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The root system of a plant is essential for plant growth and development because it absorbs nutrients and water from the soil. The root stem cells are maintained and replenished by the quiescent center and are essential for the formation of the specific root structure. In Arabidopsis , the WUSCHEL-RELATED HOMEOBOX 5 (WOX5) plays a key role in regulating root stem cell fate. However, which factor can directly modulate the stability of WOX5 protein remains totally unknown. Here, we report that the peptidase DA1 (LARGE IN CHINESE) interacts with and cleaves WOX5, resulting in the destabilization of WOX5. Genetic analyses support that DA1 acts through WOX5 to regulate root stem cell function. We further demonstrate that cytokinin (CK) signaling induces the accumulation of DA1 protein, thereby decreasing the abundance of WOX5 protein in the root. Consistent with these results, the mutation in DA1 increases the layers of columella stem cells and influences CK-induced differentiation of columella stem cells. Thus, our results reveal a previously unrecognized mechanism by which the cleavage of WOX5 by DA1 connects CK signaling and root stem cell function in Arabidopsis. [Display omitted] • DA1 interacts with and cleaves WOX5, resulting in the destabilization of WOX5 • DA1 acts through WOX5 to regulate root stem cell function • Cytokinin signaling induces the accumulation of DA1 protein • The cleavage of WOX5 by DA1 connects cytokinin signaling and root stem cell function The transcription factor WOX5 plays a key role in regulating root stem cell fate. Cui et al. find that the peptidase DA1 regulates root stem cell function by interacting with and cleaving WOX5. They further demonstrate that the cleavage of WOX5 by DA1 connects cytokinin signaling and root stem cell function in Arabidopsis. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses resulting from nonspecific early symptoms and the absence of early diagnostic biomarkers. MicroRNAs (miRNAs) play a crucial role in regulating diverse biological processes, and their abnormal expression is observed in various diseases, including cancer. Cancer stem cells (CSCs) are thought to act as a driving force in PDAC spread and recurrence. In pursuing the goal of unravelling the complexities of PDAC and its underlying molecular mechanisms, our study aimed to identify PDAC-associated miRNAs and relate them to disease progression, focusing on their involvement in various PDAC stages in patients and in reliable in vitro models, including pancreatic CSC (PaCSC) models. Methods: The miRNA profiling datasets of serum and solid biopsies of PDAC patients deposited in GEO DataSets were analyzed by REML-based meta-analysis. The panel was then investigated by Real Time PCR in serum and solid biopsies of 37 PDAC patients enrolled in the study, as well as on BxPC-3 and AsPC-1 PDAC cell lines. We extended our focus towards a possible role of PDAC-associated miRNAs in the CSC phenotype, by inducing CSC-enriched pancreatospheres from BxPC-3 and AsPC-1 PDAC cell lines and performed differential miRNA expression analysis between PaCSCs and monolayer-grown PDAC cell lines. Results: Meta-analysis showed differentially expressed miRNAs in blood samples and cancerous tissues of PDAC patients, allowing the identification of a panel of 9 PDAC-associated miRNAs. The results emerging from our patients fully confirmed the meta-analysis for the majority of miRNAs under investigation. In vitro tasks confirmed the aberrant expression of the panel of PDAC-associated miRNAs, with a dramatic dysregulation in PaCSC models. Notably, PaCSCs have shown significant overexpression of miR-4486, miR-216a-5p, and miR-216b-5p compared to PDAC cell lines, suggesting the recruitment of such miRNAs in stemness-related molecular mechanisms. Globally, our results showed a dual behaviour of miR-216a-5p and miR-216b-5p in PDAC while miR-4486, miR-361-3p, miR-125a-5p, miR-320d expression changes during the disease suggest they could promote PDAC initiation and progression. Conclusions: This study contributed to an enhanced comprehension of the role of miRNAs in the development and progression of PDAC, shedding new light on the miRNA landscape in PDAC and its intricate interplay with CSCs, and providing specific insights useful in the development of miRNA-based diagnostic biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Purpose: To assess the accuracy of High-Resolution OCT in detecting biomarkers associated with central serous chorioretinopathy (CSC) compared to standard OCT. Methods: We conducted a cross-sectional study involving CSC patients who underwent High-Resolution and standard OCT during the same visit. Using the SPECTRALIS High-Res OCT device (Heidelberg Engineering, Heidelberg, Germany), macular B-scans were obtained and compared with those acquired using a SPECTRALIS HRA + OCT device (Heidelberg Engineering, Heidelberg, Germany). Qualitative assessments were performed, and statistical analyses compared the performance of both OCT modalities. Results: Thirty-one patients diagnosed with CSC were included with a mean age of 56.3 years (± 10.2). Among them, 29% (n = 9) were classified as acute CSC (aCSC), while 71% (n = 22) had chronic CSC (cCSC). High-Resolution OCT outperformed standard OCT in detecting microstructural changes in the outer retinal layers, including a higher prevalence of disrupted interdigitation zone (IZ) (29% vs. 6%, p = 0.003) and retinal pigment epithelium (RPE) disruption (12% vs. 2%, p = 0.0024). Intergrader agreement was high (Cohen's Kappa = 0.85). Conclusion: High-Resolution OCT demonstrates promise in identifying critical biomarkers associated with CSC, particularly disruptions in the IZ and RPE. Further validation in larger cohorts is required to confirm their clinical relevance in patients with CSC. [ABSTRACT FROM AUTHOR]

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development. [ABSTRACT FROM AUTHOR]

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses resulting from nonspecific early symptoms and the absence of early diagnostic biomarkers. MicroRNAs (miRNAs) play a crucial role in regulating diverse biological processes, and their abnormal expression is observed in various diseases, including cancer. Cancer stem cells (CSCs) are thought to act as a driving force in PDAC spread and recurrence. In pursuing the goal of unravelling the complexities of PDAC and its underlying molecular mechanisms, our study aimed to identify PDAC-associated miRNAs and relate them to disease progression, focusing on their involvement in various PDAC stages in patients and in reliable in vitro models, including pancreatic CSC (PaCSC) models. Methods The miRNA profiling datasets of serum and solid biopsies of PDAC patients deposited in GEO DataSets were analyzed by REML-based meta-analysis. The panel was then investigated by Real Time PCR in serum and solid biopsies of 37 PDAC patients enrolled in the study, as well as on BxPC-3 and AsPC-1 PDAC cell lines. We extended our focus towards a possible role of PDAC-associated miRNAs in the CSC phenotype, by inducing CSC-enriched pancreatospheres from BxPC-3 and AsPC-1 PDAC cell lines and performed differential miRNA expression analysis between PaCSCs and monolayer-grown PDAC cell lines. Results Meta-analysis showed differentially expressed miRNAs in blood samples and cancerous tissues of PDAC patients, allowing the identification of a panel of 9 PDAC-associated miRNAs. The results emerging from our patients fully confirmed the meta-analysis for the majority of miRNAs under investigation. In vitro tasks confirmed the aberrant expression of the panel of PDAC-associated miRNAs, with a dramatic dysregulation in PaCSC models. Notably, PaCSCs have shown significant overexpression of miR-4486, miR-216a-5p, and miR-216b-5p compared to PDAC cell lines, suggesting the recruitment of such miRNAs in stemness-related molecular mechanisms. Globally, our results showed a dual behaviour of miR-216a-5p and miR-216b-5p in PDAC while miR-4486, miR-361-3p, miR-125a-5p, miR-320d expression changes during the disease suggest they could promote PDAC initiation and progression. Conclusions This study contributed to an enhanced comprehension of the role of miRNAs in the development and progression of PDAC, shedding new light on the miRNA landscape in PDAC and its intricate interplay with CSCs, and providing specific insights useful in the development of miRNA-based diagnostic biomarkers and therapeutic targets.

