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Numerical simulations for moderate and intense low oxygen dilution (MILD) combustion with essential solvers and detailed mechanisms involve more complications and computational time. Various advanced combustion modeling techniques have recently been developed to study MILD combustion characteristics. However, every combustion model has specific issues predicting the temperature and emissions of the MILD combustion flames. The diffusive nature of the MILD flame is considered, and individual Lewis numbers are investigated on a nonpremixed flame. The current study analyzes the methane/hydrogen flame propagation with different Lewis number combinations in a hot co-flow environment. Individual Lewis numbers for methane and hydrogen are investigated from stochiometric to ultra-rich mixtures in non-premixed flames. Several numerical simulations are performed in the OpenFOAM9 environment using a modified EDC model with tuned turbulence and combustion model constants. The numerical simulation results with hydrogen and methane Lewis numbers of 0.4 and 0.9, respectively, show promising agreement with the experimental findings of Dally1, et al. Various combustion parameters are studied with different CH4 and H2 Lewis number combinations. In addition, the unity Lewis number case is simulated and compared to the situations that are taken into consideration. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer, one of the most often diagnosed malignancies worldwide, continues to take countless women's lives. Its treatment usually involves targeting the human estrogen receptor alpha (ERα). Current research explores the potential of natural compounds to regulate ERα activity, providing a hopeful direction for breast cancer therapy. Our study utilized a comprehensive approach to identify promising natural compounds for breast cancer treatment, including quantum descriptors, molecular docking, molecular dynamics simulations, and ADMET/pharmacokinetics analysis. Results Six natural compounds derived from podophyllum medicinal plants, namely 4-demethylpodophyllotoxin (NP1), α-peltatin (NP2), podophyllotoxin (NP3), deoxypodophyllotoxin (NP4), podophyllotoxone (NP5), and β-peltatin (NP6), were investigated as potential selective estrogen receptor α (ERα) inhibiting agents for breast cancer. These compounds demonstrated the strongest binding affinity to the target enzyme, with binding energies of − 8.9 and − 8.1 kcal/mol, respectively. Further assessments of drug-likeness and ADME properties were conducted for these compounds, along with quantum calculations (HOMO–LUMO) to evaluate their reactivity. Additionally, molecular dynamics studies were performed to assess the stability of the NP1 and NP2 protein–ligand complexes. Conclusions We analyzed six natural compounds comprehensively, evaluating their ADME properties, molecular docking interactions, quantum descriptors, and dynamic simulations. Our findings demonstrate that these natural compounds are promising possibilities for treating breast cancer. Additionally, they may provide a basis for developing future compounds targeting estrogen receptor α (ERα) activity. Graphical abstract

A cost-effective and efficient solid Br0nsted acid catalyst was synthesized by loading methanesulfonic acid (MSA) on silica and was used for the acid-catalyzed Pechmann reaction to test the catalytic activity and its reusability. Derivatives of 4-methylcoumarin were synthesized in good yields within short reaction times in the presence of environmentally friendly higher n-alkanes as solvents. The regeneration study of the spent catalyst showed satisfactory results. Key words: silica supported solid acids, methanesulfonic acid, Br0nsted acidity, Pechmann reaction, derivatives of 4-methylcoumarin. On a synthetise un catalyseur acide de Br0nsted efficace et rentable d'un point de vue cout en recouvrant de la silice avec de l'acide methanesulfonique (AMS) et on l'a utilise catalyseur acide pour la reaction de Pechmann dans le but d'evaluer son activite catalytique et la possibilite de le reutiliser. On a synthetise des derives de la 4-methylcoumarine avec de bons rendements, avec des temps de reaction relativement courts, dans des solvants a base d'alcanes superieurs ecologiques. L'etude de regeneration du catalyseur utilise a donne des resultats satisfaisants. Mots-cles : acides solides supportes par de la silice, acide methanesulfonique, acidite de Bronsted, reaction de Pechman, derives de la 4-methylcoumarine., Introduction Methanesulfonic acid (C[H.sub.3]S[O.sub.3]H; MSA) is a strong Br0nsted acid ([pK.sub.a] = -1.9) and has been reported as a potential acid catalyst for various acid-catalyzed reactions. (1-3) MSA is very [...]

