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Correct regulation of meteoric surface and subsurface flow waters is a fundamental goal for the sustainable development of the territories. A new system, aimed at real-time monitoring of the rainfall and of the cumulated rainfall, is introduced and discussed in the present paper. The system implements a Sensor Network based on the IoT paradigm and can cover safety-critical "hot spots" with a relatively small number of sensors, strategically placed, in areas not covered by traditional weather radars and rain gauges, and lowering the costs of deployment and maintenance with respects to these devices. A real application case, based on the implementation of the pilot plant at the Monte Scarpino landfill (Genoa, Italy), is presented and discussed. The system performances are assessed on the basis of comparisons with data provided by a polarimetric weather radar and by a traditional rain gauge.

Treatment of high-grade osteosarcoma, the most common malignant tumor of bone, is largely based on administration of cisplatin and other DNA damaging drugs. Altered DNA repair mechanisms may thus significantly impact on either response or resistance to chemotherapy. In this study, by using a panel of human osteosarcoma cell lines, either sensitive or resistant to cisplatin, we assessed the value as candidate therapeutic targets of DNA repair-related factors belonging to the nucleotide excision repair (NER) or base excision repair (BER) pathways, as well as of a group of 18 kinases, which expression was higher in cisplatin-resistant variants compared to their parental cell lines and may be indirectly involved in DNA repair. The causal involvement of these factors in cisplatin resistance of human osteosarcoma cells was validated through gene silencing approaches and in vitro reversal of CDDP resistance. This approach highlighted a subgroup of genes, which value as promising candidate therapeutic targets was further confirmed by protein expression analyses. The in vitro activity of 15 inhibitor drugs against either these genes or their pathways was then analyzed, in order to identify the most active ones in terms of inherent activity and ability to overcome cisplatin resistance. NSC130813 (NERI02; F06) and triptolide, both targeting NER factors, proved to be the two most active agents, without evidence of cross-resistance with cisplatin. Combined in vitro treatments showed that NSC130813 and triptolide, when administered together with cisplatin, were able to improve its efficacy in both drug-sensitive and resistant osteosarcoma cells. This evidence may indicate an interesting therapeutic future option for treatment of osteosarcoma patients who present reduced responsiveness to cisplatin, even if possible effects of additive collateral toxicities must be carefully considered. Moreover, our study also showed that targeting protein kinases belonging to the mitogen-activated protein kinase (MAPK) or fibroblast growth factor receptor (FGFR) pathways might indicate new promising therapeutic perspectives in osteosarcoma, demanding for additional investigation., (Copyright © 2020 Fanelli, Tavanti, Patrizio, Vella, Fernandez-Ramos, Magagnoli, Luppi, Hattinger and Serra.)

Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated protein that endows its carrier with (lipo-)lactonase-dependent antioxidative features. Low levels of PON1 activity have been observed in association with obesity, a major risk factor for cardiovascular disease (CVD). Considering the well-recognized atheroprotective role of PON1, exogenous/endogenous factors that might modulate its levels/activity are raising great interest. Since adipokines represent a molecular link between obesity and CVD, we here explored the possible impact of these substances on PON1 activity/expression. The levels of interleukin (IL)-6, IL-8, tumor necrosis factor alpha, monocyte chemoattractant protein-1, hepatocyte growth factor, resistin, leptin, and adiponectin were measured along with arylesterase, paraoxonase, and lactonase activities of PON1 in 107 postmenopausal women. Moreover, the direct effect of resistin on PON1 expression was evaluated in vitro. Multivariate analysis revealed that only resistin was significantly and inversely correlated with PON1-lactonase activities ( r = -0.346, p < 0.001) regardless of confounding factors such as age or HDL-cholesterol. It is worth noting that no statistical link was found between adipokine and arylesterase or paraoxonase, the two promiscuous activities of PON1. Notably, resistin down-regulated PON1 expression occurred in hepatocellular carcinoma cultures. Our study suggests that resistin might be a negative modulator of PON1 expression and anti-oxidative activity.

Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for doxorubicin resistance in osteosarcoma is the increased expression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). We recently identified a library of H 2 S-releasing doxorubicins (Sdox) that were more effective than doxorubicin against resistant osteosarcoma cells. Here we investigated the molecular mechanisms of the higher efficacy of Sdox in human osteosarcoma cells with increasing resistance to doxorubicin. Differently from doxorubicin, Sdox preferentially accumulated within the endoplasmic reticulum (ER), and its accumulation was only modestly reduced in Pgp-expressing osteosarcoma cells. The increase in doxorubicin resistance was paralleled by the progressive down-regulation of genes of ER-associated protein degradation/ER-quality control (ERAD/ERQC), two processes that remove misfolded proteins and protect cell from ER stress-triggered apoptosis. Sdox, that sulfhydrated ER-associated proteins and promoted their subsequent ubiquitination, up-regulated ERAD/ERQC genes. This up-regulation, however, was insufficient to protect cells, since Sdox activated ER stress-dependent apoptotic pathways, e.g., the C/EBP-β LIP/CHOP/PUMA/caspases 12-7-3 axis. Sdox also promoted the sulfhydration of Pgp that was subsequently ubiquitinated: this process further enhanced Sdox retention and toxicity in resistant cells. Our work suggests that Sdox overcomes doxorubicin resistance in osteosarcoma cells by at least two mechanisms: it induces the degradation of Pgp following its sulfhydration and produces a huge misfolding of ER-associated proteins, triggering ER-dependent apoptosis. Sdox may represent the prototype of innovative anthracyclines, effective against doxorubicin-resistant/Pgp-expressing osteosarcoma cells by perturbing the ER functions.

Introduction: Genetic characterization of osteosarcoma has evolved during the last decade, thanks to the integrated application of conventional and new candidate-driven and genome-wide technologies. Areas covered: This review provides an overview of the state of art in genetic testing applied to osteosarcoma, with particular regard to novel candidate genetic biomarkers that can be analyzed in tumor tissue and blood samples, which might be used to predict toxicity and prognosis, detect disease relapse, and improve patients' selection criteria for tailoring treatment. Expert commentary: Genetic testing based on modern technologies is expected to indicate new osteosarcoma-related prognostic markers and driver genes, which may highlight novel therapeutic targets and patients stratification biomarkers. The definition of tailored or targeted treatment approaches may improve outcome of patients with localized tumors and, even more, of those with metastatic disease, for whom progress in cure probability is highly warranted.

Introduction: Antifolates are structural analogs of folates, which have been used as antitumor drugs for more than 60 years. The antifolate drug most commonly used for treating human tumors is methotrexate (MTX), which is utilized widely in first-line treatment protocols of high-grade osteosarcoma (HGOS). In addition to MTX, two other antifolates, trimetrexate and pemetrexed, have been tested in clinical settings for second-line treatment of recurrent HGOS with patients unfortunately showing modest activity. Areas covered: There is clinical evidence which suggsest that, like other chemotherapeutic agents, not all HGOS patients are equally responsive to antifolates and do not have the same susceptibility to experience adverse drug-related toxicities. Here, we summarize the pharmacogenomic information reported so far for genes involved in antifolate metabolism and transport and in MTX-related toxicity in HGOS patients. Expert opinion: Identification and validation of genetic biomarkers that significantly impact clinical antifolate treatment response and related toxicity may provide the basis for a future treatment modulation based on the pharmacogenetic and pharmacogenomic features of HGOS patients.