Abstract Purpose To assess the accuracy of High-Resolution OCT in detecting biomarkers associated with central serous chorioretinopathy (CSC) compared to standard OCT. Methods We conducted a cross-sectional study involving CSC patients who underwent High-Resolution and standard OCT during the same visit. Using the SPECTRALIS High-Res OCT device (Heidelberg Engineering, Heidelberg, Germany), macular B-scans were obtained and compared with those acquired using a SPECTRALIS HRA + OCT device (Heidelberg Engineering, Heidelberg, Germany). Qualitative assessments were performed, and statistical analyses compared the performance of both OCT modalities. Results Thirty-one patients diagnosed with CSC were included with a mean age of 56.3 years (± 10.2). Among them, 29% (n = 9) were classified as acute CSC (aCSC), while 71% (n = 22) had chronic CSC (cCSC). High-Resolution OCT outperformed standard OCT in detecting microstructural changes in the outer retinal layers, including a higher prevalence of disrupted interdigitation zone (IZ) (29% vs. 6%, p = 0.003) and retinal pigment epithelium (RPE) disruption (12% vs. 2%, p = 0.0024). Intergrader agreement was high (Cohen’s Kappa = 0.85). Conclusion High-Resolution OCT demonstrates promise in identifying critical biomarkers associated with CSC, particularly disruptions in the IZ and RPE. Further validation in larger cohorts is required to confirm their clinical relevance in patients with CSC.

The phenomenon of coal spontaneous combustion poses a serious threat to mine safety, and monitoring and warning of coal spontaneous combustion has become an important issue that needs to be urgently addressed in coal mines. The current monitoring and early warning methods for coal spontaneous combustion have their limitations, and a single indicator cannot accurately mark the degree of coal spontaneous combustion danger inside the goaf. Therefore, this article proposes a new method for monitoring coal spontaneous combustion through infrasound waves. Infrasound waves have advantages such as low attenuation and long transmission distance. However, current research on monitoring and warning coal spontaneous combustion in goaf through infrasound waves is not yet complete, and there is a lack of research on the characteristics of infrasound signal changes during coal spontaneous combustion. Based on this, the article first tested the characteristic temperature and release changes of indicator gases (CO, C2H4) through thermogravimetric experiments and coal oxidation and heating experiments. Then, the generation and variation of infrasonic signals during coal spontaneous combustion (CSC) was studied and analyzed using a self-designed CSC infrasonic testing system. The results showed that obvious infrasound signals could be generated during the CSC process, there is a good mapping relationship between signals and temperature. Furthermore, the analysis revealed the inherent relationship between the infrasonic signal, temperature, and indicator gas of coal at different oxidation stages. The research in this article has promoted the use of infrasound waves for temperature inversion and promoted the development of multi-parameter analysis and early warning of CSC, which is of great significance for the field of CSC monitoring. [ABSTRACT FROM AUTHOR]

Breast cancer stem cells (CSC), as a kind of tumor cells, are able to regenerate themselves, leading to apoptosis resistance and cancer relapse. In this study, we investigated the potential of Hyptis Capitata and Hyptis Brevipes compounds in preventing apoptosis resistance and inducing targeted cell cycle arrest in CSC. The cytotoxic effects of the compounds were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and the cell cycle distribution and apoptosis induction were assessed through flow cytometry analysis. The phytochemical characterization of Hyptis bravipes extract (HBE) and Hyptis capitata extract (HCE) conducted under thin layer chromatography (TLC) and highperformance liquid chromatography (HPLC) analysis. The results revealed that Hyptis Brevipes extract (HBE) exhibited strong cytotoxicity towards CSCs, with an IC50 value of 89 µg/mL. In contrast, Hyptis Capitata extract (HCE) showed weak growth inhibition, with an IC50 value greater than 500 µg/mL. Subsequent analysis demonstrated that HBE induced cell cycle arrest in the G2/M and S phases and significantly increased apoptosis in the CSC population. Furthermore, phytochemical characterization using TLC and HPLC revealed that HBE and HCE share similar constituent compounds, with HBE exhibiting a more diverse compound content and stronger cytotoxic effects. These findings provide valuable insights into the potential of Hyptis Capitata and Hyptis Brevipes compounds as targeted agents against breast cancer stem cells and contribute to understanding their chemical profiles and pharmacological properties. [ABSTRACT FROM AUTHOR]

Dedy Hermansyah,1 Siti Syarifah,2 Adi Muradi Muhar,3 Agung Putra4,5 1Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 2Department of Pharmacology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 3Department of Doctoral Degree Program, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 4Stem Cell and Cancer Research Indonesia, Semarang, Central Java, Indonesia; 5Department of Pathology Anatomy, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Central Java, IndonesiaCorrespondence: Dedy Hermansyah, Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Jl. Dr. Mansyur No. 5, Padang Bulan, Kec. Medan Baru, Kota Medan, Sumatera Utara, 20155, Indonesia, Email dedi.hermansyah@usu.ac.idBackground: Mesenchymal Stem Cells (MSCs) and Cancer Stem Cells (CSC) play pivotal roles in cancer progression and therapeutic responses. This study aimed to explored the effect of MSCs induced by paclitaxel on CSC expressing the CD44+/CD24- phenotype, focusing on Nrf2 modulation and apoptosis induction.Methods: MSCs were characterized for adherence, differentiation potential, and surface markers via standard culture, staining assays, and flow cytometry, respectively. CSCs isolated from MDA-MB-231 using MACS and were characterized based on morphology and CD44+/CD24- expression. Co-culture experiments evaluated the cytotoxic effect of Paclitaxel-induced MSCs on CSC viability using MTT assays. Flow cytometry analysis assessed apoptosis induction via annexin V-PI staining and Nrf2 and Caspase-3 gene expression were measure by qRT-PCR analysis.Results: MSCs exhibited typical adherence and differentiation capabilities, confirming their mesenchymal lineage. CSCs displayed an elongated morphology and expressed CD44+/CD24-, characteristic of stem-like behavior. Paclitaxel induced dose-dependent Nrf2 gene expression in MSCs. Co-culture with Paclitaxel-induced MSCs reduced CSC viability in a dose-dependent manner, with a significant decrease observed at a 5:1 MSCs:CSC ratio. Co-culture decreased the Nrf2 gene expression and increased apoptosis in CSCs, with higher caspase-3 gene expression compared to solitary paclitaxel treatment.Conclusion: Paclitaxel-induced MSCs decreased Nrf2 expression and significantly decreased CSC viability while enhancing apoptosis. This suggests a potential strategy to mitigate paclitaxel resistance in CD44+/CD24- CSCs. Leveraging Paclitaxel-induced MSCs presents a promising avenue for targeting Nrf2 and promoting apoptosis in CSCs, potentially improving the efficacy of chemotherapy and addressing resistance mechanisms in cancer treatment.Keywords: MSCs, paclitaxel, CSC, apoptosis, Nrf2

This study investigates the influence of a magnetic field on the microstructure and properties of Al2O3–Ni composites fabricated via centrifugal slip casting at 1500 rpm. Al2O3 and Ni powders were combined with water and deflocculants, homogenized, and then cast into a porous plaster mold surrounded by Nd-Fe-B magnets. The resulting composites, sintered in a reducing atmosphere, exhibited a three-zone structure with varying Ni content due to the combined effects of the magnetic field and centrifugal force. SEM, EDX, and XRD analyses confirmed the distribution and composition of the phases. Hardness tests revealed the highest values at the outermost zone, with a gradual decrease toward the inner zones. Compression tests employing digital image correlation revealed high internal stresses and a significant improvement in compressive strength compared to non-magnetic field methods. This study confirms that magnetic field-assisted centrifugal slip casting significantly enhances the structural, hardness, and compressive strength properties of Al2O3–Ni composites, indicating promising potential for advanced applications. [ABSTRACT FROM AUTHOR]

