bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-Time Assessment of Intracellular Metabolites in Single Cells through RNA-Based Sensors
Authors: Ortega Alvaro Darío
Published: April 2023

Quantification of the concentration of particular cellular metabolites reports on the actual utilization of metabolic pathways in physiological and pathological conditions. Metabolite concentration also constitutes the readout for screening cell factories in metabolic engineering. However, there are no direct approaches that allow for real-time assessment of the levels of intracellular metabolites in single cells. In recent years, the modular architecture of natural bacterial RNA riboswitches has inspired the design of genetically encoded synthetic RNA devices that convert the intracellular concentration of a metabolite into a quantitative fluorescent signal. These so-called RNA-based sensors are composed of a metabolite-binding RNA aptamer as the sensor domain, connected through an actuator segment to a signal-generating reporter domain. However, at present, the variety of available RNA-based sensors for intracellular metabolites is still very limited. Here, we go through natural mechanisms for metabolite sensing and regulation in cells across all kingdoms, focusing on those mediated by riboswitches. We review the design principles underlying currently developed RNA-based sensors and discuss the challenges that hindered the development of novel sensors and recent strategies to address them. We finish by introducing the current and potential applicability of synthetic RNA-based sensors for intracellular metabolites.
Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich’s Ataxia Pre-Clinical Models and Clinical Trials
Authors: Tiberi Jessica , Segatto Marco , Fiorenza Maria Teresa , La Rosa Piergiorgio
Published: April 2023

Friedreich’s ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of FXN gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signalling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signalling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, we overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies.
Initial Myeloid Cell Status Is Associated with Clinical Outcomes of Renal Cell Carcinoma
Authors: Sabrina Saima , Takeda Yuji , Kato Tomoyuki , Naito Sei , Ito Hiromi , Takai Yuki , Ushijima Masaki , Narisawa Takafumi , Kanno Hidenori , Sakurai Toshihiko , Saitoh Shinichi , Araki Akemi , Tsuchiya Norihiko , Asao Hironobu
Published: April 2023

The therapeutic outcome of immune checkpoint inhibition (ICI) can be improved through combination treatments with ICI therapy. Myeloid-derived suppressor cells (MDSCs) strongly suppress tumor immunity. MDSCs are a heterogeneous cell population, originating from the unusual differentiation of neutrophils/monocytes induced by environmental factors such as inflammation. The myeloid cell population consists of an indistinguishable mixture of various types of MDSCs and activated neutrophils/monocytes. In this study, we investigated whether the clinical outcomes of ICI therapy could be predicted by estimating the status of the myeloid cells, including MDSCs. Several MDSC indexes, such as glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80), CD16, and latency-associated peptide-1 (LAP-1; transforming growth factor-β1 precursor), were analyzed via flow cytometry using peripheral blood derived from patients with advanced renal cell carcinoma (n = 51) immediately before and during the therapy. Elevated CD16 and LAP-1 expressions after the first treatment were associated with a poor response to ICI therapy. Immediately before ICI therapy, GPI-80 expression in neutrophils was significantly higher in patients with a complete response than in those with disease progression. This is the first study to demonstrate a relationship between the status of the myeloid cells during the initial phase of ICI therapy and clinical outcomes.
Inborn Errors of Immunity in Children with Autoimmune and Allergic Complaints: A Single Center Experience from Diagnosis to Treatment
Authors: Boz Valentina , Tesser Alessandra , Girardelli Martina , Burlo Francesca , Pin Alessia , Severini Giovanni Maria , De Marchi Ginevra , Verzegnassi Federico , Naviglio Samuele , Tommasini Alberto , Valencic Erica
Published: April 2023

Inborn errors of immunity (IEI) associated with immune dysregulation are not sufficiently addressed in shared recommendation, resulting in delayed diagnosis and high morbidity. The availability of precision medicine for some of these immune defects makes it urgent to evaluate effective strategies to diagnose and treat such defects before the occurrence of severe complications. A diagnosis of an IEI in these patients enabled the use of a more specific treatment in most cases, and these have the potential to prevent further disease progression. We studied immune dysregulation diseases in 30 patients with autoimmune or allergic phenotypes, exploiting data from clinics and immunophenotype, genetic and transcriptome investigations, and 6 of them were diagnosed with a monogenic disorder. Our results confirm that a non-negligible number of children with IEIs may present with signs and symptoms of immune dysregulation and share many features with common multifactorial immune conditions. Reaching a genetic diagnosis becomes more likely in the presence of multiple clinical manifestations, especially when in association with abnormalities of lymphocytes subsets and/or immunoglobulins levels. Moreover, 5 of 6 patients that obtained a diagnosis of monogenic disorder received precision therapy, in four cases with a good or moderate response.
Adipokines as Diagnostic and Prognostic Markers for the Severity of COVID-19
Authors: Grewal Thomas , Buechler Christa
Published: April 2023

