhibitory activity against the KRAS G12D mutant, and are further to be studied in vitro and in vivo, to evaluate their therapeutic potential and the utility of these compounds against KRAS G12D mutated cancers.
Selection Strategy of F4-Style Algorithm to Solve MQ Problems Related to MPKC
Authors: Kurokawa Takashi , Ito Takuma , Shinohara Naoyuki , Yamamura Akihiro , Uchiyama Shigenori
Published: March 2023

Multivariate public-key cryptosystems are potential candidates for post-quantum cryptography. The security of multivariate public-key cryptosystems relies on the hardness of solving a system of multivariate quadratic polynomial equations. Faugère’s F4 algorithm is one of the solution techniques based on the theory of Gröbner bases and selects critical pairs to compose the Macaulay matrix. Reducing the matrix size is essential. Previous research has not fully examined how many critical pairs it takes to reduce to zero when echelonizing the Macaulay matrix in rows. Ito et al. (2021) proposed a new critical-pair selection strategy for solving multivariate quadratic problems associated with encryption schemes. Instead, this paper extends their selection strategy for solving the problems associated with digital signature schemes. Using the OpenF4 library, we compare the software performance between the integrated F4-style algorithm of the proposed methods and the original F4-style algorithm. Our experimental results demonstrate that the proposed methods can reduce the processing time of the F4-style algorithm by up to a factor of about seven under certain specific parameters. Moreover, we compute the minimum number of critical pairs to reduce to zero and propose their extrapolation outside our experimental scope for further research.
SPS-Prepared High-Entropy (Bi0.2Na0.2Sr0.2Ba0.2Ca0.2)TiO3 Lead-Free Relaxor-Ferroelectric Ceramics with High Energy Storage Density
Authors: Lu Ya , Zhang Haibo , Yang Huabin , Fan Pengyuan , Samart Chanatip , Takesue Naohisa , Tan Hua
Published: March 2023

Compared to batteries and electrochemical capacitors, dielectric capacitors are widely studied because of their huge advantages in terms of charging/discharging speed and power density. In this work, high-entropy (Bi0.2Na0.2Sr0.2Ba0.2Ca0.2)TiO3 lead-free relaxor-ferroelectric ceramics were prepared by both conventional sintering (CS) and spark plasma sintering (SPS). The results showed that the ceramic prepared by SPS obtained a high energy storage density of 6.66 J/cm3 and a satisfied energy storage efficiency of 77.2% under an electric field of 430 kV/cm. This is directly related to the high density, fine grains, number of oxygen vacancies, and composition uniformity of the SPS samples. This study provides a new path for the preparation of high-entropy dielectric energy storage ceramics with high energy storage properties.
Properties of ScAlMgO4 as Substrate for Nitride Semiconductors
Authors: Matsuoka Takashi , Morioka Hitoshi , Semboshi Satoshi , Okada Yukihiko , Yamamura Kazuya , Kuboya Shigeyuki , Okamoto Hiroshi , Fukuda Tsuguo
Published: March 2023

SCAM has been expected to be a suitable substrate for GaN blue-light-emitting-diodes (LEDs) and high-power high electron mobility transistors (HEMTs) because of its lower lattice mismatch to GaN than that of the widely used sapphire. Considering both potential device applications, the crystal lattice and optical properties of SCAM substrates were investigated on selected high quality samples. As lattice parameters, the thermal expansion coefficient as well as the lattice constant were extrapolated from room temperature to 2000 °C by using a high temperature X-ray diffraction (XRD) system with the heating unit on a sample stage. The thermal conductance, which is also important for growing bulk SCAM crystals and the operation of devices on the SCAM substrate, was measured. Raman scattering measurements were carried out to better understand crystal lattice characteristics. It was clearly confirmed that prepared SCAM crystals were of high quality. Similar to sapphire, SCAM has the high transparency over the wide wavelength range from ultraviolet to mid-infrared. The refractive index, important for the design of any optical devices, was measured. From these results, it can be said that SCAM is a suitable substrate for nitride devices, especially LEDs and solar cells.
Structural Properties of He-Irradiated Zr/Nb Multilayer Investigated by Grazing Incidence X-ray Diffraction
Authors: Wang Tao , Li Bingsheng , Li Jun , Wei Haiyuan , Zhou Junjun , Dong Pan , Li Jie , Krsjak Vladimir
Published: March 2023