Despite much research, considerable data suggest that influenza virus remains a serious health problem because i) the effectiveness of current vaccines ranges only from 19% to 60%, ii) available therapies remain ineffective in advanced stages of disease, iii) death rates vary between 25,000 and 72,000/year in the United States, and iv) avian influenza strains are now being transmitted to dairy cattle that in turn are infecting humans. To address these concerns, we have developed zanDR, a bispecific small molecule that binds and inhibits viral neuraminidase expressed on both free virus and virus-infected cells and recruits naturally occurring anti-rhamnose and anti-dinitrophenyl (DNP) antibodies with rhamnose and DNP haptens. Because the neuraminidase inhibition replicates the chemotherapeutic mechanism of zanamivir and oseltamivir, while rhamnose and DNP recruit endogenous antibodies much like an anti-influenza vaccine, zanDR reproduces most of the functions of current methods of protection against influenza virus infections. Importantly, studies on cells in culture demonstrate that both of the above protective mechanisms remain highly functional in the zanDR conjugate, while studies in lethally infected mice with advanced-stage disease establish that a single intranasal dose of zanDR not only yields 100% protection but also reduces lung viral loads faster and ~1,000× more thoroughly than current antiviral therapies. Since zanDR also lowers secretion of proinflammatory cytokines and protects against virus-induced damage to the lungs better than current therapies, we suggest that combining an immunotherapy with a chemotherapy in single pharmacological agent constitutes a promising approach for treating the more challenging forms of influenza., Competing Interests: Competing interests statement:I.S. and M.S. receive consulting fees from Eradivir Inc., A.K.K. and C.L.C. are employees at Eradivir Inc., and P.S.L. serves on the board of directors of Eradivir Inc. P.S.L., A.K.K., M.S., I.S., and M.K. are listed as inventors on a relevant patent filing (Patent No. WO2023205669A3)

Purpose: We recently developed an optical instrument to non-invasively detect fluorescently labeled circulating tumor cells (CTCs) in mice called 'Diffuse in vivo Flow Cytometry' (DiFC). OTL38 is a folate receptor (FR) targeted near-infrared (NIR) contrast agent that is FDA approved for use in fluorescence guided surgery of ovarian and lung cancer. In this work, we investigated the use OTL38 for in vivo labeling and detection of FR + CTCs with DiFC., Procedures: We tested OTL38 labeling of FR + cancer cell lines (IGROV-1 and L1210A) as well as FR- MM.1S cells in suspensions of Human Peripheral Blood Mononuclear cells (PBMCs) in vitro. We also tested OTL38 labeling and NIR-DIFC detection of FR + L1210A cells in blood circulation in nude mice in vivo., Results: 62% of IGROV-1 and 83% of L1210A were labeled above non-specific background levels in suspensions of PBMCs in vitro compared to only 2% of FR- MM.1S cells. L1210A cells could be labeled with OTL38 directly in circulation in vivo and externally detected using NIR-DiFC in mice with low false positive detection rates., Conclusions: This work shows the feasibility of labeling CTCs in vivo with OTL38 and detection with DiFC. Although further refinement of the DiFC instrument and signal processing algorithms and testing with other animal models is needed, this work may eventually pave the way for human use of DiFC., (© 2024. The Author(s).)