Accumulating evidence implicates obesity as a risk factor for increased severity of disease outcomes in patients infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Obesity is associated with adipose tissue dysfunction, which not only predisposes individuals to metabolic complications, but also substantially contributes to low-grade systemic inflammation, altered immune cell composition, and compromised immune function. This seems to impact the susceptibility and outcome of diseases caused by viruses, as obese people appear more vulnerable to developing infections and they recover later from infectious diseases than normal-weight individuals. Based on these findings, increased efforts to identify suitable diagnostic and prognostic markers in obese Coronavirus disease 2019 (COVID-19) patients to predict disease outcomes have been made. This includes the analysis of cytokines secreted from adipose tissues (adipokines), which have multiple regulatory functions in the body; for instance, modulating insulin sensitivity, blood pressure, lipid metabolism, appetite, and fertility. Most relevant in the context of viral infections, adipokines also influence the immune cell number, with consequences for overall immune cell activity and function. Hence, the analysis of the circulating levels of diverse adipokines in patients infected with SARS-CoV-2 have been considered to reveal diagnostic and prognostic COVID-19 markers. This review article summarizes the findings aimed to correlate the circulating levels of adipokines with progression and disease outcomes of COVID-19. Several studies provided insights on chemerin, adiponectin, leptin, resistin, and galectin-3 levels in SARS-CoV-2-infected patients, while limited information is yet available on the adipokines apelin and visfatin in COVID-19. Altogether, current evidence points at circulating galectin-3 and resistin levels being of diagnostic and prognostic value in COVID-19 disease.
Recent Advances in the Polish Research on Polysaccharide-Based Nanoparticles in the Context of Various Administration Routes
Authors: Młynek Mateusz , Trzciński Jakub Waldemar , Ciach Tomasz
Published: April 2023

Polysaccharides are the most abundant polymers in nature. They exhibit robust biocompatibility, reliable non-toxicity, and biodegradable character; thus, they are employed in multiple biomedical applications. The presence of chemically accessible functional groups on the backbone of biopolymers (amine, carboxyl, hydroxyl, etc.) makes them suitable materials for chemical modification or drug immobilisation. Among different drug delivery systems (DDSs), nanoparticles have been of great interest in scientific research in the last decades. In the following review, we want to address the issue of rational design of nanoparticle (NP)-based drug delivery systems in reference to the specificity of the medication administration route and resulting requirements. In the following sections, readers can find a comprehensive analysis of the articles published by authors with Polish affiliations in the last few years (2016–2023). The article emphasises NP administration routes and synthetic approaches, followed by in vitro and in vivo attempts toward pharmacokinetic (PK) studies. The ‘Future Prospects’ section was constructed to address the critical observations and gaps found in the screened studies, as well as to indicate good practices for polysaccharide-based nanoparticle preclinical evaluation.
A Pilot Study on Oxidative Stress during the Recovery Phase in Critical COVID-19 Patients in a Rehabilitation Facility: Potential Utility of the PAOT® Technology for Assessing Total Anti-Oxidative Capacity
Authors: Pincemail Joël , Rousseau Anne-Françoise , Kaux Jean-François , Cheramy-Bien Jean-Paul , Bruyère Christine , Prick Jeanine , Stern David , Kaci Mouna-Messaouda , Maertens De Noordhout Benoît , Albert Adelin , Eubelen Céline , Goff Caroline Le , Misset Benoît , Cavalier Etienne , Charlier Corinne , Meziane Smail
Published: April 2023

Background: Oxidative stress (OS) could cause various COVID-19 complications. Recently, we have developed the Pouvoir AntiOxydant Total (PAOT®) technology for reflecting the total antioxidant capacity (TAC) of biological samples. We aimed to investigate systemic oxidative stress status (OSS) and to evaluate the utility of PAOT® for assessing TAC during the recovery phase in critical COVID-19 patients in a rehabilitation facility. Materials and Methods: In a total of 12 critical COVID-19 patients in rehabilitation, 19 plasma OSS biomarkers were measured: antioxidants, TAC, trace elements, oxidative damage to lipids, and inflammatory biomarkers. TAC level was measured in plasma, saliva, skin, and urine, using PAOT and expressed as PAOT-Plasma, -Saliva, -Skin, and -Urine scores, respectively. Plasma OSS biomarker levels were compared with levels from previous studies on hospitalized COVID-19 patients and with the reference population. Correlations between four PAOT scores and plasma OSS biomarker levels were analyzed. Results: During the recovery phase, plasma levels in antioxidants (γ-tocopherol, β-carotene, total glutathione, vitamin C and thiol proteins) were significantly lower than reference intervals, whereas total hydroperoxides and myeloperoxidase (a marker of inflammation) were significantly higher. Copper negatively correlated with total hydroperoxides (r = 0.95, p = 0.001). A similar, deeply modified OSS was already observed in COVID-19 patients hospitalized in an intensive care unit. TAC evaluated in saliva, urine, and skin correlated negatively with copper and with plasma total hydroperoxides. To conclude, the systemic OSS, determined using a large number of biomarkers, was always significantly increased in cured COVID-19 patients during their recovery phase. The less costly evaluation of TAC using an electrochemical method could potentially represent a good alternative to the individual analysis of biomarkers linked to pro-oxidants.
A Simple and Affordable Method to Create Nonsense Mutation Clones of p53 for Studying the Premature Termination Codon Readthrough Activity of PTC124
Authors: Chen Chia-Chi , Liao Ruo-Yu , Yeh Fang-Yu , Lin Yu-Rou , Wu Tze-You , Pastor Alexa Escobar , Zul Danny Danilo , Hsu Yun-Chien , Wu Kuan-Yo , Liu Ke-Fang , Kannagi Reiji , Chen Jang-Yi , Cai Bi-He
Published: April 2023

