Synergistic Benefit Research Articles

Protein-functionalized and intrinsically radiolabeled [188Re]ReOx nanoparticles: advancing cancer therapy through concurrent radio-photothermal effects.

Enhancing therapeutic effectiveness is crucial for translating anticancer nanomedicines from laboratory to clinical settings. In this study, we have developed radioactive rhenium oxide nanoparticles encapsulated in human serum albumin ([188Re]ReOx-HSA NPs) for concurrent radiotherapy (RT) and photothermal therapy (PTT), aiming to optimize treatment outcomes. [188Re]ReOx-HSA NPs were synthesized by a controlled reduction of 188ReO4- in HSA medium and extensively characterized. The anticancer effect of [188Re]ReOx-HSA NPs was demonstrated in vitro in murine melanoma (B16F10) cell line. In vivo SPECT/CT imaging, autoradiography and biodistribution studies were performed after intratumoral injection of [188Re]ReOx-HSA NPs in melanoma tumor-bearing C57BL/6 mice. The potential of [188Re]ReOx-HSA NPs for combined RT and PTT treatment was also demonstrated in the aforesaid mice model. [188Re]ReOx-HSA NPs (size 4-6nm) were synthesized with high colloidal and radiochemical stability. Upon laser (808nm) exposure on B16F10 cells incubated with [188Re]ReOx-HSA NPs, only < 20% of cells were alive demonstrating high therapeutic efficacy under in vitro settings. Uniform dose distribution and retention of the radiolabeled NPs in the tumor volume were observed via SPECT/CT imaging and autoradiography studies. Tumor growth in mice model was significantly arrested with ~ 1.85 MBq dose of [188Re]ReOx-HSA NPs and simultaneous laser irradiation, demonstrating synergistic benefit of RT and PTT. These results demonstrate that intrinsically radiolabeled [188Re]ReOx-HSA NPs having unique features such as high photothermal effects and favorable nuclear decay characteristics for combined RT/PTT, hold great promise for clinical translation.

Enhancing cardiac diagnostics: a deep learning ensemble approach for precise ECG image classification

Cardiovascular diseases are a global health challenge that necessitates improvements in diagnostic accuracy and efficiency. This study examines the potential of deep learning (DL) models for the classification of electrocardiogram (ECG) images to assist in the identification of various cardiac conditions. We initiated a two-tiered experimental framework to investigate the effectiveness of several neural network architectures in this medical application. In the first experiment, eight distinct neural network models were selected based on their top-5 accuracy on the ImageNet validation dataset and were fine-tuned using transfer learning techniques. These models were assessed using a cross-validation scheme, focusing on balanced accuracy, precision, recall, and the F1-score to evaluate their classification capabilities across four cardiac conditions: Myocardial Infarction (MI), abnormal heartbeat, historical MI, and normal ECG patterns. The second experiment extended our inquiry into the power of ensemble learning. By testing all possible combinations of the chosen models, we explored 120 ensemble configurations. The resulting analysis identified the best-performing ensemble set, which did not include the least effective model based on F1 score rankings. The most effective ensemble, composed of Inception, MobileNet, and NASNetLarge, achieved an F1 score of 0.9651 and a balanced accuracy of 0.9640, indicating a superior predictive performance. The ROC curve analysis yielded near-perfect Area Under the Curve (AUC) values for all classes, underscoring the ensemble’s proficiency in distinguishing between the specified cardiac conditions. The outcomes of this research highlight the synergistic benefit of ensembles in DL applications for medical imaging and suggest a promising approach for the early detection and diagnosis of cardiac diseases, potentially improving clinical outcomes and patient care.

A potential therapeutic role of resveratrol in mitigating hepatotoxicity induced by paracetamol and alcohol.

Drug-induced hepatotoxicity, particularly from ethanol and acetaminophen (APAP), is a pressing global health challenge. This damage arises from oxidative stress and inflammation, manifesting as elevated liver enzymes and structural liver alterations. Resveratrol and silymarin, recognized for their antioxidant and anti-inflammatory properties, offer potential hepatoprotective benefits. This study investigated the hepatoprotective efficacy of resveratrol and silymarin, alone and in combination, in a rat model of ethanol- and APAP-induced liver injury. Thirty Wistar rats were divided into five groups: control, ethanol-APAP, ethanol-APAP-resveratrol, ethanol-APAP-silymarin, and ethanol-APAP-resveratrol-silymarin. Treatments were administered orally for 10days. Serum ALT and AST levels were assessed, and liver tissues underwent histological evaluation. Ethanol and APAP administration significantly elevated ALT and AST levels, alongside severe liver structural disruptions. Treatment with resveratrol or silymarin alone normalized enzyme levels and improved liver histology. Notably, the combined resveratrol-silymarin treatment exhibited greater reductions in ALT and AST levels and superior restoration of liver architecture compared to either treatment alone, indicating a synergistic hepatoprotective effect. Resveratrol and silymarin effectively counteract ethanol- and APAP-induced hepatotoxicity by mitigating oxidative stress and inflammation. Their combined use demonstrates a synergistic benefit, as evidenced by enhanced biochemical and histological improvements. These findings support the potential therapeutic role of these natural agents in managing drug-induced liver injury.