Because of upregulated expression on cancer-associated fibroblasts, fibroblast activation protein (FAP) has emerged as an attractive biomarker for the imaging and therapy of solid tumors. Although many FAP ligands have already been developed for radiopharmaceutical therapies (RPTs), most suffer from inadequate tumor uptake, insufficient tumor residence times, or off-target accumulation in healthy tissues, suggesting a need for further improvements. Methods: A new FAP-targeted RPT with a novel ligand (FAP8-PEG 3 -IP-DOTA) was designed by combining the desirable features of several previous ligand-targeted RPTs. Uptake and retention of [ 111 In]In or [ 177 Lu]Lu-FAP8-PEG 3 -IP-DOTA were assessed in KB, HT29, MDA-MB-231, and 4T1 murine tumor models by radioimaging or ex vivo biodistribution analyses. Radiotherapeutic potencies and gross toxicities were also investigated by monitoring tumor growth, body weight, and tissue damage in tumor-bearing mice. Results: FAP8-PEG 3 -IP-DOTA exhibited high affinity (half-maximal inhibitory concentration, 1.6 nM) and good selectivity for FAP relative to its closest homologs, prolyl oligopeptidase (half-maximal inhibitory concentration, ∼14.0 nM) and dipeptidyl peptidase-IV (half-maximal inhibitory concentration, ∼860 nM). SPECT/CT scans exhibited high retention in 2 different solid tumor models and minimal uptake in healthy tissues. Quantitative biodistribution analyses revealed tumor-to-healthy-tissue ratios of more than 5 times for all major organs, and live animal studies demonstrated 65%-93% suppression of tumor growth in all 4 models tested, with minimal or no evidence of systemic toxicity. Conclusion: We conclude that [ 177 Lu]Lu-FAP8-PEG 3 -IP-DOTA constitutes a promising and safe RPT candidate for FAPα-targeted radionuclide therapy of solid tumors., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Fibroblast activation protein (FAP) has attracted considerable attention as a possible target for the radiotherapy of solid tumors. Unfortunately, initial efforts to treat solid tumors with FAP-targeted radionuclides have yielded only modest clinical responses, suggesting that further improvements in the molecular design of FAP-targeted radiopharmaceutical therapies (RPT) are warranted. In this study, we report several advances on the previously described FAP6 radioligand that increase tumor retention and accelerate healthy tissue clearance. Seven FAP6 derivatives with different linkers or albumin binders were synthesized, radiolabeled, and investigated for their effects on binding and cellular uptake. The radioligands were then characterized in 4T1 tumor-bearing Balb/c mice using both single-photon emission computed tomography (SPECT) and ex vivo biodistribution analyses to identify the conjugate with the best tumor retention and tumor-to-healthy organ ratios. The results reveal an optimized FAP6 radioligand that exhibits efficacy and safety properties that potentially justify its translation into the clinic.

Orange II (O-II), a water-soluble ionic azo dye, aggregates and eventually forms needle-like crystals at concentrations greater than 0.15 M. However, when equimolar amounts of γ-cyclodextrin (γ-CD) are added to solutions containing O-II at 0.025 M or higher, the solution's appearance rapidly changes presenting a viscous, birefringent liquid, a lyotropic liquid crystalline solution. Birefringence is absent when viewing aqueous solutions of only O-II or γ-CD at concentrations greater than 0.03 M. Using ultraviolet-visible (UV-vis) and fluorescence spectroscopy, coupled with conductivity measurements, we postulate a structure for the basic "building block" of the self-assembly that eventually gives rise to a rodlike superstructure, leading to the formation of a lyotropic liquid crystalline phase., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The present study investigates the applicability of the inlet boundary species Lewis number (combined effect of molecular and flow diffusion) for the nonpremixed moderate and intense low oxygen dilution (MILD) flames. A modified reactive solver named modifiedReactingFoam is developed by including the enthalpy flux in the energy equation and using modified model constants in OpenFOAM. The present solver is tested on the delft-jet-in-hot-coflow burner operating under a moderate and intense low oxygen dilution combustion environment. Along with the flame with Reynolds number 4100, eight other jet-in-hot-coflow flames are simulated to test the capability of the present proposed solver. The main aim of the current work is to investigate the efficacy of the proposed solver in predicting the velocity field, temperatures, and flame lift-off height for the considered flames with a significant reduction in computational time. The predictions with the modified eddy dissipation concept model are improved. However, a significant deviation is still observed in the downstream direction of the burner. The numerical simulations are performed with methane Lewis numbers of 0.9-1.14 by keeping the respective constant Lewis numbers for the inlet boundary species. The modifiedReactingFoam predictions at a methane Lewis number of 1.12 are in very close agreement with the experimental results. The maximum deviation in lift-off heights is within ±3% of the experimental results. The present modified solver outperformed the other combustion models in the literature and reduced the computational time up to 10 times with a combination of DLBFoam compared to the inbuilt solver., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Folate receptors can perform folate transport, cell adhesion, and/or transcription factor functions. The beta isoform of the folate receptor (FRβ) has attracted considerable attention as a biomarker for immunosuppressive macrophages and myeloid-derived suppressor cells, however, its role in immunosuppression remains uncharacterized. We demonstrate here that FRβ cannot bind folate on healthy tissue macrophages, but does bind folate after macrophage incubation in anti-inflammatory cytokines or cancer cell-conditioned media. We further show that FRβ becomes functionally active following macrophage infiltration into solid tumors, and we exploit this tumor-induced activation to target a toll-like receptor 7 agonist specifically to immunosuppressive myeloid cells in solid tumors without altering myeloid cells in healthy tissues. We then use single-cell RNA-seq to characterize the changes in gene expression induced by the targeted repolarization of tumor-associated macrophages and finally show that their repolarization not only changes their own phenotype, but also induces a proinflammatory shift in all other immune cells of the same tumor mass, leading to potent suppression of tumor growth. Because this selective reprogramming of tumor myeloid cells is accompanied by no systemic toxicity, we propose that it should constitute a safe method to reprogram the tumor microenvironment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Huang, Utturkar, Luo, Cresswell, Herr, Zheng, Napoleon, Jiang, Zhang, Liu, Lanman, Srinivasarao, Ratliff and Low.)