(1) Background: A premature termination codon (PTC) can be induced by a type of point mutation known as a nonsense mutation, which occurs within the coding region. Approximately 3.8% of human cancer patients have nonsense mutations of p53. However, the non-aminoglycoside drug PTC124 has shown potential to promote PTC readthrough and rescue full-length proteins. The COSMIC database contains 201 types of p53 nonsense mutations in cancers. We built a simple and affordable method to create different nonsense mutation clones of p53 for the study of the PTC readthrough activity of PTC124. (2) Methods: A modified inverse PCR-based site-directed mutagenesis method was used to clone the four nonsense mutations of p53, including W91X, S94X, R306X, and R342X. Each clone was transfected into p53 null H1299 cells and then treated with 50 μM of PTC124. (3) Results: PTC124 induced p53 re-expression in H1299-R306X and H1299-R342X clones but not in H1299-W91X and H1299-S94X clones. (4) Conclusions: Our data showed that PTC124 more effectively rescued the C-terminal of p53 nonsense mutations than the N-terminal of p53 nonsense mutations. We introduced a fast and low-cost site-directed mutagenesis method to clone the different nonsense mutations of p53 for drug screening.
Effect of Low Protein Diet Supplemented with Ketoanalogs on Endothelial Function and Protein-Bound Uremic Toxins in Patients with Chronic Kidney Disease
Authors: Chang George , Shih Hong-Mou , Pan Chi-Feng , Wu Chih-Jen , Lin Cheng-Jui
Published: April 2023

Studies have demonstrated that a low-protein diet supplemented with ketoanalogs (KAs) could significantly retard progression of renal function in patients with chronic kidney disease (CKD) stages 3–5. However, its effects on endothelial function and serum levels of protein-bound uremic toxins remain elusive. Therefore, this study explored whether a low-protein diet (LPD) supplemented with KAs affects kidney function, endothelial function, and serum uremic toxin levels in a CKD-based cohort. In this retrospective cohort, we enrolled 22 stable CKD stage 3b–4 patients on LPD (0.6–0.8 g/day). Patients were categorized into control (LPD only) and study groups (LPD + KAs 6 tab/day). Serum biochemistry, total/free indoxyl sulfate (TIS/FIS), total/free p-cresyl sulfate (TPCS/FPCS), and flow-mediated dilation (FMD) were measured before and after 6 months of KA supplementation. Before the trial, there were no significant differences in kidney function, FMD, or uremic toxin levels between the control and study groups. When compared with the control group, the paired t-test showed a significant decrease in TIS and FIS (all p < 0.05) and a significant increase in FMD, eGFR, and bicarbonate (all p < 0.05). In multivariate regression analysis, an increase in FMD (p < 0.001) and a decrease in FPCS (p = 0.012) and TIS (p < 0.001) remained persistent findings when adjusted for age, systolic blood pressure (SBP), sodium, albumin, and diastolic blood pressure (DBP). LPD supplemented with KAs significantly preserves kidney function and provides additional benefits on endothelial function and protein-bound uremic toxins in patients with CKD.
Differences and Associations of NLRP3 Inflammasome Levels with Interleukins 1α, 1β, 33 and 37 in Adults with Prediabetes and Type 2 Diabetes Mellitus
Authors: Alfadul Hend , Sabico Shaun , Ansari Mohammed G. A. , Alnaami Abdullah M. , Amer Osama E. , Hussain Syed D. , Wani Kaiser , Khattak Malak N. K. , Clerici Mario , Al-Daghri Nasser M.
Published: April 2023

Inflammasome activation of the nucleotide-binding domain, leucine-rich–containing family, and pyrin domain–containing-3 (NLRP3) has been observed to be involved in the pathogenesis of numerous inflammatory diseases, including prediabetes (PD) and type 2 diabetes mellitus (T2DM). Varying levels of glycemia can trigger inflammasome activation; yet, limited studies have reported the associations between NLRP3 levels or other circulating interleukins (ILs) and glycemic status. This study investigated the differences and associations between serum levels of NLRP3 and IL-1α, IL-1β, IL-33 and IL-37 in Arab adults with PD and T2DM. A total of 407 Saudi adults (151 males and 256 females) (mean age = 41.4 ± 9.1 years and mean BMI = 30.7 ± 6.4 kg/m2) were included. Overnight-fasting serum samples were collected. The participants were stratified according to T2DM status. Serum levels of NLRP3 and ILs of interest were assessed using commercially available assays. In all participants, age- and BMI-adjusted circulating levels of IL-37 were significantly higher in the T2DM group (p = 0.02) than in healthy controls (HC) and the PD group. A general linear model analysis revealed that NLRP3 levels were significantly influenced by T2DM status; age; and ILs 18, 1α and 33 (p-values 0.03, 0.04, 0.005, 0.004 and 0.007, respectively). IL-1α and triglycerides significantly predicted NLRP3 levels by as much as 46% of the variance perceived (p < 0.01). In conclusion, T2DM status significantly influenced NLRP3 expression and other IL levels in varying degrees. Whether these altered levels of inflammasome markers can be favorably reversed through lifestyle interventions needs to be investigated prospectively in the same population.
Incentive Mechanism of BIM Application in Prefabricated Buildings Based on Evolutionary Game Analysis
Authors: Yang Chunyi , Xiong Feng , Hu Qidan , Liu Rongsheng , Li Shilong
Published: April 2023