Epicatechin and β-Glucan from Whole Highland Barley Grain Synergistic Benefit on Attenuating Hyperglycemia via Improving Hepatic Glucose Metabolism in Diabetic C57BL/6J Mice.

Our previous study proved that epicatechin (EC) and β-glucan (BG) from whole-grain highland barley synergistically modulate glucose metabolism in insulin-resistant HepG2 cells. However, the main target and the mechanism underlying the modulation of glucose metabolism in vivo remain largely unknown. In this study, cell transfection assay and microscale thermophoresis analysis revealed that EC and BG could directly bind to the insulin receptor (IR) and mammalian receptor for rapamycin (mTOR), respectively. Molecular dynamic analysis indicated that the key amino acids of binding sites were Asp, Met, Val, Lys, Ser, and Tys. EC supplementation upregulated the IRS-1/PI3K/Akt pathway, while BG upregulated the mTOR/Akt pathway. Notably, supplementation with EC + BG significantly increased Akt and glucose transporter type 4 (GLUT4) protein expressions, while decreasing glycogen synthase kinase 3β (GSK-3β) expression in liver cells as compared to the individual effects of EC and BG, indicating their synergistic effect on improving hepatic glucose uptake and glycogen synthesis. Consistently, supplementation with EC + BG significantly decreased blood glucose levels and improved oral glucose tolerance compared to EC and BG. Therefore, combined supplementation with EC and BG may bind to corresponding receptors, targeting synergistic activation of Akt expression, leading to the improvement of hepatic glucose metabolism and thereby ameliorating hyperglycemia in vivo.

Significant Reduction of Radiation-Induced Death in Mice Treated with PrC-210 and G-CSF after Irradiation.

The search for single or combined radiation countermeasures that mitigate the development of Acute Radiation Syndrome (ARS) after radiation exposure remains a prominent goal of the U.S. government. This study was undertaken to determine whether PrC-210 and G-CSF, when administered 24-48 h postirradiation, would confer an additive or synergistic survival benefit and mitigate ARS in mice that had received an otherwise 96% lethal radiation dose. Our results show that optimum systemic doses of PrC-210 and G-CSF, when administered 24 h or later after a 96% lethal dose of whole-body irradiation, conferred: 1. strong individual survival benefits (PrC-210 44%, P = 0.003), (G-CSF 48%, P = 0.0002), 2. a profound combined 85% survival benefit (P < 0.0001) when administered together, and on day 14 postirradiation, 3. peripheral white blood cell/lymphocyte counts equal to unirradiated controls, 4. dense bone marrow cell density (>65% of unirradiated controls), 5. jejunal villi density that equaled 90% of unirradiated controls, and 6. spleen weights that equaled 93% of unirradiated controls. Our results show that PrC-210 and G-CSF given together 24 h after irradiation confer strong additive efficacy by protecting the immune system, and enabling recovery of the bone marrow, and they work synergistically to enable recovery of peripheral white blood cells in circulating blood.

Homogeneous versus heterogeneous Mn(II) oxidation in peroxymonosulfate assisting chlorination: Synergistic role for enhanced Mn(II) oxidation in water treatment

Removal of Mn(II) is an essential step for addressing water discoloration in water treatment utilities worldwide. However, conventional chlorination suffers from poor oxidation of Mn(II) due to its low homogeneous oxidation kinetics. This study explored the oxidation capability of a new chemical dosing strategy employing peroxymonosulfate (PMS) to assist the chlorination process (PMS@Cl2) for effective Mn(II) oxidation. The study comprehensively explored both oxidation kinetics and underlying mechanisms associated with homogeneous and heterogeneous oxidation within the PMS@Cl2 system. At an [Mn(II)]0 of 1 mg/L, chlorination demonstrated inability in oxidizing Mn(II), with <10 % oxidation even at an elevated [Cl2] of 150 μM (∼10 mg/L). By contrast, PMS completely oxidized 100 % Mn(II) within a 30-minute reaction at a much lower [PMS] of 60 μM (kobs = 0.07 min−1 and t1/2 = 9 min), demonstrating its superior Mn(II) oxidation kinetics (over one order of magnitude faster than conventional chlorine). PMS@Cl2 exhibited an interesting synergistic benefit when combining a lower dose PMS with a higher routine dose Cl2 (loPMS@hiCl2), e.g. [PMS]:[Cl2] at 15:30 or 30:30 μM. Both conditions achieved 100 % Mn(II) oxidation, with even better values of kobs and t1/2 (0.16–0.17 min−1 and ∼4 min) relative to PMS alone at 60 µM. The synergic benefit of PMS@Cl2 was attributed to distinct functions played by PMS and Cl2 in both homogeneous and heterogeneous oxidation processes. Reactive species identification excluded the possible involvement of SO4•−, OH•, or chlorine radicals in the homogeneous oxidation of the PMS@Cl2 system. Instead, the dominant species was O2•− radical generated during the reaction of Mn(II) and PMS. Furthermore, the heterogeneous oxidation emphasized the important role of combining Cl2 dosing, which demonstrated an increased reactivity and electron transfer with the Mn−O−Mn complex, surpassing PMS. Overall, heterogeneous oxidation accelerated the oxidation kinetics of the PMS@Cl2 system by 1.1–2 orders of magnitude relative to the homogeneous oxidation of Cl2 alone. We here demonstrated that PMS@Cl2 could offer a more efficient mean of soluble Mn(II) mitigation, achieved with a relatively low routine dose of oxidant in a short reaction period. The outcomes of this study would address the existing limitations of traditional chlorine oxidation, minimizing the trade-offs associated with high residual chlorine levels after treatments for soluble manganese-containing water.

