Antitumor Research Articles

Phyto-mediated fabrication of silver nanoparticles from Scrophularia striata extract (AgNPs-SSE): a potential inducer of apoptosis in breast cancer cells.

Breast carcinoma stands out as the most widespread invasive cancer and the top contributor to cancer-related mortality in women. Nanoparticles have emerged as promising tools in cancer detection, diagnosis, and prevention. In this study, the antitumor and apoptotic capability of silver nanoparticles synthesized through Scrophularia striata extract (AgNPs-SSE) was investigated toward breast cancer cells. The produced AgNPs-SSE were identified using scanning electron micrograph (SEM), energy-dispersive X-ray (EDAX) spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD). The cell-killing effects of AgNPs-SSE on MDA-MB231 mammary carcinoma cells were evaluated in vitro using the MTT assay over 24h. Apoptosis induction was conducted by cell cycle analysis, annexin V-FITC/PI staining, reactive oxygen species (ROS) generation, and Hoechst staining. Additionally, the gene expression of βcatenin, GSK3β, and CyclinD1 was analyzed using quantitative real-time PCR (qRT-PCR). Microscopic analysis confirmed the successful fabrication of globular AgNPs-SSE, with a mean particle dimension of 19 ± 10nm. The MTT assay revealed that IC50 value of AgNPs-SSE was 48.5µg/mL for mammary carcinoma cells and 114µg/mL for normal cells. Annexin V-FITC/PI staining specified that 85.88% of cancer cells treated with AgNPs-SSE underwent either early or late apoptosis. Treatment with AgNPs-SSE also caused a considerable rise in the subG1 cell cycle population and ROS production. Furthermore, the upregulation of βcatenin and downregulation of CyclinD1 gene expression confirmed the apoptotic mechanism. In conclusion, the findings suggest that phyto-synthesized AgNPs-SSE can restrain the expansion of breast carcinoma cells and provoke apoptosis through oxidative stress. These results highlight the potential of AgNPs-SSE as an antitumor agent against breast cancer.

Monotropein represses the proliferation and angiogenesis via the AKT/NF-κB pathway in lung cancer.

Monotropein (Mon) is an iridoid glycosides extracted from Morinda officinalis F.C. How. (Rubiaceae) that shows anticancer effects on colorectal cancer. This study aimed to investigate the therapeutic effect of Mon on lung cancer. The viability, apoptosis, invasion, and tube formation of A549 and H1299 were determined by CCK8 assay, flow cytometry, transwell assay, and tube formation assay. NF-κB expression in the nucleus was detected by immunofluorescent staining. In vivo assay, BALB/c nude mice were divided into a sham group and a 2mg/kg Mon group. For the Mon group, mice were orally administered with 2mg/kg Mon. The duration of the animal study was 35days, and the tumor formation and angiogenesis were investigated. Compared with the control (Mon 0μM) group, Mon dramatically repressed the viability, invasion, tube formation, proliferation marker Ki67, N-cadherin, and VEGFA expressions in A549 cells (Mon of 25, 50, and 100µM) and H1299 cells (Mon of 50 and 100µM). Mon dramatically promoted cell apoptosis, cleaved caspase 3, and E-cadherin expressions. Besides, Mon remarkably downregulated p-AKT and p-NF-κB protein expressions. Moreover, AKT agonist SC79 reversed the anticancer effects of 100µM Mon on A549 cells. Furthermore, Mon markedly suppressed tumor growth, decreased N-cadherin, VEGFA, p-AKT, and p-NF-κB expressions, increased apoptosis and E-cadherin expression, and SC79 reversed the inhibition effects of Mon in vivo. Thus, Mon is a potential antitumor natural drug, and more signaling pathways involved in Mon-modulated lung cancer progression are worth testing for further investigation.

Innovative Applications of Bacteria and Their Derivatives in Targeted Tumor Therapy.