Second-line treatment of high-grade osteosarcoma (HGOS) patients is based on different approaches and chemotherapy protocols, which are not yet standardized. Although several drugs have been used in HGOS second-line protocols, none of them has provided fully satisfactory results and the role of rescue chemotherapy is not well defined yet. This article focuses on the drugs that have most frequently been used for second-line treatment of HGOS, highlighting the present knowledge on their mechanisms of action and resistance and on gene polymorphisms with possible impact on treatment sensitivity or toxicity. In the near future, validation of the so far identified candidate genetic biomarkers may constitute the basis for tailoring treatment by taking the patients' genetic background into account.

Cyclin-dependent kinase 2 (CDK2) has been reported to be essential for cell proliferation in several human tumours and it has been suggested as an appropriate target to be considered in order to enhance the efficacy of treatment regimens based on the use of DNA damaging drugs. We evaluated the clinical impact of CDK2 overexpression on a series of 21 high-grade osteosarcoma (OS) samples profiled by using cDNA microarrays. We also assessed the in vitro efficacy of the CDKs inhibitor roscovitine in a panel of drug-sensitive and drug-resistant human OS cell lines. OS tumour samples showed an inherent overexpression of CDK2, and high expression levels at diagnosis of this kinase appeared to negatively impact on clinical outcome. CDK2 expression also proved to be relevant for in vitro OS cells growth. These findings indicated CDK2 as a promising candidate therapeutic marker for OS and therefore we assessed the efficacy of the CDKs-inhibitor roscovitine in both drug-sensitive and -resistant OS cell lines. All cell lines resulted to be responsive to roscovitine, which was also able to increase the activity of cisplatin and doxorubicin, the two most active DNA damaging drugs used in OS chemotherapy. Our results indicated that combined treatment with conventional OS chemotherapeutic drugs and roscovitine may represent a new candidate intervention approach, which may be considered to enhance tumour cell sensitivity to DNA damaging drugs., Competing Interests: The authors have declared that no competing interests exist.

This study aimed to identify associations between germline polymorphisms and risk of high-grade osteosarcoma (HGOS) development, event-free survival (EFS) and toxicity in HGOS patients treated with neo-adjuvant chemotherapy and surgery.Germline polymorphisms of 31 genes known to be relevant for transport or metabolism of all four drugs used in HGOS chemotherapy (methotrexate, doxorubicin, cisplatin and ifosfamide) were genotyped in 196 patients with HGOS and in 470 healthy age and gender-matched controls. Of these 196 HGOS patients, a homogeneously treated group of 126 patients was considered for survival analyses (survival cohort). For 57 of these, treatment-related toxicity data were available (toxicity cohort).Eleven polymorphisms were associated with increased risk of developing HGOS (p < 0.05). The distribution of polymorphisms in patients was characterized by a higher Shannon entropy. In the survival cohort (n = 126, median follow-up = 126 months), genotypes of ABCC2&#95;1249A/G, GGH&#95;452T/C, TP53&#95;IVS2+38G/C and CYP2B6*6 were associated with EFS (p < 0.05). In the toxicity cohort (n = 57), genotypes of ABCB1&#95;1236T/C, ABCC2&#95;1249A/G, ABCC2&#95;3972A/G, ERCC1&#95;8092T/G, XPD&#95;23591A/G, XRCC3&#95;18067T/C, MTHFR&#95;1298A/C and GGH&#95;16T/C were associated with elevated risk for toxicity development (p < 0.05).The results obtained in this retrospective study indicate that the aforementioned germline polymorphisms significantly impact on the risk of HGOS development, EFS and the occurrence of chemotherapy-related toxicity. These findings should be prospectively validated with the aim of optimizing and tailoring HGOS treatment in the near future., Competing Interests: The authors have declared no conflicts of interest.

Clinical treatment response achievable with conventional chemotherapy in high-grade osteosarcoma (OS) is severely limited by the presence of intrinsic or acquired drug resistance, which in previous studies has been mainly addressed for overexpression of ABCB1 (MDR1/P-glycoprotein). This study was aimed to estimate the impact on OS drug resistance of a group of ATP binding cassette (ABC) transporters, which in other human tumors have been associated with unresponsiveness to the drugs that represent the backbone of multidrug treatment regimens for OS (doxorubicin, methotrexate, cisplatin). By using a group of 6 drug-sensitive and 20 drug-resistant human OS cell lines, the most relevant transporter which proved to be associated with the degree of drug resistance in OS cells, in addition to ABCB1, was ABCC1. We therefore evaluated the in vitro activity of the orally administrable ABCB1/ABCC1 inhibitor CBT-1(®) (Tetrandrine, NSC-77037). We found that in our OS cell lines this agent was able to revert the ABCB1/ABCC1-mediated resistance against doxorubicin, as well as against the drugs used in second-line OS treatments that are substrates of these transporters (taxotere, etoposide, vinorelbine). Our findings indicated that inhibiting ABCB1 and ABCC1 with CBT-1(®), used in association with conventional chemotherapeutic drugs, may become an interesting new therapeutic option for unresponsive or relapsed OS patients.

Introduction: Osteosarcoma (OS), the most common primary malignant bone tumor, is currently treated with pre- and postoperative chemotherapy in association with the surgical removal of the tumor. Conventional treatments allow to cure about 60 - 65% of patients with primary tumors and only 20 - 25% of patients with recurrent disease. New treatment approaches and drugs are therefore highly warranted to improve prognosis., Areas Covered: This review focuses on the therapeutic approaches that are under development or clinical evaluation in OS. Information was obtained from different and continuously updated data bases, as well as from literature searches, in which particular relevance was given to reports and reviews on new targeted therapies under clinical investigation in high-grade OS., Expert Opinion: OS is a heterogeneous tumor, with a great variability in treatment response between patients. It is therefore unlikely that a single therapeutic tool will be uniformly successful for all OS patients. This claims for the validation of new treatment approaches together with biologic/(pharmaco)genetic markers, which may select the most appropriate subgroup of patients for each treatment approach. Since some promising novel agents and treatment strategies are currently tested in Phase I/II/III clinical trials, we may hope that new therapies with superior efficacy and safety profiles will be identified in the next few years.