Zr/Nb nanoscale multilayers are regarded as one of the important candidate materials used in next-generation reactors. Understanding structural evolution induced by ion bombardment is crucial for the evaluation of lifetime performance. Magnetron sputter-deposited Zr/Nb multilayers with a periodicity of 7 nm were subjected to 300 keV He ion irradiation with three different fluences at room temperature. The depth-resolved strain and damage profiles in the Zr/Nb multilayers were investigated by grazing incidence X-ray diffraction. The tensile strain was found in the deposited Zr/Nb films. After He ion irradiation, the intensity of diffraction peaks increased. The change in diffraction peaks depends on He fluence and incident angle. Irradiation-induced pre-existing defect annealing was observed and the ability to recover the microstructure was more significant in the Zr films compared to the Nb films. Furthermore, the efficiency of defect annealing depends on the concentration of pre-existing defects and He fluence. When the He fluence exceeds the one for pre-existing defect annealing, residual defects will be formed, such as 1/3<12¯10> and 1/3<11¯00> dislocation loops in the Zr films and 1/2<111> dislocation loops in the Nb films. Finally, introducing deposited defects and interfaces can improve the radiation resistance of Zr/Nb nanoscale multilayers. These findings can be extended to other multilayers in order to develop candidate materials for fusion and fission systems with high radiation resistance.
Immune Checkpoint Inhibitors-Associated Thrombosis: Incidence, Risk Factors and Management
Authors: Wang Tzu-Fei , Carrier Marc
Published: March 2023

Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased risk of venous thromboembolism compared to non-cancer patients, and the risks increase further with anticancer therapies including ICIs. Cancer-associated thrombosis can lead to hospitalizations, delayed cancer treatment, and mortality. While thrombosis was not reported as a major complication in initial clinical trials leading to the approval of ICIs, emerging evidence from post-marketing studies revealed concerning risks of thrombosis in patients receiving ICIs. However, results remained heterogenous given differences in study designs and populations. Recent studies also showed that C-reactive protein dynamics might be an easily accessible biomarker for thrombosis and disease response in this population. In addition, early findings indicated that a commonly used anticoagulant for cancer-associated thrombosis, factor Xa inhibitors, might have potential synergistic antitumor effects when combined with ICIs. Herein we will review the current literature on the incidence, risk factors, and management of thrombosis in patients with cancer receiving ICIs. We aim to provide valuable information for clinicians in managing these patients.
Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma
Authors: Wu Jian , Fan Shengjun , Feinberg Daniel , Wang Xiaobei , Jabbar Shaima , Kang Yubin
Published: March 2023

Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein–protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.
Vertebral Primary Bone Lesions: Review of Management Options
Authors: Chalamgari Anjalika , Valle Daisy , Palau Villarreal Xuban , Foreman Marco , Liu Annika , Patel Aashay , Dave Akanksha , Lucke-Wold Brandon
Published: March 2023

The assessment and treatment of vertebral primary bone lesions continue to pose a unique yet significant challenge. Indeed, there exists little in the literature in the way of compiling and overviewing the various types of vertebral lesions, which can often have complicated intervention strategies. Given the severe consequences of mismanaged vertebral bone tumors—including the extreme loss of motor function—it is clear that such an overview of spinal lesion care is needed. Thus, in the following paper, we aim to address the assessment of various vertebral primary bone lesions, outlining the relevant nonsurgical and surgical interventional methods. We describe examples of primary benign and malignant tumors, comparing and contrasting their differences. We also highlight emerging treatments and approaches for these tumors, like cryoablation and stereotactic body radiation therapy. Ultimately, we aim to emphasize the need for further guidelines in regard to correlating lesion type with proper therapy, underscoring the innate diversity of vertebral primary bone lesions in the literature.
New and Noteworthy Taxa of the Genus Dactylorhiza Necker ex Nevski (Orchidaceae Juss.) in Kazakhstan Flora and Its Response to Global Warming
Authors: Sumbembayev Aidar A. , Nowak Sławomir , Burzacka-Hinz Aleksandra , Kosiróg-Ceynowa Adrianna , Szlachetko Dariusz L.
Published: March 2023

A critical study of the herbarium material representing the orchid genus Dactylorhiza Necker ex Nevski in Kazakhstan was conducted in 2019–2020. The information on the species composition was clarified. Dactylorhiza fuchsii subsp. hebridensis (Wilmott) Soó and D. × kerneri (Soó) Soó were identified for the first time in the country. New taxa were noted for individual botanical and geographical areas. All taxa were presented in the list and annotated with studied herbarium materials from the Kazakhstan area. Based on the collected and available locations for the studied taxa, distribution modeling was carried out for the four taxa (D. incarnata, D. majalis subsp. baltica, D. salina, and D. umbrosa). Bioclimatic data for the present and future (2041–2060) based on four possible scenarios were used. The occurrence of Dactylorhiza representatives in Kazakhstan is threatened by global climate warming. It is likely that some of them may not occur in the country in the future (D. incarnata and D. majalis subsp. baltica), losing up to 99.87% of their modern range or their range may be significantly reduced (D. salina and D. umbrosa), losing up to 80.83% of their present distribution. It is worth considering global changes in planning conservation activities and identifying areas that may play a significant role in the functioning of the national flora in the future.
Assessment of the Diversity, Distinctiveness and Conservation of Australia’s Central Queensland Coastal Rainforests Using DNA Barcoding
Authors: Howard Marion , Pearl Hilary , McDonald William J. F. , Shimizu Yoko , Srivastava Sanjeev Kumar , Shapcott Alison
Published: March 2023