In this contribution, Automat FOR Simulation of HETero-structures v2.5 software was used for unveiling the photovoltaic performance and thermal stability of relatively less explored TiO2/c-Si heterojunction solar cell architecture based on 110 μm wafers. Firstly, the dependence of the photovoltaic performance on the emitter layer, i.e. the TiO2 layer, was explored by varying its different characteristics: thickness, carrier concentration and the defect density at the TiO2/Si interface. The study revealed that the power conversion efficiency might be as high as 16.34% (even without any interfacial passivation layer) even when the thickness of the wafer was kept at 110 μm; the thickness and the doping concentration of the TiO2 emitter layer were kept as 7 nm and 1 × 1020 cm−3; respectively. The corresponding defect density at the TiO2/p-Si interface was 1 × 1012 cm−2. Furthermore, a significant gain in the power output was realized by embedding either poly-silicon on oxide or carrier selective contact layer at the rear side of the device architecture. In the case of the incorporation of poly-silicon on the oxide structure at the rear side of the metal/c-Si interface, the role of the ultra-thin tunnel oxide thickness on the device's performance was explored in detail. Next, the poly-silicon on oxide structure was replaced by the NiOx layer, an efficient hole transport layer at the rear side of the device architecture. Various performance-affecting parameters, such as NiOx thickness, NiOx band gap, and the defect density at the NiOx/Si interface, were varied at different carrier concentrations of the NiOx layer to obtain the best possible conditions for realizing the maximum power output. The study was further extended to examine the influence of the wafer lifetime on the device performance of all the simulated solar cells. Eventually, the device temperature was varied from 275 to 375 K with an interval of 25 K to investigate the thermal stability of the proposed cell architectures so that the best possible architecture could be selected for practical fabrication both in terms of photovoltaic performance and thermal stability. [ABSTRACT FROM AUTHOR]

Most Escherichia coli isolates from humans do not utilize D-sucrose as a substrate for fermentation or growth. Previous work has shown that the Csc pathway allows some E. coli to utilize sucrose for slow growth, and this pathway has been engineered in E. coli W strains to enhance use of sucrose as a feedstock for industrial applications. An alternative sucrose utilization pathway, Scr, was first identified in Klebsiella pneumoniae and has been reported in some E. coli and Salmonella enterica isolates. We show here that the Scr pathway is native to an important subset of E. coli phylogroup B2 lineages that lack the Csc pathway but grow rapidly on sucrose. Laboratory E. coli strains derived from MG1655 (phylogroup A, ST10) are unable to utilize sucrose and lack the scr and csc genes, but a recombinant plasmid-borne scr locus enables rapid growth on and fermentation of sucrose. Genome analyses of Enterobacteriaceae indicate that the scr locus is widespread in other Enterobacteriaceae; including Enterobacter and Klebsiella species, and some Citrobacter and Proteus species. In contrast, the Csc pathway is limited mostly to E. coli, some Shigella species (in which csc loci are rendered non-functional by various mutations), and Citrobacter freundii. The more efficient Scr pathway likely has greater potential than the Csc pathway for bioindustrial applications of E. coli and other Enterobacteriaceae using sucrose as a feedstock. [ABSTRACT FROM AUTHOR]

India is a developing country. The Indian government has adopted Information and Communication Technology (ICT) to provide the benefits of several schemes and different services to the public. The purpose of using ICT is to render several benefits and services effectively and quickly. In India, all the state governments are more concerned about the same. The government can easily reach out to the people with the use of e-Governance and ICT. The main purpose behind the implementation of e-governance is to provide transparent, quick, interactive, and effective services through governance to the common man at all levels. Therefore, India has implemented a National e-Governance Plan (NeGP) to accelerate the delivery of different government services to Indian residents at their neighboring or convenient places. Hence, under the NeGP an important decision was made by the government to start telecenters commonly known as Common Service Centers (CSC) in India to be established in PPP Mode (Public-Private Partnership mode). The Common Service Centers are run by local entrepreneurs with the support of the government named Village Level Entrepreneurs (VLE). The key aim of this study is to find out the different factors that motivate rural entrepreneurs to start CSCs. This study will assist the government as well as non-government agencies to motivate the youth of the village and women to start the telecentres to provide government services and successful e-governance. [ABSTRACT FROM AUTHOR]

Purpose: We evaluate morphological and functional correlations in patients with acute central serous chorioretinopathy (CSC). Methods: A prospective study was conducted on 50 patients with an acute CSC episode lasting less than 3 months. At baseline, assessments included optical coherence tomography (OCT), best-corrected visual acuity (BCVA), contrast sensitivity (CS), microperimetry (MP), and multifocal electroretinography (mfERG). A correlation analysis between OCT morphological parameters (maximal subretinal fluid height (SRF), central retinal thickness (CRT), and macular volume (MV)) and functional parameters was conducted on the affected eye for each patient. Results: Among the morphological parameters, SRF showed the strongest correlations with functional parameters (r absolute value range = 0.10–0.70). Weak correlations were observed between BCVA and morphological parameters (r absolute value range = 0.14–0.26). Average retinal sensitivity (MP-A) was the functional parameter displaying the most robust negative correlation with morphological parameters (r absolute value range = 0.61–0.70). In contrast, average contrast sensitivity (CS-A) and mfERG average amplitude density in the first (mfERG-A1) and second (mfERG-A2) ring showed weak to moderate (r absolute value range = 0.35–0.56) yet statistically significantly nonzero correlations. Conclusions: SRF and CRT could serve as the most representative morphological proxies for visual function deficit in acute CSC patients. Retinal sensitivity, as measured by MP, may be superior to BCVA in clinical research studies or when an in-depth visual function evaluation is needed. [ABSTRACT FROM AUTHOR]

Abstract Cancer stem cells (CSCs) were first discovered in the 1990s, revealing the mysteries of cancer origin, migration, recurrence and drug-resistance from a new perspective. The expression of pluripotent genes and complex signal regulatory networks are significant features of CSC, also act as core factors to affect the characteristics of CSC. Transcription is a necessary link to regulate the phenotype and potential of CSC, involving chromatin environment, nucleosome occupancy, histone modification, transcription factor (TF) availability and cis-regulatory elements, which suffer from ambient pressure. Especially, the expression and activity of pluripotent TFs are deeply affected by both internal and external factors, which is the foundation of CSC transcriptional regulation in the current research framework. Growing evidence indicates that regulating epigenetic modifications to alter cancer stemness is effective, and some special promoters and enhancers can serve as targets to influence the properties of CSC. Clarifying the factors that regulate CSC transcription will assist us directly target key stem genes and TFs, or hinder CSC transcription through environmental and other related factors, in order to achieve the goal of inhibiting CSC and tumors. This paper comprehensively reviews the traditional aspects of transcriptional regulation, and explores the progress and insights of the impact on CSC transcription and status through tumor microenvironment (TME), hypoxia, metabolism and new meaningful regulatory factors in conjunction with the latest research. Finally, we present opinions on omnidirectional targeting CSCs transcription to eliminate CSCs and address tumor resistance.