Study on the establishment of air pollutant and carbon emission inventory and collaborative emission reduction potential of China's coking industry from 2012 to 2022

Coking industry is usually regarded as a high pollution and high energy consumption industry. China is accelerating its efforts to reduce pollution and carbon emissions in the industrial sector, which has received little attention as the world's largest producer of coke. Therefore, in this study, the trend of air pollution and carbon emissions in China's coking industry and the path of coordinated emission reduction were studied. The results indicate that the average annual emissions of PM, SO2, NOx, VOCs, and CO2 in China's coking industry from 2012 to 2022 amount to 205.98, 69.47, 193.45, 599.80 Gg and 191.10 Tg, respectively. The main sources of PM, SO2, NOx, VOCs and CO2 in coking industry were coal preparation (51.5 %), charge and pushing (39.5 %), coke oven gas (99.8 %), byproduct recovery (47.0 %) and fuel combustion (87.5 %). The emissions from coking plants in central and southern Shanxi, eastern and southern Hebei, and central Shandong are the most concentrated. Ultra-low emission transformation and deep treatment of VOCs have greatly reduced pollutant emissions in key areas of air pollutant control, but the actual emission reduction effect of these measures has been weakened by the additional emissions caused by the increase of coke production in other non-key areas. The research on synergetic emission reduction path shows that there is a great synergistic benefit between air pollutants and CO2 emission reduction in coking industry. It is estimated that the APeq (air pollutants and carbon equivalent) of China's coking industry in 2025, 2028 and 2030 will decrease by 38.2 %, 63.5 % and 70.8 % respectively compared with 2022. With the continuous promotion of pollution reduction and carbon reduction measures, the emission reduction potential of China's coking industry will gradually shift from key areas to non-key areas.

The Synergistic Benefit of Combination Strategies Targeting Tumor Cell Polyamine Homeostasis.

Mammalian polyamines, including putrescine, spermidine, and spermine, are positively charged amines that are essential for all living cells including neoplastic cells. An increasing understanding of polyamine metabolism, its molecular functions, and its role in cancer has led to the interest in targeting polyamine metabolism as an anticancer strategy, as the metabolism of polyamines is frequently dysregulated in neoplastic disease. In addition, due to compensatory mechanisms, combination therapies are clinically more promising, as agents can work synergistically to achieve an effect beyond that of each strategy as a single agent. In this article, the nature of polyamines, their association with carcinogenesis, and the potential use of targeting polyamine metabolism in treating and preventing cancer as well as combination therapies are described. The goal is to review the latest strategies for targeting polyamine metabolism, highlighting new avenues for exploiting aberrant polyamine homeostasis for anticancer therapy and the mechanisms behind them.

The effects of chlorhexidine, povidone-iodine and vancomycin on growth and biofilms of pathogens that cause prosthetic joint infections: an in-vitro model

Chlorhexidine gluconate (CHG) and povidone-iodine (PI) are commonly used to prevent prosthetic joint infection (PJI) during total joint replacement; however, their effective concentrations and impact on biofilms are not well defined. To determine: (1) the in-vitro minimum inhibitory concentration of CHG and PI against model PJI-causing organisms and clinical isolates; (2) their impact on biofilm formation; (3) whether there is a synergistic benefit to combining the two solutions; and (4) whether adding the antibiotic vancomycin impacts antiseptic activity. We measured in-vitro growth and biofilm formation of Staphylococcus epidermidis, meticillin-sensitive and meticillin-resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans, as well as recent clinical isolates, in the presence of increasing concentrations of CHG and/or PI.Checkerboard assays were used to measure potential synergy of the solutions together and with vancomycin. CHG and PI inhibited growth and biofilm formation of all model organisms tested at concentrations of 0.0004% and 0.33% or lower, respectively; highly dilute concentrations paradoxically increased biofilm formation. The solutions did notsynergize with one another and acted independently of vancomycin. CHG and PI are effective at lower concentrations than typically used, establishing baselines to support further clinical trials aimed at optimizing wound disinfection. There is no synergistic advantage to using both in combination. Vancomycin is effective at inhibiting the growth of S.epidermidis and S.aureus; however, it stimulates P.aeruginosa biofilm production, suggesting in the rare case of P.aeruginosa PJI, it could exacerbate infection.