Fibroblast activation protein (FAP) has received increasing attention as an oncologic target because of its prominent expression in solid tumors but virtual absence from healthy tissues. Most radioligand therapies (RLTs) targeting FAP, however, suffer from inadequate tumor retention or clearance from healthy tissues. Herein we report a FAP-targeted RLT comprising an FAP6 ligand conjugated to DOTA and an albumin binder (4- p -iodophenylbutyric acid, or IP) for enhanced pharmacokinetics. We evaluated the performance of the resulting FAP6-IP-DOTA conjugate in 4 tumor models, 3 of which express FAP only on cancer-associated fibroblasts, that is, analogously to human tumors. Methods: Single-cell RNA-sequencing data were analyzed from 34 human breast, ovarian, colorectal, and lung cancers to quantify FAP-overexpressing cells. FAP6-DOTA conjugates were synthesized with or without an albumin binder (IP) and investigated for binding to human FAP-expressing cells. Accumulation of 111 In- or 177 Lu-labeled conjugates in KB, HT29, U87MG, and 4T1 murine tumors was also assessed by radioimaging or biodistribution analyses. Radiotherapeutic potency was quantitated by measuring tumor volumes versus time. Results: Approximately 5% of all cells in human tumors overexpressed FAP (cancer-associated fibroblasts comprised ∼77% of this FAP-positive subpopulation, whereas ∼2% were cancer cells). FAP6 conjugates bound to FAP-expressing cells with high affinity (dissociation constant, ∼1 nM). 177 Lu-FAP6-IP-DOTA achieved an 88-fold higher tumor dose than 177 Lu-FAP6-DOTA and improved all tumor-to-healthy-organ ratios. Single doses of 177 Lu-FAP6-IP-DOTA suppressed tumor growth by about 45% in all tested tumor models without causing reproducible toxicities. Conclusion: We conclude that 177 Lu-FAP6-IP-DOTA constitutes a promising candidate for FAP-targeted RLT of solid tumors., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Accurate delineation of gross tumor volumes remains a barrier to radiotherapy dose escalation and boost dosing in the treatment of solid tumors, such as prostate cancer. Magnetic resonance imaging (MRI) of tumor targets has the power to enable focal dose boosting, particularly when combined with technological advances such as MRI-linear accelerator. Fibroblast activation protein (FAP) is overexpressed in stromal components of >90% of epithelial carcinomas. Herein, the authors compare targeted MRI of prostate specific membrane antigen (PSMA) with FAP in the delineation of orthotopic prostate tumors. Control, FAP, and PSMA-targeting iron oxide nanoparticles were prepared with modification of a lymphotropic MRI agent (FerroTrace, Ferronova). Mice with orthotopic LNCaP tumors underwent MRI 24 h after intravenous injection of nanoparticles. FAP and PSMA nanoparticles produced contrast enhancement on MRI when compared to control nanoparticles. FAP-targeted MRI increased the proportion of tumor contrast-enhancing black pixels by 13%, compared to PSMA. Analysis of changes in R2 values between healthy prostates and LNCaP tumors indicated an increase in contrast-enhancing pixels in the tumor border of 15% when targeting FAP, compared to PSMA. This study demonstrates the preclinical feasibility of PSMA and FAP-targeted MRI which can enable targeted image-guided focal therapy of localized prostate cancer., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