The development of cisplatin resistance is one of the major causes of mammary cancer treatment failure, and is associated with changes in Sox4 gene expression. To investigate the characteristic changes that occur in canine mammary gland tumor (CMGT) cells following the development of acquired cisplatin resistance, along with the relationship between these changes and the Sox4 gene. We constructed cisplatin-resistant cell line, CHMpCIS, from the cell line CHMp, which was isolated from the primary lesion of a malignant CMGT. The biological characteristics of these cells were examined by Western blot analysis, Transwell assays, and mammosphere formation assays. Compared to CHMp cells, CHMpCIS cells exhibited elevated cisplatin resistance, apoptotic escape ability, enhanced epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) features, in addition to over-activation of the Wnt/β-catenin signaling pathway and increased Sox4 protein. In CMGT cases, CMGT tissues (CMGTT) expressed higher levels of Sox4 protein and mRNA compared to adjacent tissues (CAMGTT). We found that these changes were inhibited by silencing of Sox4 expression in CHMpCIS cells. Furthermore, activation of the Wnt/β-catenin signaling pathway increased Sox4 expression levels through a positive feedback loop. These results suggested that CHMpCIS cells circumvented the damage caused by cisplatin through altering the expression of the Sox4 gene and activating the Wnt/β-catenin pathway, thereby changing the cellular biological characteristics. • A cisplatin-resistant cell line was developed for canine mammary gland tumors. • The cell line underwent a series of alterations in its biological properties. • Sox4 gene silencing reversed altered biological properties of the cell line. • Sox4 protein and mRNA expression were increased in canine mammary gland tumor tissues. [ABSTRACT FROM AUTHOR]

Most Escherichia coli isolates from humans do not utilize D-sucrose as a substrate for fermentation or growth. Previous work has shown that the Csc pathway allows some E. coli to utilize sucrose for slow growth, and this pathway has been engineered in E. coli W strains to enhance use of sucrose as a feedstock for industrial applications. An alternative sucrose utilization pathway, Scr, was first identified in Klebsiella pneumoniae and has been reported in some E. coli and Salmonella enterica isolates. We show here that the Scr pathway is native to an important subset of E. coli phylogroup B2 lineages that lack the Csc pathway but grow rapidly on sucrose. Laboratory E. coli strains derived from MG1655 (phylogroup A, ST10) are unable to utilize sucrose and lack the scr and csc genes, but a recombinant plasmid-borne scr locus enables rapid growth on and fermentation of sucrose. Genome analyses of Enterobacteriaceae indicate that the scr locus is widespread in other Enterobacteriaceae; including Enterobacter and Klebsiella species, and some Citrobacter and Proteus species. In contrast, the Csc pathway is limited mostly to E. coli, some Shigella species (in which csc loci are rendered non-functional by various mutations), and Citrobacter freundii. The more efficient Scr pathway likely has greater potential than the Csc pathway for bioindustrial applications of E. coli and other Enterobacteriaceae using sucrose as a feedstock.

This study investigates the influence of a magnetic field on the microstructure and properties of Al2O3–Ni composites fabricated via centrifugal slip casting at 1500 rpm. Al2O3 and Ni powders were combined with water and deflocculants, homogenized, and then cast into a porous plaster mold surrounded by Nd-Fe-B magnets. The resulting composites, sintered in a reducing atmosphere, exhibited a three-zone structure with varying Ni content due to the combined effects of the magnetic field and centrifugal force. SEM, EDX, and XRD analyses confirmed the distribution and composition of the phases. Hardness tests revealed the highest values at the outermost zone, with a gradual decrease toward the inner zones. Compression tests employing digital image correlation revealed high internal stresses and a significant improvement in compressive strength compared to non-magnetic field methods. This study confirms that magnetic field-assisted centrifugal slip casting significantly enhances the structural, hardness, and compressive strength properties of Al2O3–Ni composites, indicating promising potential for advanced applications.

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.

Introduction. The widespread use of piezoelectric materials in various industries stimulates the study of their physical characteristics and determines the urgency of such research. In this case, modal analysis makes it possible to determine the operating frequency and the coefficient of electromechanical coupling of piezoelectric elements of various devices. These indicators are of serious theoretical and applied interest. The study was aimed at the development of numerical methods for solving the problem of determining resonance frequencies in a system of elastic bodies. To achieve this goal, we needed new approaches to the discretization of the problem based on the finite element method and the execution of the software implementation of the selected method in C# on the .net platform. Current solutions were created in the context of the ACELAN-COMPOS class library. The known methods of solving the generalized eigenvalue problem based on matrix inversion are not applicable to large-dimensional matrices. To overcome this limitation, the presented scientific work implemented the logic of constructing mass matrices and created software interfaces for exchanging data on eigenvalue problems with pre- and postprocessing modules.Materials and Methods. A platform was used to implement numerical methods .net and the C# programming language. Validation of the research results was carried out through comparing the values found with solutions obtained in well-known SAE packages (computer-aided engineering). The created routines were evaluated in terms of performance and applicability for large-scale tasks. Numerical experiments were carried out to validate new algorithms in small-dimensional problems that were solved by known methods in MATLAB. Next, the approach was tested on tasks with a large number of unknowns and taking into account the parallelization of individual operations. To avoid finding the inverse matrix, a modified Lanczos method was programmatically implemented. We examined the formats for storing matrices in RAM: triplets, CSR, СSC, Skyline. To solve a system of linear algebraic equations (SLAE), an iterative symmetric LQ method adapted to these storage formats was used.Results. New calculation modules integrated into the class library of the ACELAN-COMPOS complex were developed. Calculations were carried out to determine the applicability of various formats for storing sparse matrices in RAM and various methods for implementing operations with sparse matrices. The structure of stiffness matrices constructed for the same task, but with different renumbering of nodes of a finite element grid, was graphically visualized. In relation to the problem of the theory of electroelasticity, data on the time required to perform basic operations with stiffness matrices in various storage formats were summarized and presented in the form of a table. It has been established that the renumbering of grid nodes gives a significant increase in performance even without changing the internal structure of the matrix in memory. Taking into account the objectives of the study, the advantages and weaknesses of known matrix storage formats were named. Thus, CSR was optimal when multiplying a matrix by a vector, SKS was optimal when inverting a matrix. In problems with the number of unknowns of the order of 103, iterative methods for solving a generalized eigenvalue problem won in speed. The performance of the software implementation of the Lanczos method was evaluated. The contribution of all operations to the total solution time was measured. It has been found that the operation of solving SLAE takes up to 95% of the total time of the algorithm. When solving the SLAE by symmetric LQ method, the greatest computational costs were needed to multiply the matrix by a vector. To increase the performance of the algorithm, parallelization with shared memory was resorted to. When using eight threads, the performance gain increased by 40–50%.Discussion and Conclusion. The software modules obtained as part of the scientific work were implemented in the ACELAN-COMPOS package. Their performance for model problems with quasi-regular finite element grids was estimated. Taking into account the features of the structures of the stiffness and mass matrices obtained through solving the generalized eigenvalue problem for an electroelastic body, the preferred methods for their processing were determined.

Abstract Objective A significant proportion of patients can not benefit from neoadjuvant chemotherapy (NCT) due to drug resistance. Cancer-associated fibroblasts (CAFs) influence many biological behaviours of tumors, including chemo-resistance. This study aims to explore whether CAFs expressing FAP, CD10, and GPR77 affect the efficacy of NCT and the prognosis of patients with gastric cancer, and its mechanism. Methods One hundred seventy-one patients with locally progressive gastric adenocarcinoma who had undergone NCT and radical surgery were collected. Immunohistochemistry was used to detect the expression of FAP, CD10, and GPR77 in CAFs; the EMT markers (N-cadherin, Snail1, and Twist1) and the CSC markers (ALDH1, CD44, and LGR5) in gastric cancer cells. The χ2 test was used to analyze the relationship between the expression of CAF, EMT, and CSC markers and the clinicopathological factors, as well as the relationship between CAF markers and EMT, and CSC markers. Logistic regression and Cox risk regression were used to analyze the relationship between the expression of CAF, EMT, and CSC markers and TRG grading and OS; Kaplan-Meier analysis was used for survival analysis and plotting the curves. Results The expression of CAF markers FAP, CD10, and GPR77 was closely associated with that of EMT markers; FAP and CD10 were closely related to CSC markers. In the univariate analysis of pathological response, CAF markers (FAP, CD10, GPR77), EMT markers (N-cadherin, Snail1, Twist1), and CSC markers (ALDH1, LGR5, CD44), were all closely associated with pathological response (all p < 0.05). Only Twist1 was an independent factor affecting pathological response in multifactorial analysis (p = 0.001). In a univariate analysis of OS, expression of FAP and CD10 in CAF, as well as expression of EMT biomarkers (N-cadherin, Snail1), were significant factors influencing patient prognosis (all p