Garlic (Allium sativum L.) is a species of the onion family (Alliaceae) widely used as a food and a folk medicine. The objective of this study was to determine the effects of AGE (aged garlic extract) on pro-inflammatory genes relevant to COVID-19. To this aim, we treated bronchial epithelial IB3-1 cells with SARS-CoV-2 spike protein (S-protein) or with the COVID-19 BNT162b2 vaccine in the absence or in the presence of AGE. The results obtained demonstrated that AGE is a potent inhibitor of the S-protein-induced expression of the IL-1β, IL-6 and IL-8 genes. Bio-Plex analysis demonstrated that AGE reduced release of IL-6 and IL-8, which were highly induced by S-protein. No inhibition of cells' growth, toxicity and pro-apoptotic effects were found in AGE-treated cells. The effects of one of the major AGE constituents (S-allyl cysteine, SAC) were studied on the same experimental model systems. SAC was able to inhibit the S-protein-induced expression of IL-1β, IL-6 and IL-8 genes and extracellular release of IL-6 and IL-8, confirming that S-allyl-cysteine is one of the constituents of AGE that is responsible for inhibiting S-protein-induced pro-inflammatory genes. Docking experiments suggest that a possible mechanism of action of SAC is an interference with the activity of Toll-like receptors (TLRs), particularly TLR4, thereby inhibiting NF-κB- and NF-κB-regulated genes, such as IL-1β, IL-6 and IL-8 genes. These results suggest that both AGE and SAC deserve further experimental efforts to verify their effects on pro-inflammatory genes in SARS-CoV-2-infected cells. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma is a rare disease, but it is the most frequent malignant bone tumor. Primary treatment consists of preoperative MAP (methotrexate (MTX), doxorubicin and cisplatin) chemotherapy followed by surgery and adjuvant chemotherapy. Pathological response to preoperative chemotherapy is one of the most important prognostic factors, but molecular biomarkers are lacking. Additionally, chemotherapy-induced toxicity might jeopardize treatment completion. We evaluated variants in genes involved in DNA repair and drug metabolism pathways as predictors of response to MAP-based treatment. Material and Methods: Germline polymorphisms in MTHFR, SLC19A1, ABCB1, ABCC2, ABCC3, ERCC1, ERCC2 and GSTP1 genes were determined for association studies in 69 patients diagnosed with localized osteosarcoma who enrolled in the prospective GEIS-33 trial. P-glycoprotein expression in tumor tissue was also analyzed. Results: In the multivariate analysis, the ABCC2 rs2273697 (odds ratio [OR] 12.3, 95% CI 2.3–66.2; p = 0.003) and ERCC2 rs1799793 (OR 9.6, 95% CI 2.1–43.2; p = 0.003) variants were associated with poor pathological response. P-glycoprotein expression did not correlate with pathological response. The ABCB1 rs1128503 (OR 11.4, 95% CI 2.2–58.0; p = 0.003) and ABCC3 rs4793665 (OR 12.0, 95% CI 2.1–70.2; p = 0.006) variants were associated with MTX grade 3–4 hepatotoxicity. Conclusions: Our findings add to the evidence that genetic variants in the ABC transporters and DNA-repair genes may serve as predictive biomarkers for MAP chemotherapy and contribute to treatment personalization. [ABSTRACT FROM AUTHOR]

Background/Objectives: Interleukin 13 receptor alpha 2 (IL-13Rα2) is a receptor with a high affinity for IL-13 and is involved in the progression of human cancers. However, studies on the role of IL-13Rα2 in osteosarcoma are limited. Therefore, this study aimed to investigate the expression and roles of IL-13Rα2 in the progression of osteosarcoma. Methods: This study evaluated the roles of IL-13Rα2 in osteosarcomas by evaluating tumor tissues from 37 human osteosarcomas and osteosarcoma cells. Results: Immunohistochemical positivity of IL-13Rα2 was an independent indicator of shorter overall survival and relapse-free survival of 37 osteosarcoma patients and 26 subpopulations of patients who received adjuvant chemotherapy with multivariate analysis. In U2OS and KHOS/NP osteosarcoma cells, overexpression of IL-13Rα2 significantly increased proliferation, migration, and invasion of cells, all of which decreased with knockdown of IL-13Rα2. Overexpression of IL-13Rα2 increased expression of TGF-β, snail, cyclin D1, and BCL2 but decreased BAX, and knockdown of IL-13Rα2 caused a decrease in expression of these molecules. In addition, both in vitro and in vivo, proliferation of osteosarcoma cells increased, and apoptosis decreased with overexpression of IL-13Rα2 under treatment with doxorubicin. Knockdown of IL-13Rα2 sensitized osteosarcoma cells to the cytotoxic effect of doxorubicin. Conclusions: The results of this study suggest that the expression of IL13Rα2 might be used as a potential prognostic indicator in osteosarcoma patients. Furthermore, it is observed that IL13Rα2 influences the resistance to the chemotherapeutic agent doxorubicin. Therefore, a therapeutic trial targeting IL13Rα2 might be a new therapeutic strategy for osteosarcoma, especially those highly expressing IL13Rα2. [ABSTRACT FROM AUTHOR]

Background: Polo-like kinase 1 (PLK1) has emerged as a prognostic factor in various neoplasms, but only scarce data have been reported for high-grade osteosarcoma (OS). In this study, we assessed PLK1 expression and the efficacy of PLK1 inhibitor NMS-P937 in OS., Methods: PLK1 expression was assessed on 21 OS clinical samples and on a panel of human OS cell lines. In vitro efficacy of NMS-P937 was evaluated on nine drug-sensitive and six drug-resistant human OS cell lines, either as single agent or in combination with the drugs used in chemotherapy for OS., Results: PLK1 expression was higher in OS clinical samples and cell lines compared to normal human tissue. A higher PLK1 expression at diagnosis appeared to be associated with an unfavourable clinical outcome. PLK1 silencing produced growth inhibition, cell cycle retardation and apoptosis induction in human OS cell lines. NMS-P937 proved to be highly active in both drug-sensitive and drug-resistant cell lines, with the only exception of ABCB1-overexpressing, Doxorubicin (DX)-resistant variants. However, in these cells, the association of NMS-P937 with DX was able to revert DX-resistance by negatively interfering with ABCB1 transport activity. NMS-P937 was also able to decrease clonogenic and migration ability of human OS cell lines., Conclusion: PLK1 can be proposed as a new candidate target for OS. Targeting PLK1 in OS with NMS-P937 in association with conventional chemotherapeutic drugs may be a new interesting therapeutic option, since this approach has proved to be active against drug resistant cells.

The description of a microencapsulation procedure for Wharton's jelly mesenchymal stem cells (WJMSCs) is reported. The applied method is based on the generation of monodisperse droplets by a vibrational nozzle. An ionic alginate encapsulation procedure was utilized for the microbeads hardening. Different experimental parameters were analyzed, including frequency and amplitude of vibration, polymer pumping rate, and distance between the nozzle and the gelling bath. The produced barium-alginate microbeads were characterized by excellent morphological characteristics as well as a very narrow size distribution. The microencapsulation procedure did not alter the morphology and viability of the encapsulated WJMSCs. In addition, the current paper reports the functional properties in terms of secretive profiles of both free and encapsulated WJMSCs. The analyzed factors were members of the family of interleukins, chemokines, growth factors, and soluble forms of adhesion molecules. These experiments showed that despite encapsulation, most of the proteins analyzed were secreted both by the free and encapsulated cells, even if in a different extent. In conclusion, the described encapsulation procedure represents a promising strategy to utilize WJMSCs for possible in vivo applications in tissue engineering and biomedicine.