Prefabricated buildings have become a key area promoted in the new urbanization. Implementing BIM is one of the crucial supports for accelerating the development of prefabricated buildings. In order to effectively promote the development of BIM+ prefabricated buildings, this paper establishes an evolutionary game model between the government and prefabricated construction enterprises. The replication dynamic equation is employed to analyze the strategy choices of both participants, and the Matlab simulation is adopted to explore the evolution process of enterprises to actively use BIM. Results show that the application of new technologies can be effectively promoted by increasing the unit price of carbon trading, enlarging the tax rate difference, advancing technology, improving the level of enterprise effort, and enhancing social awareness to reduce the payment-to-income ratio of enterprises using BIM. Additionally, reasonable administrative measures, policy subsidies and fines will also positively affect government incentives and the strategy choice of enterprises using BIM. Therefore, a reasonable government incentive system can promote the development of BIM+ prefabricated buildings to a certain extent.
Numerical Investigation on the Dynamic Response of Fault-Crossing Tunnels under Strike-Slip Fault Creep-Slip and Subsequent Seismic Shaking
Authors: Peng Shuquan , Zeng Yuankai , Fan Ling , Wang Guobo , Xun Zhize , Chen Guoliang
Published: April 2023

Tunnels built in geologically active areas are prone to severe damage due to fault dislocation and subsequent earthquakes. Using the Ngong tunnel in the East African Rift Valley as an example, the dynamic response of a fault-crossing tunnel and the corresponding sensitivity are numerically simulated by considering four factors, i.e., tunnel joint stiffness, isolation layer elastic modulus, strike-slip fault creep-slip and earthquakes. The results show that a valley-shaped propagation of peak displacement at the tunnel invert occurs in the longitudinal axis direction under an earthquake alone. Then, it transforms into an S-shaped under strike-slip fault creep-slip and subsequent seismic shaking. The tunnel invert in the fault zone is susceptible to tensile and shear failures under strike-slip fault creep-slip movements of less than 15 cm and subsequent seismic shaking. Furthermore, the peak tensile and shear stress responses of the tunnel invert in the fault zone are more sensitive to fault creep-slip than earthquakes. They are also more sensitive to the isolation layer elastic modulus compared to the joint stiffness of a segmental tunnel with two segments. The stress responses can be effectively reduced when the isolation layer elastic modulus logarithmic ratio equals −4. Therefore, the isolation layer is more suitable to mitigate the potential failure under small strike-slip fault creep-slip and subsequent seismic shaking than segmental tunnels with two segments. The results of this study can provide some reference for the disaster mitigation of fault-crossing tunnels in terms of dynamic damage in active fault zones.
Design for Manufacturing and Assembly (DfMA) and Design for Deconstruction (DfD) in the Construction Industry: Challenges, Trends and Developments
Authors: Roxas Cheryl Lyne C. , Bautista Carluz R. , Dela Cruz Orlean G. , Dela Cruz Rhem Leoric C. , De Pedro John Paul Q. , Dungca Jonathan R. , Lejano Bernardo A. , Ongpeng Jason Maximino C.
Published: April 2023

A building faces several challenges across its lifecycle stages. Challenges such as production inefficiency and inadequate waste management hinder advancement in the construction industry. Furthermore, the sector has emerged as one of the largest producers of waste in the world, which can lead to detrimental impacts on the economy and the environment. Conventional approaches are insufficient to eradicate these concerns. Thus, practitioners have sought to implement novel methods to ameliorate the construction process. In this regard, design for manufacturing and assembly (DfMA) and design for deconstruction (DfD) have gained prominence, as studies have elucidated the methods’ unprecedented potential to wholly transform the construction process and mitigate the unwanted impacts brought about by the industry. This study identified the applications and benefits of DfMA and DfD in construction, as well as recent developments and research gaps, through a literature review, using Scopus as the primary database and MATLAB for conducting data text analytics. The current body of knowledge necessitates a further assessment of the following research gaps: (1) development of standard construction-oriented DfMA guidelines; (2) corroboration of the developed DfMA tools through practical application; (3) integration of these holistic design approaches with emerging technologies, such as additive manufacturing and digital fabrication; (4) comparison of structures constructed using DfMA and DfD with structures built with conventional approaches; (5) comprehensive application of DfD guidelines to structural systems; (6) integration of DfMA and DfD; (7) execution of sustainability assessment studies to evaluate the impact of DfMA and DfD; and (8) identification of solutions to the barriers to DfMA and DfD uptake in construction.
Review of Corrosion Inhibitors in Reinforced Concrete: Conventional and Green Materials
Authors: Zomorodian Amir , Behnood Ali
Published: April 2023