Purpose: Resistance to chemotherapy and radiotherapy is the primary cause of a poor prognosis in oncological patients. Researchers identified many possible mechanisms involved in gaining a therapy-resistant phenotype by cancer cells, including alterations in intracellular drug accumulation, detoxification, and enhanced DNA damage repair. All these features are characteristic of stem cells, making them the major culprit of chemoresistance. This paper reviews the most recent evidence regarding the association between the stemness phenotype and chemoresistance in head and neck cancers. It also investigates the impact of pharmacologically targeting cancer stem cell populations in this subset of malignancies. Methods: This narrative review was prepared based on the search of the PubMed database for relevant papers. Results: Head and neck cancer cells belonging to the stem cell population are distinguished by the high expression of certain surface proteins (e.g., CD10, CD44, CD133), pluripotency-related transcription factors (SOX2, OCT4, NANOG), and increased activity of aldehyde dehydrogenase (ALDH). Chemotherapy itself increases the percentage of stem-like cells. Importantly, the intratumor heterogeneity of stem cell subpopulations reflects cell plasticity which has great importance for chemoresistance induction. Conclusions: Evidence points to the advantage of combining classical chemotherapeutics with stemness modulators thanks to the joint targeting of the bulk of proliferating tumor cells and chemoresistant cancer stem cells, which could cause recurrence. [ABSTRACT FROM AUTHOR]

The epithelial–mesenchymal transition (EMT) is a cellular reprogramming process that occurs during embryonic development and adult tissue homeostasis. This process involves epithelial cells acquiring a mesenchymal phenotype. Through EMT, cancer cells acquire properties associated with a more aggressive phenotype. EMT and its opposite, mesenchymal–epithelial transition (MET), have been described in more tumors over the past ten years, including colorectal cancer (CRC). When EMT is activated, the expression of the epithelial marker E-cadherin is decreased and the expression of the mesenchymal marker vimentin is raised. As a result, cells temporarily take on a mesenchymal phenotype, becoming motile and promoting the spread of tumor cells. Epithelial–mesenchymal plasticity (EMP) has become a hot issue in CRC because strong inducers of EMT (such as transforming growth factor β, TGF-β) can initiate EMT and regulate metastasis, microenvironment, and immune system resistance in CRC. In this review, we take into account the significance of EMT-MET in CRC and the impact of the epithelial cells' plasticity on the prognosis of CRC. The analysis of connection between EMT and colorectal cancer stem cells (CCSCs) will help to further clarify the current meager understandings of EMT. Recent advances affecting important EMT transcription factors and EMT and CCSCs are highlighted. We come to the conclusion that the regulatory network for EMT in CRC is complicated, with a great deal of crosstalk and alternate paths. More thorough research is required to more effectively connect the clinical management of CRC with biomarkers and targeted treatments associated with EMT. [ABSTRACT FROM AUTHOR]

Constitutively active kinases play a crucial role in carcinogenesis, and their inhibition is a common target for molecular tumor therapy. We recently discovered the expression of two oncogenic isoforms of Bruton's Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC), Btk-p80 and BTK-p65. However, the precise role of BTK in HNSCC remains unclear. Analyses of a tissue microarray containing benign and malignant as well as inflammatory tissue samples of the head and neck region revealed the preferential expression of BTK-p80 in malignant tissue, whereas BTK-p65 expression was confirmed in over 80% of analyzed metastatic head and neck tumor cases. Therefore, processes associated with metastasis, like cancer stem cell (CSC) enrichment and the epithelial–mesenchymal transition (EMT), which in turn depend on an appropriate cytokine milieu, were analyzed. Treatment of HNSCC-derived cell lines cultured under 3D conditions with the BTK inhibitor AVL-292 caused reduced sphere formation, which was accompanied by reduced numbers of ALDH1A1+ CSCs as well as biological changes associated with the EMT. Moreover, we observed reduced NF-κB expression as well as altered NF-κB dependent pro-tumorigenic and EMT-associated cytokine release of IL-6, IFNγ, and TNFα when BTK activity was dampened. Therefore, an autocrine regulation of the oncogenic BTK-dependent process in HNSCC can be suggested, with BTK inhibition expected to be an effective treatment option for HNSCC. [ABSTRACT FROM AUTHOR]

The fourth most prevalent gynaecological malignancy affecting females globally is cervical cancer (CC). HPV (high-risk) infection has been related to the majority of CC cases. Owing to efficient screening through Pap smear and vaccination delivery, the commonness and death rate of CC have significantly decreased. Nevertheless, not all societies have access to this equally. A better therapeutic outcome may be achieved by targeting CSCs, which might play a significant impact in carcinogenesis, metastasis, recurrence, and radio / chemo –resistance of CC. The majority of tumours are made up of a tiny subset of tumour cells called CSCs that have the capability to self-renew and develop into a variety of tumour cell types. Cervical CSCs (CCSC) are challenging to recognise, which has prompted the hunt for other markers. The potential indicators of CSCs in CC are described in the current review. These CCSC indicators might be used as molecular goals to improve the effectiveness and lessen the negative effects of chemotherapy in HR-HPV-positive CC. [ABSTRACT FROM AUTHOR]

We investigated the role of TONSL, a mediator of homologous recombination repair (HRR), in stalled replication fork double-strand breaks (DSBs) in cancer. Publicly available clinical data (tumors from the ovary, breast, stomach and lung) were analyzed through KM Plotter, cBioPortal and Qomics. Cancer stem cell (CSC)-enriched cultures and bulk/general mixed cell cultures (BCCs) with RNAi were employed to determine the effect of TONSL loss in cancer cell lines from the ovary, breast, stomach, lung, colon and brain. Limited dilution assays and ALDH assays were used to quantify the loss of CSCs. Western blotting and cell-based homologous recombination assays were used to identify DNA damage derived from TONSL loss. TONSL was expressed at higher levels in cancer tissues than in normal tissues, and higher expression was an unfavorable prognostic marker for lung, stomach, breast and ovarian cancers. Higher expression of TONSL is partly associated with the coamplification of TONSL and MYC, suggesting its oncogenic role. The suppression of TONSL using RNAi revealed that it is required in the survival of CSCs in cancer cells, while BCCs could frequently survive without TONSL. TONSL dependency occurs through accumulated DNA damage-induced senescence and apoptosis in TONSL-suppressed CSCs. The expression of several other major mediators of HRR was also associated with worse prognosis, whereas the expression of error-prone nonhomologous end joining molecules was associated with better survival in lung adenocarcinoma. Collectively, these results suggest that TONSL-mediated HRR at the replication fork is critical for CSC survival; targeting TONSL may lead to the effective eradication of CSCs. [ABSTRACT FROM AUTHOR]