Despite significant progress in cancer treatment, traditional therapies still face considerable challenges, including poor targeting, severe toxic side effects, and the development of resistance. Recent advances in biotechnology have revealed the potential of bacteria and their derivatives as drug delivery systems for tumor therapy by leveraging their biological properties. Engineered bacteria, including Escherichia coli, Salmonella, and Listeria monocytogenes, along with their derivatives─outer membrane vesicles (OMVs), bacterial ghosts (BGs), and bacterial spores (BSPs)─can be loaded with a variety of antitumor agents, enabling precise targeting and sustained drug release within the tumor microenvironment (TME). These bacteria and their derivatives possess intrinsic properties that stimulate the immune system, enhancing both innate and adaptive immune responses to further amplify therapeutic effects. The ability of bacteria to naturally accumulate in hypoxic tumor regions and their versatility in genetic modifications allow for tailored drug delivery strategies that synergistically enhance the effectiveness of chemotherapy, immunotherapy, and targeted therapies. This review comprehensively examines the fundamental principles of bacterial therapy, focusing on the strategies employed for bacterial engineering, drug loading, and the use of bacteria and their derivatives in targeted tumor therapy. It also discusses the challenges faced in optimizing bacterial delivery systems, such as safety concerns, unintended immune responses, and scalability for clinical applications. By exploring these aspects, this review provides a theoretical framework for improving bacterial-based drug delivery systems, contributing to the development of more effective and personalized cancer treatments.

Anticancer Attributes and Multifaceted Pharmacological Implications of Laetrile and Amygdalin.

Laetrile, known as vitamin B17, is often used interchangeably with amygdalin. Laetrile is a semi-synthesis product of amygdalin, whereas amygdalin is a naturally occurring substance in many plants. Both compounds have a nitrile functional group that, when activated by the intestinal enzyme β-glucosidases, releases hydrogen cyanide. The two compounds have been considered for a long time as alternative therapy for cancer treatment however, findings available in the literature are discordant on the real efficacy of laetrile/amygdalin for the treatment of cancer, often highlighting a negative benefit-risk ratio. In this regard, the study aimed to comprehensively analyze the scientific data on laetrile/amygdalin, with a special emphasis on their pharmacokinetics, underlying pharmacological properties, mode of action as a potent antitumor agent, and effect on human health. The results showed that there is no clear evidence on the efficacy of cancer therapy following laetrile/amygdalin administration, especially at the clinical trial level. However, the in vitro studies of the biological activity of these compounds showed positive effects related to their antifibrotic, anti-inflammatory, antiasthmatic, and immunoregulatory processes. Laetrile's mechanism of action closely resembles amygdalin, affecting cancer signaling pathways. However, due to its cyanide toxicity, it was banned by the food and drug administration (FDA) due to safety concerns. Despite not receiving permission from the FDA, laetrile emerged as an alternative therapy in the 1970s. Nonetheless, continuing research is investigating safer methods of activating Laetrile for targeted cancer treatment. This opens interesting prospects in using these compounds in alternative medical therapies, for which, however, further research is needed.

Anti-tumor Necrosis Factor Drug Concentration Is Not Associated with Disease Outcomes in Pouchitis: A Retrospective, International Study.

Therapeutic drug monitoring is important for optimizing anti-tumor necrosis factor-α (TNF-α) therapy in inflammatory bowel disease. However, the exposure-response relationship has never been assessed in pouchitis. To explore associations between anti-TNF-α drug concentration and pouchitis disease activity in patients with a background of ulcerative colitis. A retrospective, multicenter, cross-sectional study was conducted in adult patients with pouchitis requiring anti-TNF-α treatment. Rates of clinical and endoscopic remission were calculated, and drug concentrations during maintenance therapy were compared between remission and non-remission cohorts. Sixty-three patients were included: median age, 48years (IQR 36-59) and median time since pouchitis diagnosis, 7years (IQR 2-13). Patients received infliximab, n = 27 (43%), adalimumab, n = 29 (46%), or both n = 7(11%). Thirty-two (51%) patients received concomitant immunomodulation. Median infliximab trough concentrations (mg/ml) were similar between patients in clinical remission (n = 21) vs non-remission (n = 11), 5.3 vs. 4.4, p = 0.73. For adalimumab, median drug concentrations did not significantly differ between remission/non-remission groups based on clinical (n = 18/18), 11.4 vs 7.6, p = 0.32, or endoscopic assessment, (n = 7/29), 9.0 vs. 7.8, p = 0.78. Four patients had positive anti-drug antibodies with undetectable drug concentration. In a cohort of patients with pouchitis, higher anti-TNF-α drug concentrations were not associated with more clinical or endoscopic remission.