The corrosion of metals has been a major technical, environmental, and financial challenge for many industries and has become a widespread problem in concrete structures and buildings. Various techniques such as utilization of synthetic corrosion inhibitors have been developed to provide sufficient corrosion protection to reinforcing steel. The application of green corrosion inhibitors, however, has recently attracted increasing attention since these sustainable materials decrease the rate of corrosion and increase the durability and service life of reinforced concrete structures effectively. Considering the emerging field of sustainable corrosion management, many researchers have evaluated various green corrosion inhibitors, reporting scattered results. Consequently, there is a need for a comprehensive study to review, compare, and consolidate their findings in order to identify research gaps and critical trends for further research. This article reviews the properties and effects of various inhibitors including those nontoxic environmentally friendly inhibitors functioning at high pH in concrete. It classifies a broad range of corrosion inhibitors and identifies their advantages and disadvantages. Furthermore, it proposes a set of selection criteria to choose the appropriate inhibitors based on their characteristics and sustainability requirements. It can be concluded that natural corrosion inhibitors show promising potential for extending the service life of reinforced concrete structures as a cost-effective and sustainable solution. Further investigation, however, is demanded for evaluating their technical properties including modelling functional groups for corrosion protection and their effectiveness under combined attack of corrosive ions. The findings of this paper identify the main research trends and can guide researchers to develop further research in the identified gaps towards sustainable progress in the field of civil engineering and corrosion management. It also helps practitioners in all relevant disciplines to gain effective knowledge on emerging green corrosion inhibitors.
Epigenetic Regulation in Primary CNS Tumors: An Opportunity to Bridge Old and New WHO Classifications
Authors: Dang Danielle D. , Rosenblum Jared S. , Shah Ashish H. , Zhuang Zhengping , Doucet-O’Hare Tara T.
Published: April 2023

Originally approved in 1979, a specific grading classification for central nervous system (CNS) tumors was devised by the World Health Organization (WHO) in an effort to guide cancer treatment and better understand prognosis. These “blue books” have since undergone several iterations based on tumor location, advancements in histopathology, and most recently, diagnostic molecular pathology in its fifth edition. As new research methods have evolved to elucidate complex molecular mechanisms of tumorigenesis, a need to update and integrate these findings into the WHO grading scheme has become apparent. Epigenetic tools represent an area of burgeoning interest that encompasses all non-Mendelian inherited genetic features affecting gene expression, including but not limited to chromatin remodeling complexes, DNA methylation, and histone regulating enzymes. The SWItch/Sucrose non-fermenting (SWI/SNF) chromatin remodeling complex is the largest mammalian family of chromatin remodeling proteins and is estimated to be altered in 20–25% of all human malignancies; however, the ways in which it contributes to tumorigenesis are not fully understood. We recently discovered that CNS tumors with SWI/SNF mutations have revealed an oncogenic role for endogenous retroviruses (ERVs), remnants of exogenous retroviruses that integrated into the germline and are inherited like Mendelian genes, several of which retain open reading frames for proteins whose expression putatively contributes to tumor formation. Herein, we analyzed the latest WHO classification scheme for all CNS tumors with documented SWI/SNF mutations and/or aberrant ERV expression, and we summarize this information to highlight potential research opportunities that could be integrated into the grading scheme to better delineate diagnostic criteria and therapeutic targets.
Reciprocal Regulation of Cancer-Associated Fibroblasts and Tumor Microenvironment in Gastrointestinal Cancer: Implications for Cancer Dormancy
Authors: Cheng Shih-Hsuan , Chiou Hsin-Ying Clair , Wang Jiunn-Wei , Lin Ming-Hong
Published: April 2023

Gastrointestinal (GI) cancers remain a major cause of cancer-related deaths worldwide. Despite the progress made in current treatments, patients with GI cancers still have high recurrence rates after initial treatment. Cancer dormancy, which involves the entry and escape of cancer cells from dormancy, is linked to treatment resistance, metastasis, and disease relapse. Recently, the role of the tumor microenvironment (TME) in disease progression and treatment has received increasing attention. The crosstalk between cancer-associated fibroblasts (CAF)-secreted cytokines/chemokines and other TME components, for example, extracellular matrix remodeling and immunomodulatory functions, play crucial roles in tumorigenesis. While there is limited direct evidence of a relationship between CAFs and cancer cell dormancy, this review explores the potential of CAF-secreted cytokines/chemokines to either promote cancer cell dormancy or awaken dormant cancer cells under different conditions, and the therapeutic strategies that may be applicable. By understanding the interactions between cytokines/chemokines released by CAFs and the TME, and their impact on the entry/escape of cancer dormancy, researchers may develop new strategies to reduce the risk of therapeutic relapse in patients with GI cancers.
Stem Cell Origin of Cancer: Implications of Oncogenesis Recapitulating Embryogenesis in Cancer Care
Authors: Tu Shi-Ming , Aydin Ahmet Murat , Maraboyina Sanjay , Chen Zhongning , Singh Sunny , Gokden Neriman , Langford Timothy
Published: April 2023