Combination of pirtobrutinib and lentiviral transduced bispecific anti-CD20/CD19 (LV20.19) CAR T-cell therapy to improve outcomes in patients with relapsed/refractory lymphoma.

7043 Background: Combination trials of BTK inhibitors (BTKi) with CAR-T have suggested potential synergistic benefit by improving CAR-T immunophenotype and clinical outcomes but are limited by increased toxicity. We report immunophenotype, cytokine profile, and patient outcomes with the new non-covalent BTKi, pirtobrutinib (pirto) when given prior to LV20.19 CAR-T and compare the final CAR product to pts who did not receive pirtobrutinib prior to CAR. Methods: Pts received LV20.19 CAR-T as part of a phase 1/2 trial (NCT04186520). Only pts who received pirto £4 weeks prior to apheresis were included. To determine the impact of pirto on LV20.19 CAR-T, we calculated both polyfunctionality (PFA) and polyfunctional strength index (PSI) for each product using the Isoplexis. Descriptive statistics, t-tests and Kaplan-Meier method were used as appropriate. Results: 11 pts received pirto prior to LV20.19 CAR-T (Table). Median age was 65 (50-80) yrs and median prior lines of therapy were 4 (2-8). There were 4 MCL pts, 5 Richter’s (RT)/CLL, 1 MZL and 1 DLBCL. Median duration of pirto was 4 (1-20) mo. Pts were on pirto for a median of 12 (1-22) days prior to apheresis. All except 1 pts received target CAR-T dose. The day 28 ORR was 82% (CR=7, PR=2). After a median follow up of 13 mo, 3 pts died (PD, Covid, Guillain Barre). The median PFS and OS were both 30.8 mo while the 1-year PFS and OS rates were 9 and 15 mo respectively. 9 pts had CRS and 2 had ICANS, all grades 1-2, while 4 had IEC-HS. One pt had afib recurrence and 1 pt had CMV viremia within 30 days of CAR-T. Among the pts with immunophenotypic data (n=10), there were no differences in naïve or more differentiated T-cell percentages in apheresis and final CAR-T products when compared to pts who did not receive pirto before LV20.19 CAR-T (n=57). Although not statistically significant, both PFA (CD4=61.8 vs 59, CD8= 49.8 vs 46.9) and PSI (CD4= 1752 vs 1608, CD8=1299 vs 1079) were higher with pirto pre-treated pts, suggesting a potential trend towards improved CAR-T functionality. Conclusions: These data represent the largest experience of pirto prior to CAR-T apheresis and demonstrate that pirto can be safely used as a bridge to LV20.19 CAR-T without negatively impacting their immunophenotype and potentially improving functionality. These data support our planned phase 1 clinical trial to assess the safety of pirto as bridging and maintenance therapy with LV20.19 CAR-T (NCT05990465). [Table: see text]

Abstract B027: The MAT2A inhibitor IDE397: a novel combination backbone for urothelial cancer subjects with MTAP deficiency