Estrogen-responsive genes often have an estrogen response element (ERE) positioned next to activator protein-1 (AP-1) binding sites. Considering that the interaction between ERE and AP-1 elements has been described for the modulation of bone-specific genes, we investigated the 17-beta-estradiol responsiveness and the role of these cis-elements present in the F promoter of the human estrogen receptor alpha (ERalpha) gene. The F promoter, containing the sequence analyzed here, is one of the multiple promoters of the human ERalpha gene and is the only active promoter in bone tissue. Through electrophoretic mobility shift (EMSA), chromatin immunoprecipitation (ChIP), and re-ChIP assays, we investigated the binding of ERalpha and four members of the AP-1 family (c-Jun, c-fos, Fra-2, and ATF2) to a region located approximately 800 bp upstream of the transcriptional start site of exon F of the human ERalpha gene in SaOS-2 osteoblast-like cells. Reporter gene assay experiments in combination with DNA binding assays demonstrated that F promoter activity is under the control of upstream cis-acting elements which are recognized by specific combinations of ERalpha, c-Jun, c-fos, and ATF2 homo- and heterodimers. Moreover, ChIP and re-ChIP experiments showed that these nuclear factors bind the F promoter in vivo with a simultaneous occupancy stimulated by 17-beta-estradiol. Taken together, our findings support a model in which ERalpha/AP-1 complexes modulate F promoter activity under conditions of 17-beta-estradiol stimulation., ((c) 2008 Wiley-Liss, Inc.)

Osteoclasts (OCs) are specialized bone-resorbing cells. For "in vitro" analysis, they may be obtained from the precursors present in peripheral blood (PB) or umbilical cord blood (UCB), but there has been no detailed analysis of how the kind of source and cell culture conditions may affect the behavior of these cells. Here we analyzed the behavior of OCs after transfection with specific transcription factor decoy molecules founding that the OCs from PB undergo apoptosis when nuclear factor kappa B (NF-kB) or NFATc1 were removed, or when ERalpha expression was increased. Conversely, OCs from UCB showed a strong resistance to apoptotic stimuli. We found that survival signals including Bcl-2, Bcl-XL, and Survivin are present in the OCs/UCB, but not in OCs/PB. The resistance to apoptosis seems to be not correlated with NF-kB, NFATc1, or ERalpha expression level, or with the activation of ERK and Akt proteins. One of the mechanisms responsible for bone remodeling is apoptosis, and being susceptible of therapeutic manipulation, the OCs are extensively employed to investigate cell response to therapies for the treatment of bone loss associated with several diseases, including periodontitis, osteoporosis, and metastatic osteolysis. Therefore, our evidences are to be taken in consideration when both the effects of biological modifiers are tested and OCs apoptosis molecular mechanisms are investigated.

We have used cytokine protein array to analyze the secretion of cytokines from an osteoblastic clone derived from human umbilical cord blood mesenchymal stem cells (MSCs) cultured in an osteogenic differentiation medium. The analysis demonstrated the unexpected ability of osteoblast committed cells and their early progenitors to produce significant amounts of a range of soluble immune mediators without in vitro exposure to clinically relevant bacterial pathogens. The cells were expanded and their osteogenic potential analyzed over 45 days of culture was revealed by the expression of osteoblast-specific markers (alkaline phosphatase and Runx2), and by matrix mineralization. Over this culture period, the cells secreted particularly high levels of IL-8, MCP-1 and VEGF, but did not express IL-2, IL-7, IL-17, eotaxin, G-CSF and IFN-gamma. These findings should encourage the use of human umbilical cord blood as a potential stem cells source for bone regeneration.

The nuclear factor of activated T cell cytoplasmic 1 (NFATc1) is a member of the NFAT family and is strictly implicated in the growth and development of bone. Most studies have focused on the effects of NFATc1 activation on osteoclastogenesis. On the contrary, the specific roles of NFAT in osteoblast differentiation are not well understood and, in some instances, reports of its role are contradictory. In the present study, we demonstrated that NFATc1 was involved in the transcriptional regulation of human estrogen receptor alpha (ERalpha) gene in SaOS-2 osteoblastic like cells. NFATc1 was specifically recruited "in vivo" at C and F distal promoters of ERalpha gene. In addition, it is here identified as the negative transcription factor removed by the RA4-3'decoy oligonucleotide able to induce ERalpha expression in osteoblasts. Ca(2+)/calcineurin-NFAT-mediated signaling pathways and ERalpha-dependent signals are involved in diverse cellular reactions by regulating gene expression under both physiological and pathological conditions. Therefore, our data might be useful for proper manipulation of NFATc1- and ERalpha-mediated cellular reactions in different bone disorders, such as osteoporosis.

Several studies into the mechanisms involved in control of osteoblast-specific gene expression have identified Runx2 and ERalpha (estrogen receptor alpha) as essential regulators of osteoblast differentiation. Recently, interactions between Runx2 and ERalpha have been described. Here, we investigate the role of Runx2 on the regulation of ERalpha expression by determining its interaction with the F promoter, one of the multiple promoters of the human ERalpha gene and the only one active in bone. We found that, in this promoter, three Runx2-like sites are present. By electrophoretic mobility shift assay in combination with supershift and ChIP experiments, we demonstrated that Runx2 preferentially binds one of the Runx2 motifs of the F promoter. To understand whether or not they are involved in influencing F promoter activity, different promoter-reporter deletion and mutation constructs were transiently transfected into human osteoblastic cells. Comparison of luciferase activities allowed the identification of a prevalent negative role of a sequence context, within the -117,877/-117,426 region, which may be under the control of Runx2 (a) site. Finally, silencing and overexpression of endogenous Runx2 provided evidence that Runx2 has a more complex role than initially expected. In fact, Runx2 (a) and Runx2 (b) sites carried out opposite roles which are conditioned by Runx2 levels in bone cells. Therefore, the resulting F promoter activity may be tightly regulated by a dynamic interplay between these two Runx2 sites, with a predominance of negative effect of the Runx2 (a) site.

In clinical settings, computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) are commonly employed in brain imaging to assist clinicians in determining the type of stroke in patients. However, these modalities are associated with potential hazards or limitations. In contrast, microwave imaging emerges as a promising technique, offering advantages such as non-ionizing radiation, low cost, lightweight, and portability. The primary challenges faced by microwave tomography include the severe ill-posedness of the electromagnetic inverse scattering problem and the time-consuming nature and unsatisfactory resolution of iterative quantitative algorithms. This paper proposes a learning electric field enhancement imaging method (LEFEIM) to achieve quantitative brain imaging based on a microwave tomography system. LEFEIM comprises two cascaded networks. The first, based on a convolutional neural network, utilizes the electric field from the receiving antenna to predict the electric field distribution within the imaging domain. The second network employs the electric field distribution as input to learn the dielectric constant distribution, thereby realizing quantitative brain imaging. Compared to the Born Iterative Method (BIM), LEFEIM significantly improves imaging time, while enhancing imaging quality and goodness-of-fit to a certain extent. Simultaneously, LEFEIM exhibits anti-noise capabilities. [ABSTRACT FROM AUTHOR]