From this perspective, we wonder about the clinical implications of oncology recapturing ontogeny in the contexts of neoantigens, tumor biomarkers, and cancer targets. We ponder about the biological ramifications of finding remnants of mini-organs and residuals of tiny embryos in some tumors. We reminisce about classical experiments showing that the embryonic microenvironment possesses antitumorigenic properties. Ironically, a stem-ness niche—in the wrong place at the wrong time—is also an onco-niche. We marvel at the paradox of TGF-beta both as a tumor suppressor and a tumor promoter. We query about the dualism of EMT as a stem-ness trait engaged in both normal development and abnormal disease states, including various cancers. It is uncanny that during fetal development, proto-oncogenes wax, while tumor-suppressor genes wane. Similarly, during cancer development, proto-oncogenes awaken, while tumor-suppressor genes slumber. Importantly, targeting stem-like pathways has therapeutic implications because stem-ness may be the true driver, if not engine, of the malignant process. Furthermore, anti-stem-like activity elicits anti-cancer effects for a variety of cancers because stem-ness features may be a universal property of cancer. When a fetus survives and thrives despite immune surveillance and all the restraints of nature and the constraints of its niche, it is a perfect baby. Similarly, when a neoplasm survives and thrives in an otherwise healthy and immune-competent host, is it a perfect tumor? Therefore, a pertinent narrative of cancer depends on a proper perspective of cancer. If malignant cells are derived from stem cells, and both cells are intrinsically RB1 negative and TP53 null, do the absence of RB1 and loss of TP53 really matter in this whole narrative and an entirely different perspective of cancer?
Insights into EGFR Mutations and Oncogenic KRAS Mutations in Non-Small-Cell Lung Cancer
Authors: Rosell Rafael , Aguilar-Hernández Andrés , González-Cao María
Published: April 2023

Genetic mutations can activate different sets of proto-oncogenes and tumor suppressors genes [...]
The miR-141/200c-STAT4 Axis Contributes to Leukemogenesis by Enhancing Cell Proliferation in T-PLL
Authors: Otte Moritz , Stachelscheid Johanna , Glaß Markus , Wahnschaffe Linus , Jiang Qu , Lone Waseem , Ianevski Aleksandr , Aittokallio Tero , Iqbal Javeed , Hallek Michael , Hüttelmaier Stefan , Schrader Alexandra , Braun Till , Herling Marco
Published: April 2023

T-prolymphocytic leukemia (T-PLL) is a rare and mature T-cell malignancy with characteristic chemotherapy-refractory behavior and a poor prognosis. Molecular concepts of disease development have been restricted to protein-coding genes. Recent global microRNA (miR) expression profiles revealed miR-141-3p and miR-200c-3p (miR-141/200c) as two of the highest differentially expressed miRs in T-PLL cells versus healthy donor-derived T cells. Furthermore, miR-141/200c expression separates T-PLL cases into two subgroups with high and low expression, respectively. Evaluating the potential pro-oncogenic function of miR-141/200c deregulation, we discovered accelerated proliferation and reduced stress-induced cell death induction upon stable miR-141/200c overexpression in mature T-cell leukemia/lymphoma lines. We further characterized a miR-141/200c-specific transcriptome involving the altered expression of genes associated with enhanced cell cycle transition, impaired DNA damage responses, and augmented survival signaling pathways. Among those genes, we identified STAT4 as a potential miR-141/200c target. Low STAT4 expression (in the absence of miR-141/200c upregulation) was associated with an immature phenotype of primary T-PLL cells as well as with a shortened overall survival of T-PLL patients. Overall, we demonstrate an aberrant miR-141/200c-STAT4 axis, showing for the first time the potential pathogenetic implications of a miR cluster, as well as of STAT4, in the leukemogenesis of this orphan disease.
Targeting FGFRs Using PD173074 as a Novel Therapeutic Strategy in Cholangiocarcinoma
Authors: Balasubramanian Brinda , Yacqub-Usman Kiren , Venkatraman Simran , Myint Kyaw Zwar , Juengsamarn Jitlada , Sarkhampee Poowanai , Lertsawatvicha Nithi , Sripa Jittiyawadee , Kuakpaetoon Thiti , Suriyonplengsaeng Chinnawut , Wongprasert Kanokpan , Grabowska Anna M. , Bates David O. , Janvilisri Tavan , Tohtong Rutaiwan
Published: April 2023

Cholangiocarcinoma (CCA) is an architecturally complex tumour with high heterogeneity. Discovery at later stages makes treatment challenging. However, the lack of early detection methodologies and the asymptomatic nature of CCA make early diagnosis more difficult. Recent studies revealed the fusions in Fibroblast Growth Factor Receptors (FGFRs), a sub-family of RTKs, as promising targets for targeted therapy for CCA. Particularly, FGFR2 fusions have been of particular interest, as translocations have been found in approximately 13% of CCA patients. Pursuing this, Pemigatinib, a small-molecule inhibitor of FGFR, became the first targeted therapy drug to be granted accelerated approval by the FDA for treating CCA patients harbouring FGFR2 fusions who have failed first-line chemotherapy. However, despite the availability of Pemigatinib, a very limited group of patients benefit from this treatment. Moreover, as the underlying mechanism of FGFR signalling is poorly elucidated in CCA, therapeutic inhibitors designed to inhibit this pathway are prone to primary and acquired resistance, as witnessed amongst other Tyrosine Kinase Inhibitors (TKIs). While acknowledging the limited cohort that benefits from FGFR inhibitors, and the poorly elucidated mechanism of the FGFR pathway, we sought to characterise the potential of FGFR inhibitors in CCA patients without FGFR2 fusions. Here we demonstrate aberrant FGFR expression in CCA samples using bioinformatics and further confirm phosphorylated-FGFR expression in paraffinised CCA tissues using immunohistochemistry. Our results highlight p-FGFR as a biomarker to guide FGFR-targeted therapies. Furthermore, CCA cell lines with FGFR expression were sensitive to a selective pan-FGFR inhibitor, PD173074, suggesting that this drug can be used to suppress CCA cells irrespective of the FGFR2 fusions. Finally, the correlation analysis utilising publicly available cohorts suggested the possibility of crosstalk amongst the FGFR and EGFR family of receptors as they are significantly co-expressed. Accordingly, dual inhibition of FGFRs and EGFR by PD173074 and EGFR inhibitor erlotinib was synergistic in CCA. Hence, the findings from this study provide support for further clinical investigation of PD173074, as well as other FGFR inhibitors, to benefit a larger cohort of patients. Altogether, this study shows for the first time the potential of FGFRs and the importance of dual inhibition as a novel therapeutic strategy in CCA.
CD19 (+) B Cell Combined with Prognostic Nutritional Index Predicts the Clinical Outcomes of Patients with Gastric Cancer Who Underwent Surgery
Authors: Sun Hao , Wang Huibo , Pan Hongming , Zuo Yanjiao , Zhao Ruihu , Huang Rong , Xue Yingwei , Song Hongjiang
Published: April 2023