Abiraterone acetate fixed-dosed combinations with ibuprofen-based therapeutic eutectic and deep eutectic solvents.

In recent years, deep eutectic solvents (DESs) with their outstanding solubilization properties have emerged as strong candidates for oral enabling formulations of poorly soluble drugs. This study explores the use of drug-based therapeutic DESs (THEDESs) to solubilize a poorly soluble compound with the aim of providing a fixed-dose combination of two complementary therapeutic agents. Specifically, potential anticancer effects of ibuprofen (IBU) are harnessed in a novel type of THEDES to dissolve higher amounts of abiraterone acetate (AbAc), an antitumor agent. Four IBU-based combinations were studied: 1:4 M ratio with octanoic acid (OctA), 1:5 with nonanoic acid (NonA), 1:3 with decanoic acid (DeA) or 1:2 with dodecanoic acid (DoA). Fatty acids of different chain lengths were analyzed and discussed considering surface charge densities obtained via quantum chemistry. The THEDESs listed could apparently dissolve AbAc amounts up to 1311.0 ± 125.4 mg/g in IBU:OctA THEDES, 1151.7 ± 22.2 mg/g in IBU:NonA, 1160.4 ± 33.5 mg/g in IBU:DeA, and 231.3 ± 10.7 mg/g in IBU:DoA. In vitro dissolution of the simultaneously released drugs reached 37.8 ± 9.0 % to 64.2 ± 1.0 % for IBU and 5.0 ± 3.3 % to 19.4 ± 0.1 % for AbAc. This increased to between 60.4 ± 2.8 % and 79.4 ± 5.0 % of released IBU, and 23.6 ± 1.0 % to 57.3 ± 5.8 % of released AbAc, with 20 % (w/w) Tween 80 added to the formulations. This showed the significant potential of drug-containing THEDESs as solubilizing agents for poorly soluble drugs, in the form of fixed-dose combinations of synergistic APIs.

Diversity-oriented synthesis of stereodefined tetrasubstituted alkenes via a modular alkyne gem-addition strategy

Stereocontrolled construction of tetrasubstituted olefins has been an attractive issue yet remains challenging for synthetic chemists. In this manuscript, alkynyl selenides, when treated with ArBCl2, are subject to an exclusive 1,1-carboboration, affording tetrasubstituted alkenes with excellent levels of E-selectivity. Detailed mechanistic studies, supported by DFT calculations, elucidates the role of selenium in this 1,1-addition process. Coupled with subsequent C-B and C-Se bond transformations, this 1,1-addition protocol constitutes a modular access to stereodefined all-carbon tetrasubstituted alkenes. The merit of this approach is demonstrated by programmed assembly of diverse functionalized multi-arylated alkenes, especially enabling the stereospecific synthesis of all six possible stereoisomers of tetraarylethene (TAE) derived from the random permutation of four distinct aryl substituents around the double bond. The diversity-oriented synthesis is further utilized to explore different TAE luminogenic properties and potential Se-containing antitumor lead compounds.

2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol (chlonisol): blood content in rats after intravenous administration and chemical resistance