Abstract Methylthioadenosine phosphorylase (MTAP) loss, due to focal homozygous deletions in chromosome 9 (9p21.3), occurs in over 25% of urothelial carcinoma and is an adverse prognostic factor for overall survival. Furthermore, MTAP-deleted tumors are associated with a “cold” tumor immune microenvironment and are resistant to immune checkpoint inhibitor therapy. Loss of MTAP confers a dependency on methionine adenosyltransferase 2A (MAT2A), which catalyzes the production of the primary methyl donor for all cellular methyltransferase reactions, S-adenosyl methionine (SAM). IDE397, a potent small molecule inhibitor of MAT2A, was developed to selectively exploit this synthetic lethal vulnerability in MTAP −/− tumors. The accumulation of the metabolite MTA in MTAP −/− tumors combined with a reduction of SAM by MAT2A inhibition results in selective inhibition of PRMT5, a methyltransferase that governs spliceosome fidelity. This triggers pre-mRNA splicing defects that may induce RNA polymerase stalling and can cause R-loop accumulation. Furthermore, due to essential roles in 1-carbon metabolism, MAT2A inhibition together with MTAP loss leads to depletion of metabolites required for both de novo and salvage nucleotide biosynthesis, thus preventing effective management of DNA replication and DNA damage repair. Notably, R-loops must be resolved by topoisomerase activity (TOP1) to prevent replication conflict and mitotic catastrophe. These combinatorial mechanistic relationships underpin a hypothesis that dual inhibition of MAT2A and TOP1 will fully capitalize on the synthetic lethal vulnerabilities associated with MTAP loss in urothelial cancers (replication stress, genomic instability). Consistent with this, IDE397 in combination with TOP1 inhibitors demonstrated synergistic combination benefit in MTAP −/− bladder cancer cell lines in vitro and in cell-line derived xenograft (CDX) models in vivo. IDE397 exposure was associated with heavily disordered methionine metabolism and accumulation of DNA damage response intermediates. In the ongoing Phase 1 dose escalation/expansion study of IDE397 in MTAP −/− solid tumors (NCT04794699), measurable tumor shrinkage has been observed in urothelial cancers (including a CR per RECIST 1.1) along with molecular responses on serial ctDNA measurements. Supported by our preclinical data, and the clinical observation that MTAP −/− urothelial cancers may be more sensitive to sacituzumab govitecan (SG); a TROP-2-targeting TOP1 ADC (UNITE study; JCO.2023.41.16_suppl.4572), a combination of SG+IDE397 could represent a novel early-line therapy for these patients with high unmet need. We plan to evaluate the combination of SG+IDE397 in MTAP-/- urothelial cancers in the next stage of the ongoing IDE397 trial (NCT04794699). Citation Format: Claire L. Neilan, Marcus M. Fischer, Damien Garbett, Arjun A. Rao, Mili Mandal, Michael A. White, Jasgit C. Sachdev. The MAT2A inhibitor IDE397: a novel combination backbone for urothelial cancer subjects with MTAP deficiency [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B027.

Synergistic Effect of Transmyocardial Revascularization and Platelet-Rich Plasma on Improving Cardiac Function After Coronary Artery Bypass Grafting.

Background Coronary artery disease (CAD) is a global health burden, contributing to mortality and morbidity. A proportion of patients with CAD suffer from diffuse CAD, where conventional revascularization techniques such as percutaneous coronary intervention and coronary artery bypass grafting (CABG) may be insufficient to adequately restore myocardial perfusion. Transmyocardial revascularization (TMR) uses a laser to create microscopic channels in the myocardium, inducing inflammation, angiogenesis, and neovascularization to improve perfusion to ischemic regions. Platelet-rich plasma (PRP) is an autologous concentrate of platelets that contains a myriad of growth factors and bioactive proteins, which have been shown to promote tissue regeneration and wound healing. The combination of TMR and PRP therapies has been proposed to synergistically enhance myocardial revascularization and functional recovery in patients with advanced CAD undergoing surgical revascularization. Methods This study evaluated the efficacy of combining TMR and PRP with CABG in improving cardiac function in diffuse CAD patients. Fifty-two patients were randomized to CABG alone (n = 16), CABG+TMR (n = 17), CABG+PRP (n = 10), and CABG+TMR+PRP (n = 9). TMR was performed using a holmium:YAG laser to create 10 channels in the inferolateral left ventricular wall. PRP was prepared from autologous whole blood and injected into the myocardium adjacent to the TMR channels. Cardiac function was assessed using speckle-tracking echocardiography preoperatively, postoperatively, and at one-year follow-up. Adverse events, including post-operative atrial fibrillation, acute kidney injury, and readmissions, were also recorded. Statistical analyses were performed to compare outcomes between the treatment groups. Results The CABG+TMR+PRP group showed significantly improved global longitudinal strain (GLS) at one year compared to CABG alone (mean GLS -15.96 vs -12.09, p = 0.02). Post-operative left ventricular ejection fraction trended higher in the TMR+PRP group (57.78%) vs other groups, but not significantly. Post-operative atrial fibrillation was higher in the TMR+PRP group (67% vs 25%, p = 0.04), potentially reflecting increased inflammation. No significant differences were observed in other adverse events. Conclusions The results of this study suggest a synergistic benefit of combining TMR and PRP therapies as an adjunct to CABG in patients with diffuse CAD. The significant improvement in GLS at one year in the TMR+PRP group compared to CABG alone indicates enhanced myocardial remodeling and functional recovery, which may translate to improved long-term outcomes. The higher incidence of postoperative atrial fibrillation in the TMR+PRP group warrants further investigation but may reflect the heightened inflammatory response necessary for angiogenesis and tissue regeneration. Prospective, randomized controlled trials with larger sample sizes and longer follow-up periods are needed to validate these findings and optimize treatment protocols. Nonetheless, concomitant TMR+PRP therapy represents a promising approach to augmenting myocardial revascularization and recovery in patients with advanced CAD undergoing surgical revascularization.