(1) Background: The aim of this study was to explore the predictive ability of lymphocyte subsets for the prognosis of gastric cancer patients who underwent surgery and the prognostic value of CD19 (+) B cell combined with the Prognostic Nutritional Index (PNI). (2) Methods: This study involved 291 patients with gastric cancer who underwent surgery at our institution between January 2016 and December 2017. All patients had complete clinical data and peripheral lymphocyte subsets. Differences in clinical and pathological characteristics were examined using the Chi-square test or independent sample t-tests. The difference in survival was evaluated using Kaplan–Meier survival curves and the Log-rank test. Cox’s regression analysis was performed to identify independent prognostic indicators, and nomograms were used to predict survival probabilities. (3) Results: Patients were categorized into three groups based on their CD19 (+) B cell and PNI levels, with 56 cases in group one, 190 cases in group two, and 45 cases in group three. Patients in group one had a shorter progression-free survival (PFS) (HR = 0.444, p < 0.001) and overall survival (OS) (HR = 0.435, p < 0.001). CD19 (+) B cell–PNI had the highest area under the curve (AUC) compared with other indicators, and it was also identified as an independent prognostic factor. Moreover, CD3 (+) T cell, CD3 (+) CD8 (+) T cell, and CD3 (+) CD16 (+) CD56 (+) NK T cell were all negatively correlated with the prognosis, while CD19 (+) B cell was positively associated with the prognosis. The C-index and 95% confidence interval (CI) of nomograms for PFS and OS were 0.772 (0.752–0.833) and 0.773 (0.752–0.835), respectively. (4) Conclusions: Lymphocyte subsets including CD3 (+) T cell, CD3 (+) CD8 (+) T cell, CD3 (+) CD16 (+) CD56 (+) NK T cell, and CD19 (+) B cell were related to the clinical outcomes of patients with gastric cancer who underwent surgery. Additionally, PNI combined with CD19 (+) B cell had higher prognostic value and could be used to identify patients with a high risk of metastasis and recurrence after surgery.
Education and Empowering Special Forces to Eradicate Secret Defectors: Immune System-Based Treatment Approaches for Mature T- and NK-Cell Malignancies
Authors: Braun Till , Schrader Alexandra
Published: April 2023

Mature T- and NK-cell leukemia/lymphoma (MTCL/L) constitute a heterogeneous group of, currently, 30 distinct neoplastic entities that are overall rare, and all present with a challenging molecular markup. Thus, so far, the use of first-line cancer treatment modalities, including chemotherapies, achieve only limited clinical responses associated with discouraging prognoses. Recently, cancer immunotherapy has evolved rapidly, allowing us to help patients with, e.g., solid tumors and also relapsed/refractory B-cell malignancies to achieve durable clinical responses. In this review, we systematically unveiled the distinct immunotherapeutic approaches available, emphasizing the special impediments faced when trying to employ immune system defense mechanisms to target ‘one of their own—gone mad’. We summarized the preclinical and clinical efforts made to employ the various platforms of cancer immunotherapies including antibody-drug conjugates, monoclonal as well as bispecific antibodies, immune-checkpoint blockades, and CAR T cell therapies. We emphasized the challenges to, but also the goals of, what needs to be done to achieve similar successes as seen for B-cell entities.
Rate of Malignant Transformation Differs Based on Diagnostic Criteria for Oral Lichenoid Conditions: A Systematic Review and Meta-Analysis of 24,277 Patients
Authors: Li Jing-Wen , Li Kar Yan , Chan Bik Wan Amy , McGrath Colman Patrick , Zheng Li-Wu
Published: April 2023