Background. The domestic antitumor compound 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol (chlonisol) has high antitumor activity on a wide range of experimental tumors.Goal. To study the content of chlonisol in the blood of rats at different times after intravenous administration and its chemical stability in 0.9 % sodium chloride solution, urine and blood serum.Methods. The concentration of chlonisol in various media was determined by HPLC. In vivo studies on 10 male rats with a body weight of 180–200 g. the concentration of chlonisol in the blood of rats was determined 2, 30, 60, 90 and 120 minutes after its intravenous administration at a dose of 40 mg/kg. In in vitro experiments, a 0.1 % solution of chlonisol was incubated at 37 °C in three media: 0.9 % sodium chloride solution, blood serum and urine. Aliquots were selected at different intervals and analyzed for the content of chlonisol. The stability of chlonisol was evaluated in relation to its concentration before and after incubation, expressed as a percentage.Results. When chlonisol was administered intravenously at a dose of 40 mg/kg to rats, its complete disappearance from the blood was observed within 2 hours. The half-life was 27 minutes. Of the three media studied in vitro experiments, chlonisol was the most stable in 0.9 % sodium chloride solution(89 % of the initial level after 10 hours of incubation at 37 °C). Less stable, but for a long time – in urine (60 % of the initial after 1 hour of incubation and 37 % after 2 hours). The lowest resistance of chlonisol was in the blood serum (a decrease in concentration to 11 % after 1 hour and to 0 after 2 hours of incubation).Conclusion. The results obtained allow us to make assumptions about possible ways of using chlonisol: The high stability of chlonisol in 0.9 % sodium chloride solution will allow its long-term drip intravenous infusions, as well as perfusion intraarterial chemotherapy. Maintaining the concentration of chlonisol in urine at 60 % of the initial level for 1 hour will allow the use of intravesical instillations of chlonisol in superficial bladder cancer.

NEDD4-Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction.

The decrease in S-nitrosoglutathione reductase (GSNOR) leads to an elevation of S-nitrosylation, thereby exacerbating the progression of cardiomyopathy in response to hemodynamic stress. However, the mechanisms under GSNOR decrease remain unclear. Here, we identify NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) as a novel molecule that plays a crucial role in the pathogenesis of pressure overload-induced cardiac hypertrophy, by modulating GSNOR levels, thereby demonstrating significant therapeutic potential. Protein synthesis and degradation inhibitors were used to verify the reasons for the decrease in GSNOR. Mass spectrometry and database filtering were used to uncover NEDD4, the E3 Ub (ubiquitin) ligase, involved in GSNOR decrease. NEDD4 cardiomyocyte-specific deficiency mice were used to evaluate the role of NEDD4 and NEDD4-induced ubiquitination of GSNOR in cardiac hypertrophy in vivo. Both IBM, a highly specific NEDD4 inhibitor, and indole-3-carbinol, a NEDD4 inhibitor currently undergoing phase 2 clinical trial, were used to effectively suppress the NEDD4/GSNOR axis. GSNOR protein levels were reduced, while mRNA levels remained unchanged in myocardium samples from hypertrophic patients and transverse aortic constriction-induced mice, indicating GSNOR is regulated by ubiquitination. NEDD4, an E3 Ub ligase, was associated with GSNOR ubiquitination, which exhibited significantly higher expression levels in hypertrophic myocardial samples. Moreover, either the NEDD4 enzyme-dead mutant or GSNOR nonubiquitylated mutant decreased GSNOR ubiquitination and inhibited cardiac hypertrophic growth. Cardiomyocyte-specific NEDD4 deficiency inhibited cardiac hypertrophy in vitro and in vivo. NEDD4 inhibitor IBM effectively suppressed GSNOR ubiquitination and cardiac hypertrophy. Clinically, indole-3-carbinol, a NEDD4 inhibitor in phase II clinical trials used as an antitumor drug, demonstrated comparable efficacy. Our findings showed that upregulated NEDD4 leads to GSNOR ubiquitination and subsequent degradation, thereby facilitating the progression of cardiac hypertrophy. NEDD4 inhibitors may serve as a potential therapeutic strategy for the treatment of cardiac hypertrophy and heart failure.

Nanoenzyme-based sensors for the detection of anti-tumor drugs.