Abstract LB221: Novel molecular targeted tumor targeted oncolytic peptide for the treatment of therapy resistant progressive neuroblastoma

Abstract Cancer treatments, particularly for solid tumors like neuroblastoma, often entail severe side effects, resistance, and the potential for secondary malignancies. To address these challenges, we explored an innovative approach employing tumor-targeting peptides. Recently, we unveiled the tumor evolution regulatory role of retinal-degeneration protein-3 (RD3) in therapy defying progressive tumors. Here in we investigated the therapeutic potential of RD3 peptides. Utilizing neuroblastoma, the most common cancer at infancy, as the tumor model, we investigated the delivery and therapeutic potential RD3 peptide. Five peptides representing unique regions, each with a C-terminal TAT tag for fluorescence and an N-terminal amide cap were developed. Peptide homing capabilities (Cell Tracking aasay) and relative potential in modifying metastatic state including invasion (Matrigel invasion assay), migration (scratch-wound assay), clonal expansion (LDTA) and tumorosphere formation (LDTA) was investigated utilizing patient derived clinical therapy defied progressive NB cells NB-EBc1 from adrenal mass and SK-N-FI from bone marrow. Whole genome RNA sequencing was performed using novogene (Illumina) platform. All peptides screened displayed tumor cell internalization and inflicted cell death at varying degrees. Among the five peptides investigated, two peptides (RD3 Pep-1 and RD3 Pep-3) profoundly inhibited cell proliferation, migration, invasion, and tumorosphere formation. A novel molecular targeted oncolytic peptide, validated through RNA sequencing, demonstrates promising efficacy for treating therapy-resistant progressive neuroblastoma. These outcomes uniquely highlight the therapeutic potential of RD3 peptides, offering a novel therapeutic candidate to counter therapy defying progressive disease. Further, the results defined the synergistic benefit RD3 peptide deliver with the current clinical maintenance therapy (GD2 immunotherapy for neuroblastoma). Together, these results identified a molecular targeted novel oncolytic peptide that could complement current standards of maintenance therapy for therapy defying progressive disease. Funding: This work was partially or in full, funded by Oklahoma Center for the Advancement of Science and Technology, OCAST-HR19-04; National Institutes of Health, NIH-P20GM103639 and; NIH-NCI- Cancer Center Support Grant P30CA225520 and Department of Defense DoD-CA210339. Citation Format: Dinesh Babu Somasundaram, Poorvi Subramanian, Sreenidhi Mohanvelu, Sheeja Aravindan, Natarajan Aravindan. Novel molecular targeted tumor targeted oncolytic peptide for the treatment of therapy resistant progressive neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB221.

Natural Phenolic‐Metal Framework Strengthened Mesona Chinensis Polysaccharides Microgels for Improved Viability of Probiotics to Alleviate the Liver Injury and Gut Microbiota Dysbiosis

AbstractOral probiotics meet challenges during processing, storage, and gastrointestinal harsh conditions. Polysaccharide‐based hydrogels delivery system is promising in probiotic protection, but its semi‐solid and weak strength, and often requires additional cross‐links to solidify its structure. Herein a ferric ion co‐crosslinked microgel of Mesona chinensis polysaccharides and mechanically strengthened by phenolic‐metal frameworks of naturally bound brown bioactives is designed. These microgels has an intact structure in acidic condition and ruptured only at pH neutral conditions which can responsively release highly viable probiotics with high mucoadhesion and colonization. Brown bioactives are naturally bound to polysaccharides (MCPC) by hydrophobic interactions and hydrogen bonding, and they exhibited outstanding anti‐inflammatory and antioxidant properties. Moreover, these brown bioactives are the precise prebiotics which can specifically improve the abundance of Akkermansia genus in gut in vivo. Then, the probiotics Akkermansia muciniphila (AKK) are loaded into brown bioactives frameworks strengthened microgels. There is a more synergistic healthy benefit between MCPC components and loaded AKK compared with free and pasteurized AKK. MCPC microgels can deliver high viable AKK specifically to gut consequently modulating the microbiota balance, and protecting the intestinal barriers. MCPC microgels also delivered the antioxidant brown bioactives specifically into liver to alleviate the hepatic oxidative stress and inflammation.

Terapia farmacológica en insuficiencia cardiaca fracción de eyección reducida: ¿cómo, cuánto, a quién?

Heart failure (HF) is a clinical syndrome characterized by a combination of symptoms and signs caused by structural and/or functional cardiac abnormalities, confirmed by elevated levels of natriuretic peptides and/or objective evidence of pulmonary or systemic congestion (1-2).Guidelines have been proposed to guide treatment based on the left ventricular ejection fraction (EF), dividing it into three categories: HF with preserved EF (EF &gt; 50%), HF with mildly reduced EF (EF 40-49%), and HF with reduced EF (EF &lt; 40%). Currently, certain drugs have demonstrated a reduction in mortality and morbidity. When combined, these drugs provide an even greater synergistic benefit. In 2021, the European Society of Cardiology (ESC) published an editorial regarding the best therapy for HFrEF. These drugs include Inhibitors of the Renin-Angiotensin- Aldosterone System (IERAA), Beta-Blockers (BB), Mineralocorticoid Receptor Antagonists (MRA), and Sodium-Glucose Cotransporter Inhibitors (iSGLT2), also known as the “four horsemen.” The initiation of these four combined drugs represents the optimal therapy for HFrEF. However, individual patient profiles should be considered to provide personalized, optimal therapy, taking into account potential side effects. This work aims to summarize the key points as outlined by the ESC regarding optimal therapy for HFrEF and how to choose it.