Objectives: This systematic review and meta-analysis aims to evaluate the evidence on the malignant potential of oral lichenoid conditions (OLCs) including oral lichen planus (OLP), oral lichenoid lesions (OLL), and lichenoid mucositis dysplasia (LMD). In addition, it aims to compare the rate of malignant transformation (MT) in OLP patients diagnosed according to different diagnostic criteria, and to investigate the possible risk factors for OLP MT into OSCC. Materials and methods: A standardized search strategy was applied across four databases (PubMed, Embase, Web of Science, and Scopus). Screening, identification and reporting followed the PRISMA framework. Data on MT were calculated as a pooled proportion (PP), subgroup analyses and possible risk factors for MT were pooled as odds ratios (ORs). Results: Among 54 studies with 24,277 patients, the PP for OLCs MT was 1.07% (95% CI [0.82, 1.32]). The estimated MT rate for OLP, OLL and LMD was 0.94%, 1.95% and 6.31%, respectively. The PP OLP MT rate using the 2003 modified WHO criteria group was lower than that using the non-2003 criteria (0.86%; 95% CI [0.51, 1.22] versus 1.01%; 95% CI [0.67, 1.35]). A higher odds ratio of MT was observed for red OLP lesions (OR = 3.52; 95% CI [2.20, 5.64]), smokers (OR = 1.79; 95% CI [1.02, 3.03]), alcohol consumers (OR = 3.27, 95% CI [1.11, 9.64]) and those infected with HCV (OR = 2.55, 95% CI [1.58, 4.13]), compared to those without these risk factors. Conclusions: OLP and OLL carry a low risk of developing OSCC. MT rates differed based on diagnostic criteria. A higher odds ratio of MT was observed among red OLP lesions, smokers, alcohol consumers, and HCV-positive patients. These findings have implications for practice and policies.
Engineering of a Hybrid g-C3N4/ZnO-W/Cox Heterojunction Photocatalyst for the Removal of Methylene Blue Dye
Authors: Malik Misbah , Ibrahim Sobhy M. , Nazir Muhammad Altaf , Tahir Asif A. , Tufail Muhammad Khurram , Shah Syed Shoaib Ahmad , Anum Aqsa , Wattoo Muhammad Ahmad , Rehman Aziz ur
Published: April 2023

Robust hybrid g-C3N4/ZnO-W/Cox heterojunction composites were synthesized using graphitic carbon nitride (g-C3N4) and ZnO-W nanoparticles (NPs) and different concentrations of Co dopant. The hybrid heterojunction composites were prepared by simple and low-cost coprecipitation methods. The fabricated catalyst was explored and investigated using various characterization techniques such as FTIR, XRD, FESEM and EDX. The surface morphology of the as-prepared hybrid nanocomposites with particle sizes in the range of 15–16 nm was validated by SEM analysis. The elemental composition of the synthesized composites was confirmed by EDS analysis. Photocatalysis using a photon as the sole energy source is considered a challenging approach for organic transformations under ambient conditions. The photocatalytic activity of the heterojunctions was tested by photodegrading methylene blue (MB) dye in the presence of sunlight. The reduced band gap of the heterojunction composite of 3.22–2.28 eV revealed that the incorporation of metal ions played an imperative role in modulating the light absorption range for photocatalytic applications. The as-synthesized g-C3N4/ZnO-W/Co0.010 composite suppressed the charge recombination ability during the photocatalytic degradation of methylene blue (MB) dye. The ternary heterojunction C3N4/ZnO-W/Co0.010 composite showed an impressive photocatalytic performance with 90% degradation of MB under visible light within 90 min of irradiation, compared to the outcomes achieved with the other compositions. Lastly, the synthesized composites showed good recyclability and mechanical stability over five cycles, confirming them as promising photocatalyst options in the future.
Photodegradation of Bisphenol a in Water via Round-the-Clock Visible Light Driven Dual Layer Hollow Fiber Membrane
Authors: Sukaini Khalis , Mohamed Noor Siti Hawa , Mansur Sumarni , Jaffar Filzah Hazirah , Kamaludin Roziana , Othman Mohd Hafiz Dzarfan , Kusworo Tutuk Djoko , Wong Keng Yinn
Published: April 2023

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that can cause adverse effects on human health. The incorporation of materials as visible light photocatalysts and its energy storage capability allow for the photodegradation of BPA, especially in the absence of a light source. To date, there have been no significant studies regarding energy storage in membrane technology, with only a focus on the suspension form. Hence, this study was conducted to degrade the pollutant through a co-extrusion process using a mixture of copper (II) oxide and tungsten oxide as the photocatalyst and energy storage materials, respectively. Both materials were embedded into polyvinylidene (PVDF) membranes to produce a Cu2O/WO3/PVDF dual-layer hollow fiber (DLHF) membrane. The outer dope extrusion flow rate was set at 3 mL/min, 6 mL/min, and 9 mL/min with photocatalyst:polymer ratios of 0.3, 0.50, and 0.7 Cu2O/WO3/PVDF, respectively. The performance of the membranes for each ratio was evaluated using 2 ppm of BPA with visible light irradiation. The results showed that each membrane’s outer and inner layers featured finger-like void structures, while the intermediate part had a sponge-like structure. The membrane with the photocatalyst:polymer ratio of 0.5 was hydrophilic and had a high porosity of 54.97%, resulting in a high flow of 510 L/m2h. Under visible light irradiation, a 0.5 Cu2O/PVDF DLHF membrane with a 6-mL/min outer dope flow rate was able to remove 97.82% of 2-ppm BPA without copper leaching into the water sample. Under dark conditions, the DLHF sample showed the capability of energy storage performance and could drive certain degradation after lighting off up to 70.73% of 2-ppm BPA. The photocatalytic DLHF membrane with the ratio of 0.5 was the most optimal due to its potential morphology and ability to degrade a large amount of BPA. It is important to emphasize that usage of materials with the capability for energy storage can provide a significant contribution toward more practical membranes, so photodegradation can occur even in dark conditions.