Natural enzymes are a class of biological catalysts that can catalyze a specific substrate. Although natural enzymes have catalytic activity, they are susceptible to the influence of external environment such as temperature, and storage requirementsare more stringent. Since the first discovery of magnetic Fe3O4 nanoparticles with peroxidase-like activity in 2007, the research on nanoenzymes has entered a rapid development stage. Nanoenzymes synthesized by chemical methods not only have the catalytic activity of natural enzymes but also are more stable, easy to store, and convenient to prepare. Anthracyclines, as a commonly used anti-tumor chemotherapy drug, will produce many side effects such as myelosuppression and liver function damage after long-term use, which will affect its therapeutic effects. This paper reviews the characteristics, classification, and mechanisms of nanoenzymes. The detection of anti-tumor drugs, especially anthracycline drugs, using a nanoenzyme-based sensor was emphatically introduced. On this basis, the application of nanoenzyme-based sensors in the detection of anti-tumor drugs is prospected.

P0861 Comparative effectiveness and safety of ustekinumab versus anti-tumour necrosis Factor agents as first- or second-line biologics in Crohn´s disease: a real-world multicentric observational study

Abstract Background Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin-12/23, has demonstrated efficacy in patients with Crohn’s disease (CD). However, comparative real-world data regarding the positioning of biologic therapies, particularly UST versus anti-tumour necrosis factor (TNF) agents, remain limited. This study aimed to compare the effectiveness and safety of UST and anti-TNF agents in biologic-naïve and biologic-failure CD patients. Methods A multicentre retrospective cohort study was conducted, including patients with moderate to severe CD initiating first- or second-line biologic treatment with UST or anti-TNF agents [infliximab (IFX) or adalimumab (ADA)]. Propensity score adjustment (1/PS) was applied to address confounders. Primary endpoints were clinical remission (Harvey-Bradshaw Index ≤3), endoscopic remission (SES-CD ≤3 or Rutgeerts score I0), and steroid-free clinical remission at week 52. Secondary outcomes included clinical response, primary/secondary loss of response, treatment persistence, biochemical remission, adverse events (AEs), hospitalisation, and surgeries. Results A total of 536 CD patients (172 IFX, 132 ADA, 236 UST) were analysed. Clinical remission at week 52 was achieved by 78.1% of UST and 75.7% of anti-TNF patients in the biologic-naïve group (p=0.25), and 52.2% of UST and 50.5% of anti-TNF in biologic-failure patients (p=0.31). Steroid-free clinical remission rates were similar between UST and anti-TNF groups: 80.5% vs 80.1% (p=0.99) in biologic-naïve and 81.2% vs 77.3% (p=0.46) in biologic-failure patients. Endoscopic remission was observed in 74.8% of UST vs 68.8% of anti-TNF patients (p=0.81) in biologic-naïve, and 50.6% vs 46.8% (p=0.72) in biologic-failure. Serious AEs were more frequent with anti-TNF agents in biologic-failure patients (28.3% vs 12.5%; p<0.01). UST demonstrated higher treatment persistence in biologic-naïve patients (96.9% vs 80.8%; p=0.029) and lower CD relapse rates (3.08% vs 11.11%; p=0.01). Conclusion UST and anti-TNF agents exhibit comparable effectiveness for CD treatment regardless of prior biologic exposure. UST showed superior treatment persistence and a better safety profile, particularly in biologic-naïve patients.

P0216 PANoptosis-related genes can predict the progression of ulcerative colitis and colitis-associated colorectal cancer