Programmed death ligand 1 (PD‐L1) plays an important role in the occurrence of hepatocellular carcinoma (HCC). The present study indicated that epithelial–mesenchymal transition (EMT) and induction of cancer stem cell (CSC)‐like properties contribute to metastasis of cancers. However, the molecular mechanisms underlying PD‐L1 and EMT and CSC phenotypes in HCC remain to be elucidated. Here, we report that PD‐L1 regulates not only EMT but also the stem‐like transition in liver cancer cells. We observed high PD‐L1 expression in CD133+ liver CSCs and CSC‐enriched tumor spheres. Altering PD‐L1 expression promoted liver CSC phenotypes by increasing the expression of stemness genes, the CD133+ cell population sizes, and the ability to form tumor spheres. Programmed death ligand 1 enhanced HCC cell tumorigenicity and invasion in nude mice. Additionally, PD‐L1 overexpression in cells significantly increased cell motility and invasion, as well as the EMT process. Conversely, suppression of PD‐L1 in cells had an opposite effect. Prolonged treatment of HCC cells with Akt inhibitor prefosine leads to activation of serum and glucocorticoid kinase 2 (SGK2) and rescued downregulation of PD‐L1. Mechanistically, PD‐L1 directly interacted with SGK2. Programmed death ligand 1 upregulated SGK2 and activated the SGK2/β‐catenin signaling pathway, and promoted EMT and CSC expansion in liver cancer cells, highlighting the role of SGK2 in PD‐L1‐mediated EMT and CSC phenotypes in liver cancer cells. In conclusion, our findings suggest that PD‐L1 activated the SGK2/β‐catenin signaling pathway, to induce EMT and acquisition of a stem cell phenotype. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer associated with an early age of onset, greater propensity towards metastasis, and poorer clinical outcomes. It accounts for 10% to 20% of newly diagnosed breast cancer cases and disproportionately affects individuals from the African American race. While TNBC is sensitive to chemotherapy, it is also prone to relapse. This is because chemotherapy successfully targets the primary TNBC tumor cell but often fails to target the subpopulation of TNBC stem cells. TNBC stem cells display cancerous traits such as cell cycle progression, survival, proliferation, apoptosis inhibition, and epithelial-mesenchymal transition. To study the cancer initiating behavior of the TNBC stem cells, we studied their underlying signaling pathways using Boolean networks(BN). BNs are effective in capturing the causal interactions taking place in signaling pathways. We built the BN from the pathway literature and used it to evaluate the efficacies of eleven targeted inhibitory drugs in suppressing cancer-promoting genes. We simulated the BN when the pathways had single or multiple mutations, with a maximum of three mutations at a time. Our findings indicated that STAT3, GLI, and NF- $\kappa $ B are the most optimal targets for inhibition. These genes are known regulators of the cancer-promoting genes in the pathway,hence our model agrees with the existing biological literature. Therefore inhibiting these three genes has the potential to prevent TNBC relapse. Additionally, our studies found that drug efficacies decreased as mutations increased in the pathway. Furthermore, we noticed that combinations of drugs performed better than single drugs.

Abstract Background To report an unusual case of central serous chorioretinopathy in a patient with angioid streaks. Case presentation The authors describe a case report of a 26-year old male patient presenting acute scotoma and metamorphopsia in OD. He had been diagnosed with angioid streaks complicated with choroidal neovascularization and referred to us for treatment. The patient presented an ETDRS score of 85 letters (20/20) in OD and in OS. The anterior segment examination was unremarkable. Fundoscopy revealed bilateral angioid streaks (AS) and peau d’orange, as well as a small neurosensory retinal detachment in the macula of OD. A multimodal retinal analysis, including fundus photography, infra-red and fundus autofluorescence imaging, spectral-domain optical coherence tomography, optical coherence tomography angiography, fluorescein and indocyanine green angiography was performed. The diagnosis of central serous chorioretinopathy was made in the absence of any identifiable choroidal neovascularization. He was submitted to half-dose photodynamic therapy with verteporfin. One month later, he reported no visual complaints, his vision was 85 letters (20/20) in OD and a complete resolution of the sub-retinal fluid was registered. No signs of choroidal neovascularization were detected on the optical coherence tomography angiography (OCTA). A complete medical workup evaluation was made to exclude systemic diseases usually associated with AS. Conclusions To the authors’ knowledge, this is the second reported case of CSC associated with angioid streaks. The focal abnormalities in the Bruch’s membrane and the irregular vascular choriocapillary network associated with AS might predispose to CSC.

Our study evaluated visual function changes after subthreshold micropulse laser (SML) treatment in persistent central serous chorioretinopathy (CSC) and SML safety profile. We conducted a prospective study including 31 fovea-involving CSC patients. The natural course was observed for the first 3 months, SML was performed at 3 months, and SML effectiveness was observed at 6 months. At all three clinical visits, optical coherence tomography (OCT), best corrected visual acuity (BCVA), contrast sensitivity (CS) in five spatial frequencies (1.5, 3.0, 6.0, 12.0, and 18.0 cycles per degree (cpd)), microperimetry (MP), and multifocal electroretinography (mfERG) were performed. The SML safety profile was evaluated with functional and morphological parameters. In the cohort of all CSC patients treated with SML, the statistically significant average improvement was observed in BCVA (p = 0.007), CS-1.5 (p = 0.020), CS-3.0 (p = 0.050), CS-12.0 (p < 0.001), CS-18.0 (p = 0.002), CS (CS-A) (p < 0.001), MP in the central ring (MP-C) (p = 0.020), peripheral ring (MP-P) (p = 0.042), and average retinal sensitivity (MP-A) (p = 0.010). After the SML treatment, mean changes in mfERG amplitudes and implicit times in our cohort were not statistically significant. No morphological or functional adverse effects of SML treatment were observed. SML treatment in persistent CSC episodes leads to significant functional improvement and has an excellent safety profile. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are known to be one of the factors that make cancer treatment difficult. Many researchers are thus conducting research to efficiently destroy CSCs. Therefore, we sought to suggest a new target that can efficiently suppress CSCs. In this study, we observed a high expression of Ran-binding protein 1 (RanBP1) in lung cancer stem cells (LCSCs) and glioma stem cells (GSCs). Upregulated RanBP1 expression is strongly associated with the expression of CSC marker proteins and CSC regulators. In addition, an elevated RanBP1 expression is strongly associated with a poor patient prognosis. CSCs have the ability to resist radiation, and RanBP1 regulates this ability. RanBP1 also affects the metastasis-associated epithelial–mesenchymal transition (EMT) phenomenon. EMT marker proteins and regulatory proteins are affected by RanBP1 expression, and cell motility was regulated according to RanBP1 expression. The cancer microenvironment influences cancer growth, metastasis, and cancer treatment. RanBP1 can modulate the cancer microenvironment by regulating the cytokine IL-18. Secreted IL-18 acts on cancer cells and promotes cancer malignancy. Our results reveal, for the first time, that RanBP1 is an important regulator in LCSCs and GSCs, suggesting that it holds potential for use as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Simple Summary: A three-dimensional spheroid cell culture model resembles the architecture and cellular characteristics of solid tumors much more closely than the conventional monolayer cell cultures often applied in preclinical drug testing. In this study, we validate the efficacy of the RIST treatment protocol, a novel multimodal treatment regimen for high-risk neuroblastoma, in a neuroblastoma spheroid cell culture model characterized by an augmented neoplastic phenotype. The results also indicate the importance of the neuroblastoma spheroid model for preclinical drug testing in a rigorous, robust and efficient high-throughput format, which can be beneficial to identify more effective treatment options for children with high-risk neuroblastoma in the future. Background: The outcome for patients with high-risk neuroblastoma remains poor and novel treatment strategies are urgently needed. The RIST protocol represents a novel metronomic and multimodal treatment strategy for high-risk neuroblastoma combining molecular-targeted drugs as 'pre-treatment' with a conventional chemotherapy backbone, currently evaluated in a phase II clinical trial. For preclinical drug testing, cancer cell growth as spheroid compared to mo-nolayer cultures is of advantage since it reproduces a wide range of tumor characteristics, including the three-dimensional architecture and cancer stem cell (CSC) properties. The objective of this study was to establish a neuroblastoma spheroid model for the rigorous assessment of the RIST treatment protocol. Methods: Evaluation of CSC marker expression was performed by mRNA and protein analysis and spheroid viability by luminescence-based assays. Aberrant expression of RNA-binding protein La in neuroblastoma was assessed by tissue microarray analysis and patients' data mining. Results: Spheroid cultures showed increased expression of a subgroup of CSC-like markers (CXCR4, NANOG and BMI) and higher Thr389 phosphorylation of the neuroblastoma-associated RNA-binding protein La when compared to monolayer cultures. Molecular-targeted 'pre-treatment' of spheroids decreased neoplastic signaling and CSC marker expression. Conclusions: The RIST treatment protocol efficiently reduced the viability of neuroblastoma spheroids characterized by advanced CSC properties. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor cells from the same specimen are functionally heterogeneous. Cancer stem cells (CSCs) are populations of tumor cells with self-renewal and differentiation properties. CSCs are found in nearly all solid and hematological tumors and are characterized by various surface or intracellular markers. These markers can be used to develop tumor-specific antibodies, cytotoxic immune cells, vaccines, and direct immune responses to the tumor cells, including CSC populations. This review discusses the emerging CSC-directed immunotherapies, the current state of their clinical development, the approaches to improve their safety and efficacy, and future strategies to strengthen anti-CSC immunotherapy. The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are a subset of cancer cells that have the abilities of normal stem cells. CSCs are cancer cell pioneers with self-renewal abilities that can cause CSCs to differentiate into several cancer cells. Because CSCs are resistant to conventional therapies, killing CSCs necessitates the use of a compound with powerful anticancer properties. Trisindoline has been shown to have powerful anticancer properties. Trisindoline has been synthesized into several modifications, the most recent of which is Trisindoline-5. The goal of this study is to find out what the IC50 value of Trisindoline-5 is. The cytotoxicity assay using Microculture Tetrazolium Technique Assay (MTT Assay) is used to determine IC50. The IC50 value of the Trisindoline-5 compound is 24.683 μM at 24 hours incubation, which classifies it as a medium cytotoxic compound, 17.067 μM at 48 hours incubation, which classifies it as a highly toxic compound, and 6497 μM at 72 hours incubation, which classifies it as a compound with no toxicity. While the IC50 value of doxorubicin is 1.611 μM after 24 hours, 2.334 μM after 48 hours, and 5.324 μM after 72 hours, it is classified as a compound with highly toxic activity.