Globally threatened dry rainforests are poorly studied and conserved when compared to mesic rainforests. Investigations of dry rainforest communities within Australia are no exception. We assessed the community diversity, distinctiveness and level of conservation in Central Queensland coastal dry rainforest communities. Our three-marker DNA barcode-based phylogeny, based on rainforest species from the Central Queensland Coast, was combined with the phylogeny from Southeast Queensland. The phylogenetic tree and Central Queensland Coast (CQC) community species lists were used to evaluate phylogenetic diversity (PD) estimates and species composition to pinpoint regions of significant rainforest biodiversity. We evaluated the patterns and relationships between rainforest communities of the biogeographical areas of Central Queensland Coast and Southeast Queensland, and within and between Subregions. Subsequently, we identified areas of the highest distinctiveness and diversity in phylogenetically even rainforest communities, consistent with refugia, and areas significantly more related than random, consistent with expansion into disturbed or harsher areas. We found clear patterns of phylogenetic clustering that suggest that selection pressures for moisture and geology were strong drivers of rainforest distribution and species diversity. These results showed that smaller dry rainforests in Central Queensland Coast (CQC) represented areas of regional plant migration but were inadequately protected. To sustain species diversity and distribution under intense selection pressures of moisture availability and substrate type throughout this dry and geologically complex region, the future conservation of smaller patches is essential.
Forest Matters Most for Hirsutiella zachvatkini (Schluger, 1948): A Survey of Rodent Infestation in Four Localities within the Mazury Lake District, NE Poland
Authors: Moniuszko Hanna , Wężyk Dagmara , Chrabąszcz Mariusz , Alsarraf Mustafa , Grzybek Maciej , Nowicka Joanna , Krupińska Martyna , Goll Aleksander , Romanek Wiktoria , Małaszewicz Wiktoria , Scholz Elżbieta , Behnke Jerzy M. , Bajer Anna
Published: March 2023

The family Trombiculidae encompasses numerous and widespread mites, the larvae of which are obligatory parasites of vertebrates. Our research objective was to assess how trombiculid burdens on rodents inhabiting three forested and one open area in NE Poland vary in relation to host identity, sex and body size, and how they are influenced by qualities of the habitat. Trapped rodents (n = 240) were measured, weighted and screened for ectoparasites. Apodemus flavicollis (n = 42) and Myodes glareolus (n = 173) harbored a total of 4652 Hirsutiella zachchvatkini larvae. Statistical tests revealed that both prevalence and abundance were significantly higher in voles (93%, 27 larvae/ind.) than in mice (14%, 0.24 larvae/ind.) but there was no effect of host sex. Among the localities, H. zachvatkini was most prevalent (98%) and abundant (41 larvae/ind.) in rodents from the deciduous mixed forest in Tałty compared to fallow land (2.6%, 0.13 larvae/ind.). The highest prevalence and abundance were found in bank voles; in this host species in Tałty, prevalence reached 100% and the mean abundance was >42 larvae/ind. Significant positive correlations were found between the body mass and body length of voles and the number of attached larvae. Our results confirm the sylvan nature of H. zachvatkini and its preference for bank voles inhabiting deciduous forests with rich and humid undergrowth. The lack of a sex bias and the moderate correlation between mite burden and host size are in line with observations already made on other rodent-associated Trombiculidae.
CAD-Based Design Optimization of Four-Bar Mechanisms: An Emergency Ventilator Case Study
Authors: Ben Yahya Abdelmajid , Van Oosterwyck Nick , Knaepkens Ferre , Houwen Simon , Herregodts Stijn , Herregodts Jan , Vanwalleghem Bart , Cuyt Annie , Derammelaere Stijn
Published: March 2023

The design optimization of mechanisms is promising as it results in more energy-efficient machines without compromising performance. However, machine builders do not apply state-of-the-art methods, as these algorithms require case-specific theoretical analysis. Moreover, the design synthesis approaches in the literature predominantly utilize heuristic optimizers, leading to suboptimal local minima. This paper introduces a widely applicable workflow, guaranteeing the global optimum. The constraints describing the feasible region of the possible designs are essential to find the global optimum. Therefore, kinematic analysis of the point-to-point planar four-bar mechanism is discussed. Within the feasible design space, objective value samples were generated through the CAD multi-body software. These motion simulations determine the required torque to fulfill the movement for a combination of design parameters. This replaces the cumbersome analytic derivation of the torque. This paper introduces sparse interpolation techniques to avoid brute force sampling of the design space. The advantage of this approach is that it is easily scalable to more design parameters, as the interpolation method minimizes the number of necessary samples. This paper explains the mathematical background of our developed interpolation approach. However, a step-by-step procedure is introduced to allow the employment of the interpolation technique by machine designers without the necessity to understand the underlying mathematics. Finally, the mathematical expression, obtained from the interpolation, enables applying global optimizers. In a case study of an emergency ventilator mechanism with three design parameters, 1870 CAD motion simulations allowed reducing the RMS torque of the mechanism by 67%.