Abstract Background Ulcerative colitis (UC) is a complex inflammatory bowel disease that significantly increases the risk of developing colitis-associated colorectal cancer (CAC). The etiology of UC remains unclear, and the mechanisms underlying its progression to CAC require further exploration. Recent studies have identified a novel form of cell death called pan-apoptosis, which is closely linked to inflammatory diseases. However, its specific role in UC and CAC progression is not yet fully understood. This study aims to develop a reliable predictive model based on pan-apoptosis using high-throughput RNA sequencing and validate it, along with an analysis of cellular characteristics in UC patients through single-cell sequencing data. This research offers new insights for the prognosis and treatment of UC patients. Methods This study collected single-cell and high-throughput sequencing data from UC patients and defined a pan-apoptosis gene set. The dataset was analyzed for immune infiltration, differential expression, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Additionally, weighted gene co-expression network analysis (WGCNA) was used to identify key genes associated with UC, which were then utilized to construct a predictive model. Finally, single-cell data analysis was conducted on UC patients, followed by in vitro validation of the expression of key genes. Results By analyzing differentially expressed genes in UC samples and using the pan-apoptosis gene set, WGCNA identified key genes associated with UC, including CASP1, LCN2, STAT3, and ZBP1. These genes were used to construct a pan-apoptosis-related predictive model, establishing a pan-apoptosis-related score (PAR-Score). The results showed that PAR-Score has strong classification ability and is positively correlated with immune cell infiltration and the inflammatory microenvironment in UC patients. Notably, CAC patients had significantly higher PAR-Scores. Single-cell sequencing data confirmed that monocyte activity in UC patients is linked to pan-apoptosis, while intercellular communication among immune cells was notably reduced. The expression levels of key genes in the predictive model were validated in vivo. Drug predictions targeting these genes suggested that Leridistim, interferon-γ, and other compounds could serve as potential therapeutic agents for UC or CAC. Conclusion The predictive model established based on pan-apoptosis exhibits good predictive performance, providing new perspectives for assessing the condition and progression of UC patients, and opening up new avenues for the treatment of UC and CAC in the future. References Nature. 2007;448(7152):427-434. doi:10.1038/nature060052. Jess T, Rungoe C, Peyrin L. Risk of Colorectal Cancer in Patients With Ulcerative Colitis: A Meta-analysis of Population-Based Cohort Studies. 2012;10(6). 3. Shin J, Baek GH, Cha B, et al. Complementary Therapeutic Effect of Fecal Microbiota Transplantation in Ulcerative Colitis after the Response to Anti-Tumor Necrosis Factor Alpha Agent Was Lost: A Case Report. Published online 2024. doi:10.3390/biomedicines12040800 Front Cell Infect Microbiol. 2019;9:406. doi:10.3389/fcimb.2019.00406 J Immunol. 2022;209(9):1625-1633. doi:10.4049/jimmunol.2200508 World J Gastroenterol. 2014;20(44):16389. doi:10.3748/wjg.v20.i44.16389

P0914 Clinical outcomes of dose-escalated adalimumab in Inflammatory Bowel Disease: A retrospective tertiary centre experience

Abstract Background Despite anti-tumour necrosis factor-α agents (anti-TNF-α) – infliximab (IFX) and adalimumab (ADA) changing the landscape of inflammatory bowel disease (IBD) treatments over the last decade, their use is limited by secondary loss of response (SLOR).1 Anti-TNF-α dose escalation is frequently employed in patients with SLOR and/or low drug levels.2-3 The long-term effectiveness and safety of dose-escalated ADA remains unclear. Hence, we evaluated clinical outcomes following ADA dose escalation in a tertiary centre IBD cohort. We aimed to determine the effectiveness and safety of dose-escalated ADA in IBD patients who had inadequate response to standard dosing ADA after initial response and in patients undergoing escalated induction. Methods We conducted a retrospective analysis of IBD patients who underwent ADA dose escalation between 2018-2024 at a tertiary IBD centre. Dose escalation was defined as an increase in dose (> 40 mg) and/or frequency [> every 2 weeks (Q2W)]. Primary outcomes included clinical improvement (HBI), biochemical markers (CRP, faecal calprotectin), and treatment persistence, assessed at 3-12 months and annually up to 3 years following dose escalation. Secondary outcomes included adverse events (AE). Results A total of 50 patients (median age 35 years, 48% female) were included, of which 47 patients (94%) had Crohn’s disease (CD) and 3 patients (6%) had ulcerative colitis (UC) (Figure 1). Indications for dose escalation included SLOR (36/50; 72%), low drug levels (10/50; 20%) and escalated induction following failure of an alternative biologic therapy (4/50; 8%). Dose-escalated ADA led to a significant improvement in HBI at 3-12 months (p=0.018). This improvement was maintained at 12 months (p=0.009) and 2 years (p=0.010). Significant initial improvements in biochemical markers were reported at 3-12 months (CRP: p=0.048; faecal calprotectin: p=0.023). These improvements were not maintained at any further follow-up points (p>0.05). Treatment persistence was high at 3-12 months (82%), however, only 45% of patients persisted at 3 years. Persistence was higher for biologic-naïve patients (56%) compared with biologic-exposed patients (37%) at 3 years. Four patients reported AE. Urticaria around the injection site (n=2) led to discontinuation in a single patient. Other AE included rheumatological symptoms (n=1) and recurrent catheter-associated urinary tract infections (n=1), the latter prompting de-escalation. Conclusion Dose-escalated ADA appears to be an effective and safe strategy for achieving sustained clinical improvements and early biochemical improvements in IBD patients. Higher persistence in biologic-naïve patients suggests that this strategy may be more effective in this group.