Castration resistant prostate cancer (CRPC) is responsive to androgen receptor (AR) axis targeted agents; however, patients invariably relapse with resistant disease that often progresses to neuroendocrine prostate cancer (NEPC). Treatment-related NEPC (t-NEPC) is highly aggressive with limited therapeutic options and poor survival outcomes. The molecular basis for NEPC progression remains incompletely understood. The MUC1 gene evolved in mammals to protect barrier tissues from loss of homeostasis. MUC1 encodes the transmembrane MUC1-C subunit, which is activated by inflammation and contributes to wound repair. However, chronic activation of MUC1-C contributes to lineage plasticity and carcinogenesis. Studies in human NEPC cell models have demonstrated that MUC1-C suppresses the AR axis and induces the Yamanaka OSKM pluripotency factors. MUC1-C interacts directly with MYC and activates the expression of the BRN2 neural transcription factor (TF) and other effectors, such as ASCL1, of the NE phenotype. MUC1-C also induces the NOTCH1 stemness TF in promoting the NEPC cancer stem cell (CSC) state. These MUC1-C-driven pathways are coupled with activation of the SWI/SNF embryonic stem BAF (esBAF) and polybromo-BAF (PBAF) chromatin remodeling complexes and global changes in chromatin architecture. The effects of MUC1-C on chromatin accessibility integrate the CSC state with the control of redox balance and induction of self-renewal capacity. Importantly, targeting MUC1-C inhibits NEPC self-renewal, tumorigenicity and therapeutic resistance. This dependence on MUC1-C extends to other NE carcinomas, such as SCLC and MCC, and identify MUC1-C as a target for the treatment of these aggressive malignancies with the anti-MUC1 agents now under clinical and preclinical development. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which no effective targeted therapies are available. Growing evidence suggests that chemotherapy-resistant cancer cells with stem-like properties (CSC) may repopulate the tumor. The androgen receptor (AR) is expressed in up to 50% of TNBCs, and AR inhibition decreases CSC and tumor initiation. Runt-related transcription factor 1 (RUNX1) correlates with poor prognosis in TNBC and is regulated by the AR in prostate cancer. Our group has shown that RUNX1 promotes TNBC cell migration and regulates tumor gene expression. We hypothesized that RUNX1 is regulated by the AR and that both may work together in TNBC CSC to promote disease recurrence following chemotherapy. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments in MDA-MB-453 revealed AR binding to RUNX1 regulatory regions. RUNX1 expression is upregulated by dihydrotestosterone (DHT) in MDA-MB-453 and in an AR+-TNBC HCI-009 patient-derived xenograft (PDX) tumors (p < 0.05). RUNX1 is increased in a CSC-like experimental model in MDA-MB-453 and SUM-159PT cells (p < 0.05). Inhibition of RUNX1 transcriptional activity reduced the expression of CSC markers. Interestingly, RUNX1 inhibition reduced cell viability and enhanced paclitaxel and enzalutamide sensitivity. Targeting RUNX1 may be an attractive strategy to potentiate the anti-tumor effects of AR inhibition, specifically in the slow-growing CSC-like populations that resist chemotherapy which lead to metastatic disease. [ABSTRACT FROM AUTHOR]