Osteosarcoma, recognized for its aggressiveness and resistance to chemotherapy, notably doxorubicin, poses significant treatment challenges. This comprehensive study investigated the CXCR4–CARM1–YAP signaling axis and its pivotal function in controlling aerobic glycolysis, which plays a crucial role in doxorubicin resistance. Detailed analysis of Dox‐resistant 143b/MG63‐DoxR cells has uncovered the overexpression of CXCR4. Utilizing a combination of molecular biology techniques including gene silencing, aerobic glycolysis assays such as Seahorse experiments, RNA sequencing, and immunofluorescence staining. The study provides insight into the mechanistic pathways involved. Results demonstrated that disrupting CXCR4 expression sensitizes cells to doxorubicin‐induced apoptosis and alters glycolytic activity. Further RNA sequencing revealed that CARM1 modulated this effect through its influence on glycolysis, with immunofluorescence of clinical samples confirming the overexpression of CXCR4 and CARM1 in drug‐resistant tumors. Chromatin immunoprecipitation studies further highlighted the role of CARM1, showing it to be regulated by methylation at the H3R17 site, which in turn affected YAP expression. Crucially, in vivo experiments illustrated that CARM1 overexpression could counteract the tumor growth suppression that resulted from CXCR4 inhibition. These insights revealed the intricate mechanisms at play in osteosarcoma resistance to doxorubicin and pointed toward potential new therapeutic strategies that could target this metabolic and signaling network to overcome drug resistance and improve patient outcomes. [ABSTRACT FROM AUTHOR]

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is a common and important post-translational modification (PTM) linking O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues in proteins. Extensive research indicates its impact on target protein stability, activity, and interactions. O-linked N-acetylglucosamine transferase (OGT) is a critical enzyme that catalyzes O-GlcNAc modification, responsible for adding O-GlcNAc to proteins. OGT and O-GlcNAcylation are overexpressed in many tumors and closely associated with tumor growth, invasion, metabolism, drug resistance, and immune evasion. This review delineates the biochemical functions of OGT and summarizes its effects and mechanisms in tumors. Targeting OGT presents a promising novel approach for treating human malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to determine the gene expression profiles associated with chemotherapeutic responses in conventional osteosarcomas (COS) within South Africa. We observed a significant downregulation in the ATP binding cassette subfamily C members (ABCC3 and ABCB1-p-glycoprotein), excision repair cross-complimenting group 1 (ERCC 1), replication factor C subunit 1 (RFC1), and tumour protein 53 (p53) genes in the COS tumours compared to the healthy donors. Furthermore, an upregulated ERCC1 gene expression level predicted a poor chemotherapeutic response. Additionally, the predictors of COS chemotherapeutic response comprised age, chondroblastic and osteoblastic histological subtypes, and ABCC3, ERCC1, and RFC1 gene expression. Background: We determined the predictive gene expression profiles associated with chemo-response in conventional osteosarcomas (COS) within South Africa. Materials and methods: In 28 patients, we performed an RNA extraction, cDNA synthesis, and quantitative analysis using the RT-PCR 2−∆∆CT method to determine the fold change in gene expression alongside GAPDH (housekeeping gene). Results: We observed a significant downregulation in the mRNA expression profiles of ABCB1-p-glycoprotein (p = 0.0007), ABCC3 (p = 0.002), ERCC1 (p = 0.007), p-53 (p = 0.007), and RFC1 (p = 0.003) in the COS patients compared to the healthy donors. Furthermore, ABCB1-p-glycoprotein (p = 0.008) and ABCC3 (p = 0.020) exhibited a significant downregulation in the COS tumour tissues when compared to the healthy donors. In our univariate logistic regression, the predictors of chemotherapeutic response comprised ERCC1 [restricted cubic spline (RCS) knot: OR −0.27; CI −0.504 to −0.032; p = 0.036]; osteoblastic subtype [OR −0.36; CI −0.652 to −0.092; p = 0.026); fibroblastic subtype [OR 0.91; CI 0.569 to 1.248; p < 0.001]; and mixed subtype [OR 0.53; CI 0.232 to 0.032; p = 0.032]. In our multivariable logistic regression, the significant predictors of chemotherapeutic response comprised age [RCS knot: OR −2.5; CI −3.616 to −1.378; p = 0.022]; ABCC3 [RCS knot: OR 0.67; CI 0.407 to 0.936, p = 0.016]; ERCC1 [RCS knot: OR 0.57; CI 0.235 to 0.901; p = 0.044]; RFC1 [RCS knot: OR −1.04; CI −1.592 to −0.487; p = 0.035]; chondroblastic subtype [OR −0.83; CI −1.106 to −0.520; p = 0.012]; and osteoblastic subtype [OR −1.28; CI −1.664 to −0.901; p = 0.007]. Conclusions: In this South African cohort, we observed the unique gene expression profiles of osteosarcoma tumourigenesis and chemotherapeutic responses. These may serve as prognostication and therapeutic targets. Larger-scale research is needed on the African continent. [ABSTRACT FROM AUTHOR]

We review the effects of two transcription factor decoy oligonucleotides on apoptosis of human osteoclasts (OCs). The first decoy molecule was designed to inhibit nuclear factor kappa-B (NF-kappaB) binding to target sequence, the second to increase estrogen receptor (ER) alpha expression. We found that both decoy molecules are potent inducers of apoptosis of human OCs, associated with increase of caspase 3 activity and decrease of interleukin 6 expression. In addition, we provide evidence indicating that these oligonucleotides are active in vivo in inducing OCs apoptosis. Because OCs are essential for skeletal development and remodeling throughout the life of animal and man, the approach described is of potential clinical importance.

Background: This study aimed to explore the impact of Diacerein (DIC) on endocrine and cardio-metabolic changes in polycystic ovarian syndrome (PCOS) mouse model. Methods: A total of 18 adult female mice (Parkes strain), aged 4–5 weeks, were randomly assigned to three groups, each comprising 6 animals, as follows: Group I (control), received normal diet and normal saline as vehicle for 51 days; Group II received Letrozole (LET; 6 mg/kg bw) for 21 days to induce PCOS; Group III received LET, followed by daily oral gavage administration of DIC (35 mg/kg bw) for 30 days. Results: This study indicates that treatment with LET resulted in PCOS with characteristics such as polycystic ovaries, elevated testosterone, weight gain, visceral adiposity, high levels of insulin as well as fasting blood glucose in addition to insulin resistance, improper handling of ovarian lipids, atherogenic dyslipidemia, impaired Na + /K + -ATPase activity and serum, cardiac, and ovarian oxidative stress. Serum/ovarian adiponectin levels were lowered in LET-treated mice. In mice treated with LET, we also discovered a reduction in cardiac and serum paraoxonase 1 (PON1). Interestingly, DIC restored ovarian andcardio-metabolic abnormalities in LET-induced PCOS mice. DIC prevented the endocrine and cardio-metabolic changes brought on by letrozole-induced PCOS in mice. Conclusion: The ameliorative effects of DIC on letrozole-induced PCOS with concurrent oxidative stress, abdominal fat deposition, cardiac and ovarian substrate mishandling, glucometabolic dysfunction, and adiponectin/PON1 activation support the idea that DIC perhaps, restore compromised endocrine and cardio-metabolic regulators in PCOS. [ABSTRACT FROM AUTHOR]