BladderGATE: Atezolizumab + intravesical BCG (bacillus Calmette-Guerin) upfront combination in patients with high risk non-muscle invasive bladder cancer (NMIBC)—Phase I-II ONCOSUR study.

595 Background: Intravesical Bacillus Calmette-Guerin (BCG) induction + BCG maintenance after transurethral resection is the current standard of care for patients (pts) with high-risk non-muscle invasive bladder cancer (NMIBC). Recurrence rate at 2 years and 5 years are around 30-40% and 70-80% respectively. Atezolizumab is a IgG1 monoclonal antibody targeting PD-L1 and is associated with long-term durable remissions in pts with metastatic urothelial cancer (MS. van der Heijden . Eur Urol 2021) and for pts with unresponsive NMIBC (PC. Black . Eur Urol 2023) with excellent results. Atezolizumab in combination with standard BCG could provide synergistic benefit for pts with NMIBC. BladderGATE (NCT04134000) is a phase Ib-II study which evaluates the safety and efficacy of upfront atezolizumab + intravesical BCG in pts with high-risk NMIBC. Methods: Pt had confirmed histopathology of high-risk NMIBC, BCG naïve or stopped &gt;2 years ago, WHO PS 0-2 and adequate hematologic and organ function. Dose-escalation design to identify DLT and MTD (9 pts) and to evaluate safety and efficacy in an expansion cohort (30 pts) were programed. Pt received six weekly induction instillations, and maintenance instillations at 3, 6 and 12 months + intravenously atezolizumab 1200 mg every 3 weeks, up to 1 year. Urine/blood and tissue samples were collected for translational and biomarker correlative study. Primary objective is disease free survival. Secondary objectives include safety profile and quality of life. Results: Finally 36 pt were included, median age 70 years, 86% men, 61% of pt were former smokers, 22% smokers and 17% had never smoked, and tumor size was ≥3 cm in 44% of pt. With a 22 months median follow-up, 56% of pt had completed BCG treatment and 89% had received adequate BCG treatment (5 induction plus at least 2 maintenance instillations). Thirteen pts discontinued atezolizumab due to immune-related AEs (7 pts) (g2 dermatitis, g3 hepatitis, encephalitis, pneumonitis, myocarditis, adrenal insufficiency and psoriasis), due to early-relapse disease (3 pts) and progressive-disease (3 pts). All irAEs were solved and no toxic death were reported. Of the 36 pts analyzed, 6 pts showed local recurrence (17%), 5 pts with high-risk NMIBC (14%) and 1 pt with low-risk NMIBC, 1 pt with UTUC, and 3 pts with local muscle invasive bladder cancer progressive-disease (8 %). Preliminary 2-year disease free survival is 72.8% (95% CI: 56.1% - 89.5%). Conclusions: The combination strategy of atezolizumab + intravesical BCG upfront in high-risk NMIBC pts appears feasible and safe. A 14% of 2-years local recurrence-rate and 8% of local progressive-disease are promising results, pending to randomized Ph3 ALBAN study data (GETUG). Supported by Roche-Spain. Clinical trial information: NCT03425201 .

Combined Effect of Biochar and Plant Growth-Promoting Rhizbacteria on Physiological Responses of Canola (Brassica napus L.) Subjected to Drought Stress

Biochar (BC) and plant growth-promoting microbes (PGPR) could represent a suitable agronomical strategy to mitigate the impacts of drought in arid agro-environmental conditions. However, there is currently little understanding of the synergistic benefit of combining BC and PGPR to increase drought tolerance in oilseeds. In this study, the physiological response of two water-stressed canola (Brassica napus L.) plants subjected to the application of BC obtained from waste wood of Morus alba applied solely or in combination with PGPR strains (Pseudomonas sp.) was evaluated. The experiment consists of two genotypes and nine treatments [(C-Control, T1-15 days drought (15DD), T2-30 days drought (30DD), T3-15 days of drought + PG (15DD + PG), T4-30 days of drought + PG (30DD + PG), T5-15 days drought + biochar (15DD + BC), T6-30 days drought + biochar (30DD + BC), T7-15 days drought + biochar + PG (15DD + BC + PG), T8-30 days drought + biochar + PG (30DD + BC + PG)]. Drought stress decreased emergence energy (EE), leaf area index (LAI), leaf area ratio (LAR), root shoot ratio (RSR), moisture content of leaves (MCL), percent moisture content (%MC), moisture content of shoot (MCS) and moisture content of root (MCR), and relative water content (RWC) in both varieties of Brassica napus L., which in contrast, it is increased by the collective application of both biochar and PGPR. In both varieties, N, P, K, Mg, and Ca concentrations were highest in all the biochar and PGPRs separate and combined treatments, while lowest in 15 and 30 days drought treatments. Osmolyte contents like Glycine betaine (GB) and sugar remarkably increased in the stress condition and then reduced due to the synergistic application of biochar and PGPR. Drought stress has a repressive effect on the antioxidant enzymatic system like Peroxidase (POD), Superoxide dismutase (SOD), and glutathione reductase (GR) as well as total flavonoids, phenolics, and protein content. The antioxidant enzymes and phenolic compounds were dramatically increased by the combined action of biochar and PGPRs. A significant increase in EE, LAR, RSR, and RWC under 15 and 30 days drought conditions, evidently highlighting the synergistic effect of BC and PGPR. The results conclude a substantial and positive effect of the combined use of BC and PGPR strains on canola's response to induced drought stress, by regulating the physiological, biochemical, and agronomic traits of the plants.Graphical