Cancer recurrence and drug resistance following treatment, as well as metastatic forms of cancer, are trends that are commonly encountered in cancer management. Amidst the growing popularity of personalized medicine and targeted therapy as effective cancer treatment, studies involving the use of stem cells in cancer therapy are gaining ground as promising translational treatment options that are actively pursued by researchers due to their unique tumor-homing activities and anti-cancer properties. Therefore, this review will highlight cancer interactions with commonly studied stem cell types, namely, mesenchymal stroma/stem cells (MSC), induced pluripotent stem cells (iPSC), iPSC-derived MSC (iMSC), and cancer stem cells (CSC). A particular focus will be on the effects of paracrine signaling activities and exosomal miRNA interaction released by MSC and iMSCs within the tumor microenvironment (TME) along with their therapeutic potential as anti-cancer delivery agents. Similarly, the role of exosomal miRNA released by CSCs will be further discussed in the context of its role in cancer recurrence and metastatic spread, which leads to a better understanding of how such exosomal miRNA could be used as potential forms of non-cell-based cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Modern radiotherapy offers several options for the treatment of brain metastases from breast cancer. The radioresistant subpopulation of cancer stem cells (CSCs) pose a particular challenge to a complete cure. This is attributable to the enhanced activation of molecular defense mechanisms that prevent cell death as a consequence of DNA damage. Another fundamental feature of CSCs is their evasion of the immune system. Combining inhibitors of both properties with irradiation may be an attractive option to advance existing therapies, and this is the subject of the data summarized here. Breast cancer is the most diagnosed cancer in women, and symptomatic brain metastases (BCBMs) occur in 15–20% of metastatic breast cancer cases. Despite technological advances in radiation therapy (RT), the prognosis of patients is limited. This has been attributed to radioresistant breast cancer stem cells (BCSCs), among other factors. The aim of this review article is to summarize the evidence of cancer-stem-cell-mediated radioresistance in brain metastases of breast cancer from radiobiologic and radiation oncologic perspectives to allow for the better interpretability of preclinical and clinical evidence and to facilitate its translation into new therapeutic strategies. To this end, the etiology of brain metastasis in breast cancer, its radiotherapeutic treatment options, resistance mechanisms in BCSCs, and effects of molecularly targeted therapies in combination with radiotherapy involving immune checkpoint inhibitors are described and classified. This is considered in the context of the central nervous system (CNS) as a particular metastatic niche involving the blood–brain barrier and the CNS immune system. The compilation of this existing knowledge serves to identify possible synergistic effects between systemic molecularly targeted therapies and ionizing radiation (IR) by considering both BCSCs' relevant resistance mechanisms and effects on normal tissue of the CNS. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer is the most lethal type of gynecological cancer. The leading cause of ovarian cancer patients' death is late diagnosis, disease progression, and metastasis, defined by the spread of invasive cancer cells. About 80% of ovarian cancer patients have disseminated disease at the time of diagnosis. Ovarian cancer metastasis can occur via the transcoelomic, hematogenous, or lymphatic route. Understanding the mechanisms that drive the process of cancer cell dissemination is the key to the development and successful implementation of new diagnostic and treatment methods, particularly drugs and/or therapies targeting metastasis. This review describes ovarian cancer cell dissemination linked to circulating tumor cells (CTCs), with special emphasis on cell biology and their clinical significance. Metastatic ovarian cancer is the main reason for treatment failures and consequent deaths. Ovarian cancer is predisposed to intraperitoneal dissemination. In comparison to the transcoelomic route, distant metastasis via lymph vessels and blood is less common. The mechanisms related to these two modes of cancer spread are poorly understood. Nevertheless, the presence of tumor cells circulating in the blood of OC patients is a well-established phenomenon confirming the significant role of lymphatic and hematogenous metastasis. Thus, the detection of CTCs may provide a minimally invasive tool for the identification of ovarian cancer, monitoring disease progression, and treatment effectiveness. This review focuses on the biology of ovarian CTCs and the role they may play in cancer diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Evidence has revealed that transcription factors play essential roles in regulation of multiple cellular processes, including cell proliferation, metastasis, EMT, cancer stem cells and chemoresistance. Dysregulated expression levels of transcription factors contribute to tumorigenesis and malignant progression. The expression of transcription factors is tightly governed by several signaling pathways, noncoding RNAs and E3 ubiquitin ligases. Cancer stem cells (CSCs) have been validated in regulation of tumor metastasis, reoccurrence and chemoresistance in human cancer. Transcription factors have been verified to participate in regulation of CSC formation, including Oct4, SOX2, KLF4, c-Myc, Nanog, GATA, SALL4, Bmi-1, OLIG2, POU3F2 and FOX proteins. In this review article, we will describe the critical role of CSC-related transcription factors. We will further discuss which E3 ligases regulate the degradation of these CSC-related transcription factors and their underlying mechanisms. We also mentioned the functions and mechanisms of EMT-associated transcription factors such as ZEB1, ZEB2, Snail, Slug, Twist1 and Twist2. Furthermore, we highlight the therapeutic potential via targeting E3 ubiquitin ligases for modulation of these transcription factors. [ABSTRACT FROM AUTHOR]

Purpose : This study aims to investigate retinal and choroidal vascular reactivity to carbogen in central serous chorioretinopathy (CSC) patients. Methods: An experimental pilot study including 68 eyes from 20 CSC patients and 14 age and sex-matched controls was performed. The participants inhaled carbogen (5% CO2 + 95% O2) for 2 min through a high-concentration disposable mask. A 30° disc-centered fundus imaging using infra-red (IR) and macular spectral domain optical coherence tomography (SD-OCT) using the enhanced depth imaging (EDI) technique was performed, both at baseline and after a 2-min gas exposure. A parametric model fitting-based approach for automatic retinal blood vessel caliber estimation was used to assess the mean variation in both arterial and venous vasculature. Choroidal thickness was measured in two different ways: the subfoveal choroidal thickness (SFCT) was calculated using a manual caliper and the mean central choroidal thickness (MCCT) was assessed using an automatic software. Results: No significant differences were detected in baseline hemodynamic parameters between both groups. A significant positive correlation was found between the participants' age and arterial diameter variation (p < 0.001, r = 0.447), meaning that younger participants presented a more vasoconstrictive response (negative variation) than older ones. No significant differences were detected in the vasoreactive response between CSC and controls for both arterial and venous vessels (p = 0.63 and p = 0.85, respectively). Although the vascular reactivity was not related to the activity of CSC, it was related to the time of disease, for both the arterial (p = 0.02, r = 0.381) and venous (p = 0.001, r = 0.530) beds. SFCT and MCCT were highly correlated (r = 0.830, p < 0.001). Both SFCT and MCCT significantly increased in CSC patients (p < 0.001 and p < 0.001) but not in controls (p = 0.059 and 0.247). A significant negative correlation between CSC patients' age and MCCT variation (r = − 0.340, p = 0.049) was detected. In CSC patients, the choroidal thickness variation was not related to the activity state, time of disease, or previous photodynamic treatment. Conclusion: Vasoreactivity to carbogen was similar in the retinal vessels but significantly higher in the choroidal vessels of CSC patients when compared to controls, strengthening the hypothesis of a choroidal regulation dysfunction in this pathology. [ABSTRACT FROM AUTHOR]

Lung cancer, especially non-small cell lung cancer (NSCLC), is one of the most complex diseases, despite the existence of effective treatments such as chemotherapy and immunotherapy. Since cancer stem cells (CSCs) are responsible for chemo- and radio-resistance, metastasis, and cancer recurrence, finding new therapeutic targets for CSCs is critical. Dinactin is a natural secondary metabolite produced by microorganisms. Recently, dinactin has been revealed as a promising antitumor antibiotic via various mechanisms. However, the evidence relating to cell cycle progression regulation is constrained, and effects on cancer stemness have not been elucidated. Therefore, the aim of this study is to evaluate the new function of dinactin in anti-NSCLC proliferation, focusing on cell cycle progression and cancer stemness properties in Lu99 and A549 cells. Flow cytometry and immunoblotting analyses revealed that 0.1–1 µM of dinactin suppresses cell growth through induction of the G0/G1 phase associated with down-regulation of cyclins A, B, and D3, and cdk2 protein expression. The tumor-sphere forming capacity was used to assess the effect of dinactin on the cancer stemness potential in NSCLC cells. At a concentration of 1 nM, dinactin reduced both the number and size of the tumor-spheres. The quantitative RT-PCR analyses indicated that dinactin suppressed sphere formation by significantly reducing expression of CSC markers (i.e., ALDH1A1, Nanog, Oct4, and Sox2) in Lu99 cells. Consequently, dinactin could be a promising strategy for NSCLC therapy targeting CSCs. [ABSTRACT FROM AUTHOR]

There is growing evidence which indicates that the development and the biological features of cancer such as the invasion, metastases and recurrence are related to the presence and behavior of the cancer stem cells (CSC). However, the regulatory mechanisms underlying CSCs-specific properties are poorly determined, the Hippo pathway has emerged as a fundamental regulator underlying CSCs stemness. Immunohistochemical method was used to examine the immunoexpression of SOX2, TAZ and α-SMA in oral squamous cells carcinomas: with metastases – OSCC M+ (n = 42), and without metastases – OSCC M– (n = 44), and 17 control cases. The immunoexpression of SOX2, TAZ and α-SMA was significantly increased in both group of OSCC in comparison to control groups. Moreover, significantly increased TAZ and α-SMA immunoexpression were found in OSCC M+ compared to OSCC M-. In OSCC M+ and OSCC M- groups there were statistically significant correlations between the immunoexpression of TAZ vs SOX2 (r = 0.56, p < 0.001; r = 0.33, p < 0.03 respectively), and TAZ vs α-SMA (r = 0.64, p < 0.001; r = 0.67, p < 0.001 respectively). Moreover, there was statistically significant association between TAZ high /SOX2 high coexistent immunoexpression and the presence of metastases (p < 0.007). Our results may suggest that SOX2 and TAZ could potentially cooperate and contribute to process of metastasis, especially in cases with TAZ high /SOX2 high expression.