Cyclists are considered to be vulnerable road users (VRUs) and need protection from potential collisions with cars and other vehicles induced by unsafe driving, dangerous road conditions, or weak cycling infrastructure. Integrating mmWave radars into cycling safety measures presents an efficient solution to this problem given their compact size, low power consumption, and low cost compared to other sensors. This paper introduces an mmWave radar-based bike safety system designed to offer real-time alerts to cyclists. The system consists of a low-power radar sensor affixed to the bicycle, connected to a micro-controller, and delivering a preliminary classification of detected obstacles. An efficient two-level clustering based on the accumulation of radar point clouds from multiple frames with a temporal projection from previous frames into the current frame is proposed. The clustering is followed by a coarse classification algorithm in which we use relevant features extracted from the resulting clusters. An annotated RadBike dataset composed of radar point cloud data synchronized with RGB camera images is developed to evaluate our system. The two-level clustering outperforms the DBSCAN algorithm, achieving a v-measure score of 0.91, compared to 0.88 with classical DBSCAN. Different classifiers, including decision trees, random forests, support vector machines (SVMs), and AdaBoost, have been assessed, with an overall accuracy of 87% for the three main object classes: four-wheeled, two-wheeled, and others. The system has the ability to improve rider safety on the road and substantially reduce the frequency of incidents involving cyclists. [ABSTRACT FROM AUTHOR]

This document is a special issue of the International Journal of Molecular Sciences focused on the development and synthesis of biologically active compounds. The articles in this issue cover a range of topics, including the search for new compounds with antiproliferative and cytotoxic activities, the use of cosolvents to improve the solubility of lipophilic compounds, the challenges in developing bioactive compounds of natural origin into drugs, and the study of the cytotoxic, antibacterial, antiaggregation, and antiphytopathogenic activities of synthesized compounds. The issue also includes research on catalytic antibodies and the design of substances to inhibit HIV-1 integrase. [Extracted from the article]

Aim: To investigate the mechanism of doxorubicin (DOX)-induced immunogenic cell death (ICD) and to improve immunotherapy efficacy. Materials & methods: In this study, hybrid vesicles containing DOX (HV-DOX) were prepared by thin-film hydration with extrusion, and the formulated nanoparticles were characterized physically. Furthermore, in vitro experiments and animal models were used to investigate the efficacy and new mechanisms of chemotherapy combined with immunotherapy. Results: DOX improved tumor immunogenicity by alkalinizing lysosomes, inhibiting tumor cell autophagy and inducing ICD. HVs could activate dendritic cell maturation, synergistically enhancing chemotherapeutic immunity. Conclusion: The mechanism of DOX-induced ICD was explored, and antitumor immunity was synergistically activated by HV-DOX to improve chemotherapeutic drug loading and provide relevant antigenic information. [ABSTRACT FROM AUTHOR]

Diabetes, particularly type 2 diabetes (T2D), is the main component of metabolic syndrome. It is highly prevalent and has drastically increased with sedentary lifestyles, notably behaviors linked to ease of access and minimal physical activity. Central to this condition is insulin, which plays a pivotal role in regulating glucose levels in the body by aiding glucose uptake and storage in cells, and what happens to diabetes? In diabetes, there is a disruption and malfunction in insulin regulation. Despite numerous efforts, effectively addressing diabetes remains a challenge. This article explores the potential of photoactivatable drugs in diabetes treatment, with a focus on light-activated insulin. We discuss its advantages and significant implications. This article is expected to enrich the existing literature substantially, offering a comprehensive analysis of potential strategies for improving diabetes management. With its minimal physical intrusion, light-activated insulin promises to improve patient comfort and treatment adherence. It offers precise regulation and localized impact, potentially mitigating the risks associated with conventional diabetes treatments. Additionally, light-activated insulin is capable of explicitly targeting RNA and epigenetic factors. This innovative approach may pave the way for more personalized and effective diabetes treatments, addressing not only the symptoms but also the underlying biological causes of the disease. The advancement of light-activated insulin could revolutionize diabetes management. This study represents a pioneering introduction to this novel modality for diabetes management. [ABSTRACT FROM AUTHOR]

Background and objective: Osteosarcoma is a common primary malignant tumor of bone, and doxorubicin is one of the most widely used therapeutic drugs. While the problem of doxorubicin resistance limits the long-term treatment benefits in osteosarcoma patients. The role of miRNAs and their target genes in osteosarcoma have become increasingly prominent. Currently, there is no report on miR-506-3p reversing doxorubicin resistance by targeting STAT3 in osteosarcoma. The purpose of this study was to investigate the molecular mechanism that overexpression of miR-506-3p reverses doxorubicin resistance in drug-resistant osteosarcoma cells. Methods: Doxorubicin-resistant osteosarcoma cells (U-2OS/Dox) were constructed by intermittent stepwise increasing stoichiometry. The target genes of miR-506-3p were predicted by bioinformatics approach and the targeting relationship between miR-506-3p and STAT3 was detected using dual luciferase reporter assay. U-2OS/Dox cells were treated with miR-506-3p overexpression and STAT3 silencing respectively. Then Western blot and RTqPCR were used to detect the protein and mRNA expression levels of JAK2/ STAT3 signaling pathway, drug-resistant and apoptotic associated molecules. The migration and invasion were assessed by cell scratch assay and transwell assay. The cell proliferative viability and apoptosis were investigated by CCK8 assay and flow cytometry assay. Results: U-2OS/Dox cells were successfully constructed with a 14.4-fold resistance. MiR-506-3p is directly bound to the 3′-UTR of STAT3 mRNA. Compared with U-2OS cells, the mRNA expression of miR-506-3p was reduced in U-2OS/Dox cells. Overexpression of miR-506-3p decreased the mRNA expression levels of JAK2, STAT3, MDR1/ABCB1, MRP1/ABCC1, Survivin and Bcl-2, and decreased the protein expression levels of p-JAK2, STAT3, MDR1/ ABCB1, MRP1/ABCC1, Survivin and Bcl-2, and conversely increased Bax expression. It also inhibited the proliferation, migration and invasion of U- 2OS/Dox cells and promoted cells apoptosis. The results of STAT3 silencing experiments in the above indicators were consistent with that of miR-506-3p overexpression. Conclusion: Overexpression of miR-506-3p could inhibit the JAK2/ STAT3 pathway and the malignant biological behaviors, then further reverse doxorubicin resistance in drug-resistant osteosarcoma cells. The study reported a new molecular mechanism for reversing the resistance of osteosarcoma to doxorubicin chemotherapy and provided theoretical support for solving the clinical problems of doxorubicin resistance in osteosarcoma. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OSA) presents a clinical challenge and has a low 5‐year survival rate. Currently, the lack of advanced stratification models makes personalized therapy difficult. This study aims to identify novel biomarkers to stratify high‐risk OSA patients and guide treatment. Methods: We combined 10 machine‐learning algorithms into 101 combinations, from which the optimal model was established for predicting overall survival based on transcriptomic profiles for 254 samples. Alterations in transcriptomic, genomic and epigenomic landscapes were assessed to elucidate mechanisms driving poor prognosis. Single‐cell RNA sequencing (scRNA‐seq) unveiled genes overexpressed in OSA cells as potential therapeutic targets, one of which was validated via tissue staining, knockdown and pharmacological inhibition. We characterized changes in multiple phenotypes, including proliferation, colony formation, migration, invasion, apoptosis, chemosensitivity and in vivo tumourigenicity. RNA‐seq and Western blotting elucidated the impact of squalene epoxidase (SQLE) suppression on signalling pathways. Results: The artificial intelligence‐derived prognostic index (AIDPI), generated by our model, was an independent prognostic biomarker, outperforming clinicopathological factors and previously published signatures. Incorporating the AIDPI with clinical factors into a nomogram improved predictive accuracy. For user convenience, both the model and nomogram are accessible online. Patients in the high‐AIDPI group exhibited chemoresistance, coupled with overexpression of MYC and SQLE, increased mTORC1 signalling, disrupted PI3K–Akt signalling, and diminished immune infiltration. ScRNA‐seq revealed high expression of MYC and SQLE in OSA cells. Elevated SQLE expression correlated with chemoresistance and worse outcomes in OSA patients. Therapeutically, silencing SQLE suppressed OSA malignancy and enhanced chemosensitivity, mediated by cholesterol depletion and suppression of the FAK/PI3K/Akt/mTOR pathway. Furthermore, the SQLE‐specific inhibitor FR194738 demonstrated anti‐OSA effects in vivo and exhibited synergistic effects with chemotherapeutic agents. Conclusions: AIDPI is a robust biomarker for identifying the high‐risk subset of OSA patients. The SQLE protein emerges as a metabolic vulnerability in these patients, providing a target with translational potential. [ABSTRACT FROM AUTHOR]