Retrieval of circulating tumor cells (CTC) has proven valuable for assessing a patient's cancer burden, evaluating response to therapy, and analyzing which drug might treat a cancer best. Although most isolation methods retrieve CTCs based on size, shape, or capture by tumor-specific antibodies, we explore here the use of small molecule tumor-specific ligands linked to magnetic beads for CTC capture. We have designed folic acid-biotin conjugates with different linkers for the capture of folate receptor (FR) + tumor cells spiked into whole blood, and application of the same technology to isolate FR + CTCs from the peripheral blood of both tumor-bearing mice and non-small cell lung patients. We demonstrate that folic acid linked via a rigid linker to a flexible PEG spacer that is in turn tethered to a magnetic bead enables optimal CTC retrieval, reaching nearly 100% capture when 100 cancer cells are spiked into 1 mL of aqueous buffer and ~ 90% capture when the same quantity of cells is diluted into whole blood. In a live animal model, the same methodology is shown to efficiently retrieve CTCs from tumor-bearing mice, yielding cancer cell counts that are proportional to total tumor burden. More importantly, the same method is shown to collect ~ 29 CTCs/8 mL peripheral blood from patients with non-small cell lung cancer. Since the ligand-presentation strategy optimized here should also prove useful in targeting other nanoparticles to other cells, the methods described below should have general applicability in the design of nanoparticles for cell-specific targeting., (© 2022. The Author(s).)

Although chimeric antigen receptor (CAR) T cells have demonstrated significant promise in suppressing hematopoietic cancers, their applications in treating solid tumors have been limited by onset of CAR T cell exhaustion that accompanies continuous CAR T cell exposure to tumor antigen. To address this limitation, we have exploited the abilities of recently designed universal CARs to bind fluorescein and internalize a fluorescein-TLR7 agonist conjugate by CAR-mediated endocytosis. We demonstrate here that anti-fluorescein CAR-mediated uptake of a fluorescein-TLR7-3 conjugate can reactivate exhausted CAR T cells, leading to dramatic reduction in T cell exhaustion markers (PD-1 + Tim-3 + ) and shrinkage of otherwise resistant tumors without inducing systemic activation of the immune system. We conclude that CAR T cell exhaustion can be reversed by administration of a CAR-targeted TLR7 agonist, thereby enabling the CAR T cells to successfully treat solid tumors without incurring the systemic toxicity that commonly accompanies administration of nontargeted TLR7 agonists., (© 2022 Wiley-VCH GmbH.)

Tumor-targeted fluorescent dyes have been shown to significantly improve a surgeon's ability to locate and resect occult malignant lesions, thereby enhancing a patient's chances of long term survival. Although several tumor-targeted fluorescent dyes have been developed for imaging specific subsets of human cancers, no tumor-targeted dye has been designed that can image all cancer types. Based on observations that fibroblast activation protein (FAP) is upregulated on cancer-associated fibroblasts (CAFs) that infiltrate essentially all solid tumors, we have undertaken to develop a FAP-targeted fluorescent dye that can image CAFs without accumulating in healthy cells or fibroblasts. We report here that FTL-S-S0456, a novel FAP-targeted near infrared dye that binds FAP with high affinity (∼12 nM) and specificity (>5000-fold over PREP and DPP-IV), concentrates in all seven solid tumor types examined, yielding fluorescence images with high tumor to background ratios that persist for several days. We conclude that FTL-S-S0456 constitutes an excellent ligand-targeted near infrared dye that enables intra-operative imaging of most if not all solid tumors.