A novel profit allocation rule of complex product development networks under the position value

A fair and reasonable profit allocation mechanism is the key to ensuring the stability of complex product development networks. Considering the disconnectedness of development networks, this paper takes the Position value to allocate profits. Initially, this paper constructs the profit function of complex product development networks, which serves as the characteristic function in graph cooperative games. Subsequently, a real-world case is presented to demonstrate the profit allocation process using the Position value, allowing for an examination of the relationship between profits and firms’ investments. Moreover, various factors are investigated to assess their influence on the profit allocation result, and a comparison is made between the Position value and the Myerson value. By adjusting the parameters and observing the numerical simulation, the research delves into the impact of key parameters on firms’ profit allocation. The findings indicate that the network position and investment are directly proportional to firms’ allocated profits. Additionally, the synergistic coefficient and benefit coefficient positively moderate firms’ profits, while the cost coefficient of investment negatively moderates them. Notably, the Position value proves to be more suitable for complex product development networks than the Myerson value.

Assessing Chronic Pain Among Adults Diagnosed with Diabetes Residing in Rural Appalachia.

Appalachian populations have some of the highest rates of overdose and comorbidity, all of which are considered risk factors for and contributors to chronic pain. The purpose of this study was to examine the associations of comorbidity, disability (physical limitations), and depression with chronic pain among a community-based sample of Appalachian adults living with diabetes. This study used baseline data to conduct a secondary analysis of cross-sectional data (n=356). Data included sociodemographic, disability (physical limitations), chronic pain, and depression measures. These data were collected and analyzed from 2017-2019. Multiple logistic regression was used to investigate the association between comorbidity, disability, depression, and chronic pain. Participants were predominantly non Hispanic white (98.0%), women (64.6%), and had a mean age of 64.2 years. Comorbidity (p=.044), physical limitations (pp. Chronic pain affects physical and psychosocial health among those diagnosed with diabetes who live in rural Appalachian communities. Alleviating chronic pain could have a synergistic benefit to healthy functioning.

Exploring the evolutionary mechanism of the cross-regional cooperation of construction waste recycling enterprises: A perspective of complex network evolutionary game

Cooperation and information sharing among various regional departments play a crucial role in facilitating the equitable disposal of construction waste across regions, fostering regional coordination in waste management. This paper establishes the complex network evolutionary game model of cross-regional cooperation of construction waste recycling enterprises, and conducts numerical simulation to analyze the strategic adjustment process of recycling enterprises under the coordination and complementarity of market mechanism and government mechanism, and explores the Pareto optimal conditions that are conducive to cross-regional cooperation of recycling enterprises. The result indicates that with the increase of the market scale of cross-regional treatment of construction waste, it can effectively improve the willingness of cross-regional cooperation of recycling enterprises. In the market mechanism, both the profit distribution and synergistic benefit have a significant impact on the cross-regional cooperation behavior of construction waste recycling enterprises, while the impact of spillover benefit is relatively minor in comparison. In various network scales, the profit distribution coefficients exhibit threshold values within the ranges of 0.3–0.35, 0.25 to 0.3, and 0.25 to 0.3, respectively. Within the government mechanism, the government subsidy coefficient falls within the threshold of 0.3–0.4. Notably, greater government support proves more conducive to advancing cross-regional cooperation among recycling enterprises. For small-scale and medium-scale markets, there exists a threshold for default penalties ranging between 4 and 5. In contrast, large-scale markets have a default penalty threshold between 3 and 4. Imposing reasonable penalties for contract breaches can effectively stimulate the sustainable and consistent development of cross-regional cooperation among recycling enterprises. These findings establish a foundation for shaping cross-regional cooperation strategies for recycling enterprises, enhancing the efficiency of construction waste treatment, and fostering the coordinated development of urban areas.