Space infrared dim target recognition is an important applications of space situational awareness (SSA). Due to the weak observability and lack of geometric texture of the target, it may be unreliable to rely only on grayscale features for recognition. In this paper, an intelligent information decision-level fusion method for target recognition which takes full advantage of the ensemble classifier and Dempster–Shafer (DS) theory is proposed. To deal with the problem that DS produces counterintuitive results when evidence conflicts, a contraction–expansion function is introduced to modify the body of evidence to mitigate conflicts between pieces of evidence. In this method, preprocessing and feature extraction are first performed on the multi-frame dual-band infrared images to obtain the features of the target, which include long-wave radiant intensity, medium–long-wave radiant intensity, temperature, emissivity–area product, micromotion period, and velocity. Then, the radiation intensities are fed to the random convolutional kernel transform (ROCKET) architecture for recognition. For the micromotion period feature, a support vector machine (SVM) classifier is used, and the remaining categories of the features are input into the long short-term memory network (LSTM) for recognition, respectively. The posterior probabilities corresponding to each category, which are the result outputs of each classifier, are constructed using the basic probability assignment (BPA) function of the DS. Finally, the discrimination of the space target category is implemented according to improved DS fusion rules and decision rules. Continuous multi-frame infrared images of six flight scenes are used to evaluate the effectiveness of the proposed method. The experimental results indicate that the recognition accuracy of the proposed method in this paper can reach 93% under the strong noise level (signal-to-noise ratio is 5). Its performance outperforms single-feature recognition and other benchmark algorithms based on DS theory, which demonstrates that the proposed method can effectively enhance the recognition accuracy of space infrared dim targets. [ABSTRACT FROM AUTHOR]

Immunosuppressive elements within the tumor microenvironment are the primary drivers of tumorigenesis and malignant advancement. The presence, as well as the crosstalk between myeloid-derived suppressor cells (MDSCs), osteosarcoma-associated macrophages (OS-Ms), regulatory T cells (Tregs), and endothelial cells (ECs) with osteosarcoma cells cause the poor prognosis of OS. In addition, the consequent immunosuppressive factors favor the loss of treatment potential. Nanoparticles offer a means to dynamically and locally manipulate immuno-nanoparticles, which present a promising strategy for transforming OS-TME. Additionally, chimeric antigen receptor (CAR) technology is effective in combating OS. This review summarizes the essential mechanisms of immunosuppressive cells in the OS-TME and the current immune-associated strategies. The last part highlights the limitations of existing therapies and offers insights into future research directions. [ABSTRACT FROM AUTHOR]

Background: DNA repair plays a major role in maintaining genomic stability, thus limiting the transformation of normal cells into cancer cells. However, in cancer patients treated with DNA-targeting drugs, DNA repair can decrease efficacy by removing the damage generated by such molecules that is needed to induce pharmacological activity. Inhibiting DNA repair thus represents an interesting approach to potentiating the activity of chemotherapy in this setting., Objectives: Here, we continue the characterization of an inhibitor of the interaction between Excision Repair Cross-Complementing Rrodent repair deficiency complementation group 1 (ERCC1) and Xeroderma Pigmentousum group F (XPF) (B9), two key proteins of nucleotide excision repair., Methods: We used various cell lines and co-incubation studies for the determination of cell survival and DNA repair capacities., Results: We show that it is synergistic with other platinum derivatives than previously described, and that synergy is lacking in cells not expressing ERCC1 or XPF. Finally, a series of experiments show that potentiation is observed only in cells expressing wild-type p53., Conclusion: Our results confirm the mechanism of action of our ERCC1-XPF inhibitor and give important additional data on this approach to enhance the activity of already existing cancer drugs., (© 2025 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Doxorubicin (DOX) is a cytotoxic drug used for the treatment of breast cancer (BC). However, the rapid emergence of resistance toward doxorubicin threatens its clinical application, thus the need for combination therapy. Here, we interrogate the role of Emodin, a chemical compound with tumor inhibitory properties, in the resistance of BC to Doxorubicin. We first evaluated the efficacy of Emodin in the treatment of BC cells. We then used &#+947;H2A to examine doxorubicin-induced DNA damage in BC cells, with or without Emodin. Data from CCK-8, flow cytometry, and tumor xenograft assays showed that Emodin suppresses the growth of BC cells. Further, we demonstrated that Emodin enhances γH2A levels in BC cells. Moreover, bioinformatics analysis and western blot assays indicated that Emodin down-regulates the AKT1 expression, and marginally decreases the levels of DNA damage proteins (XRCC1, PARP1, and RAD51) as well as increased p53 expression in BC cells. Taken together, our data demonstrates that Emodin affects cell proliferation, and DNA damage pathways in BC cells, thus increasing the sensitivity of BC cells to doxorubicin. Besides, we confirmed that Emodin confers sensitization of BC to doxorubicin through AKT1-mediated DNA. [ABSTRACT FROM AUTHOR]

In order to achieve miniaturization, short-range radar (SRR) generally adopts millimeter-wave (MMW) radar with a frequency-modulated continuous-wave (FMCW) system, which may make the stop–go–stop assumption in traditional synthetic aperture radar (SAR) imaging algorithms invalid. In addition, in order to observe a large enough area, SRR often needs a wide radar beam, which may cause serious range–azimuth coupling when using SRR for SAR imaging. The above two problems may make the traditional SAR imaging algorithm invalid in SRR SAR imaging. Taking the SRR SAR imaging application into account, traditional frequency domain SAR imaging algorithms are analyzed and improved in this paper. Firstly, the intra-pulse motion (IPM) caused by the FMCW system and the two-dimensional coupling (TDC) in the case of a wide beam are analyzed. Subsequently, the applicability of the range Doppler algorithm (RDA), the frequency scaling algorithm (FSA) and the range migration algorithm (RMA) for SRR SAR is analyzed. Then, improvement measures are put forward to address the aliasing and folding phenomena caused by the wide-beam problem in the FSA and RMA, respectively. Finally, the effectiveness of the proposed algorithm is verified using simulation data and real measured data collected using an MMW radar fixed on a slide rail. [ABSTRACT FROM AUTHOR]

This paper introduces a computationally inexpensive technique for moving target detection in challenging outdoor environments using millimeter-wave (mmWave) frequency-modulated continuous-wave (FMCW) radars leveraging traditional signal processing methodologies. Conventional learning-based techniques for moving target detection suffer when there are variations in environmental conditions. Hence, the work described here leverages robust digital signal processing (DSP) methods, including wavelet transform, FIR filtering, and peak detection, to efficiently address variations in reflective data. The evaluation of this method is conducted in an outdoor environment, which includes obstructions like woods and trees, producing an accuracy score of 92.0% and precision of 91.5%. Notably, this approach outperforms deep learning methods when it comes to operating in changing environments that project extreme data variations. [ABSTRACT FROM AUTHOR]

Introduction: Methotrexate (MTX) is one of the most important drugs included in the first-line protocols to treat high-grade osteosarcoma (HGOS). Although several polymorphisms have been reported to be associated with drug response or MTX-related toxicity in pharmacogenetic studies, their role in the development of MTX resistance in HGOS is still unclear. Methods: Therefore, in this study, 22 single nucleotide polymorphisms (SNPs) in 4 genes of the folatemetabolism, 7 MTX transporter genes, and 2 SNPs of the tumor protein p53 (TP53) genewere investigated using a custommultimodal-targeted nextgeneration sequencing (mmNGS) approach in 8 MTX-resistant and 12 MTX-sensitive human HGOS cell lines. The panel was validated by TaqMan genotyping assays. Results: High instability of TP53 rs1642785 was observed in all U-2OS/MTX variants. Allele changes of the solute carrier family 19 member 1/replication factor C subunit 1 (SLC19A1, previously known as RFC1) and rs1051266 were identified in all Saos-2/MTX-resistant variants in both DNA-and RNA- derived libraries compared to the parental Saos-2 cell line. Allele changes of methylenetetrahydrofolate reductase (MTHFR) rs1801133 were identified only in the RNA-derived libraries of the two U2OS variants with the highest MTX resistance level. Significantly upregulated gene expression associated with the development of MTX resistance was revealed for dihydrofolate reductase (DHFR) whereas SLC19A1 was downregulated. In addition, a fusion transcript of DHFR (ex4) and MutS Homolog 3 (MSH3) (ex9) was identified in the RNA libraries derived from the two U-2OS variants with the highest MTX resistance level. Conclusion: This innovative mmNGS approach enabled the simultaneous exploration of SNPs at DNA and RNA levels in human HGOS cell lines, providing evidence of the functional involvement of allele changes associated with the development of MTX resistance. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OS) is a form of primary bone malignancy associated with poor prognostic outcomes. Recent work has highlighted vasculogenic mimicry (VM) as a key mechanism that supports aggressive tumor growth. The patterns of VM-associated gene expression in OS and the relationship between these genes and patient outcomes, however, have yet to be defined. Methods: Here, 48 VM-related genes were systematically assessed to examine correlations between the expression of these genes and OS patient prognosis in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohort. Patients were classified into three OS subtypes. Differentially expressed genes for these three OS subtypes were then compared with hub genes detected in a weighted gene co-expression network analysis, leading to the identification of 163 overlapping genes that were subject to further biological activity analyses. A three-gene signature (CGREF1, CORT, and GALNT14) was ultimately constructed through a least absolute shrinkage and selection operator Cox regression analysis, and this signature was used to separate patients into low- and high-risk groups. The K–M survival analysis, receiver operating characteristic analysis, and decision curve analysis were adopted to evaluate the prognostic prediction performance of the signature. Furthermore, the expression patterns of three genes derived from the prognostic model were validated by quantitative real-time polymerase chain reaction (RT-qPCR). Results: VM-associated gene expression patterns were successfully established, and three VM subtypes of OS that were associated with patient prognosis and copy number variants were defined. The developed three-gene signature was constructed, which served as independent prognostic markers and prediction factors for the clinicopathological features of OS. Finally, lastly, the signature may also have a guiding effect on the sensitivity of different chemotherapeutic drugs. Conclusion: Overall, these analyses facilitated the development of a prognostic VM-associated gene signature capable of predicting OS patient outcomes. This signature may be of value for both studies of the mechanistic basis for VM and clinical decision-making in the context of OS patient management. [ABSTRACT FROM AUTHOR]

3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has broad-spectrum antitumor activity. However, its role in osteosarcoma (OS) remains unclear. Therefore, this study explored the effects of 3-AP on OS in vitro and in vivo using three human OS cell lines (MG-63, U2-OS, and 143B) and a nude mice model generated by transplanting 143B cells. The cells and mice were treated with DMSO (control) or gradient concentrations of 3-AP. Then, various assays (e.g., cell counting kit-8, flow cytometry, immunohistochemistry, and western blotting) were performed to assess cell viability and apoptosis levels, as well as γH2A.X (DNA damage correlation), ribonucleotide reductase catalytic subunit M1 and M2 (RRM1 and RRM2, respectively) protein levels (iron-dependent correlation). 3-AP time- and dose-dependably suppressed growth and induced apoptosis in all three OS cell lines, and ferric ammonium citrate (FAC) blocked these effects. Moreover, 3-AP decreased RRM2 and total ribonucleotide reductase (RRM1 plus RRM2) protein expression but significantly increased γH2A.X expression; treatment did not affect RRM1 expression. Again, FAC treatment attenuated these effects. In vivo, the number of apoptotic cells in the tumor slices increased in the 3-AP-treated mice compared to the control mice. 3-AP treatment also decreased Ki-67 and p21 expression, suggesting inhibited OS growth. Furthermore, the expression of RRM1, RRM2, and transferrin receptor protein 1 (i.e., Tfr1) indicated that 3-AP inhibited OS growth via an iron-dependent pathway. In conclusion, 3-AP exhibits anticancer activity in OS by decreasing the activity of iron-dependent pathways, which could be a promising therapeutic strategy for OS. [ABSTRACT FROM AUTHOR]

Frequency modulated continuous wave (FMCW) radar is increasingly used for various detection and classification applications in different fields, such as autonomous vehicles and mining fields. Our objective is to increase the classification accuracy of objects detected using millimeter-wave radar. We have developed an approach based on millimeter-wave radar. The proposed solution combines the use of an FMCW radar, a YOLOv7 model, and the Pix2Pix architecture. The latter architecture was used to reduce noise in the heatmaps. We create a dataset of 4125 heatmaps annotated with five different object classes. To evaluate the proposed approach, 14 different models were trained using the annotated heatmap dataset. In the initial experiment, we compared the models using metrics such as mean average precision (mAP), precision, and recall. The results showed that the proposed model of YOLOv7 (YOLOv7-PM) was the most efficient in terms of mAP_0.5, which reached 90.1%, and achieved a mAP_0.5:0.95 of 49.51%. In the second experiment, we compared the models with a cleaned dataset generated using the Pix2Pix architecture. As a result, we observed improved performances, with the Pix2Pix + YOLOv7-PM model achieving the best mAP_0.5, reaching 91.82%, and a mAP_0.5:0.95 of 52.59%. [ABSTRACT FROM AUTHOR]