What we know about the new coronavirus infection in cancer patients

The article presents data from a retrospective study of COVID-19 outcomes in cancer patients from 24 regions of the Russian Federation.The study included 1,055 patients who had a Coronavirus disease 2019, including 451 (42.7 %) men and 604 (57.3) women. The mean age was 58.7 years (29–90); 108 (10.2 %) patients were diagnosed with various comorbidities. 627 (59.4 %) were receiving antitumor drug therapy at the time of diagnosis of COVID-19, and 332 (31.5 %) received antitumor chemotherapy.Most patients had asymptomatic or mild COVID-19: asymptomatic in 205 (19.4 %) patients, and mild — in 517 (49.0 %) patients. Moderate / severe COVID-19 was observed in 268 (25.4 %) patients, while severe / critical COVID-19 was diagnosed in 65 (6.2 %). 1204601776 25 (2.4 %) patients died after COVID-19. The average age of cancer patients who died was 66.3 years (31–84). Among the deceased patients, 16 (64.0 %) were women and 9 (36.0 %) were men. To determine the factors increasing the risk of death in cancer patients we performed univariate and multivariate analyses. Conclusions: based on the presented data, the probability of death from COVID-19 was associated with the anti-tumor therapy administered during the disease. This conclusion obliges us to stop antitumor chemotherapy during the COVID-19 disease.

Computational simulation study of flow dynamics in plga microsphere generation using lab-on-a-chip for prostatic embolisation

Abstract Introduction Transarterial chemoembolisation is a therapeutic approach for vascularised tumours, such as prostate tumours, involving the administration of drug-eluting microspheres. Its efficacy arises from the combined effects of anti-tumour drugs and blood flow occlusion. Microspheres are now commonly generated using lab-on-a-chip systems. This study presents a computational simulation model to evaluate the input flow conditions required to produce PLGA microspheres of specific sizes. Methods The simulations were conducted using COMSOL Multiphysics 5.5, with rheological data for PLGA and the continuous phase derived from prior studies. The chip design was based on standard commercial double-T models, featuring 300 µm inlet and 500 µm outlet channels. Eight simulations were performed, varying the input velocity ratio (Rv = Vc/Vd) while maintaining a constant Vd of 8 mm/s. The evaluated ratios included: 1.500, 1.750, 1.875, 2.000, 2.125, 2.250, 2.375, and 2.500. Results The findings indicate that no microspheres are generated at Rv values below 1.875 or above 2.375. For intermediate ratios, microsphere sizes ranged from 240 to 275 µm, with droplet generation rates of 32 to 37 spheres per second for Rv values between 1.750 and 2.250, respectively. Conclusion This computational simulation system provides a rapid method for evaluating flow conditions. For the proposed chip geometry, it is possible to generate an average of 35 microspheres per second with a diameter of 250 µm in PLGA.

P1309 Is there any association between genetic polymorphisms and response to Anti-TNFs in patients with inflammatory bowel disease ? Experience of a Tunisian IBD center

Abstract Background Although highly effective, primary failure and loss of response to anti tumor necrosis factors (anti-TNF) alpha in inflammatory bowel disease (IBD) are common and associated with poor clinical outcomes. Multiple factors, including genetics, have been involved in the response to anti TNF alpha therapy. Thus, the purpose of our study was to evaluate the impact of the polymorphism of the SNPs rs1799724 (TNF alpha), rs767455 (TNFRSF1A), and rs1061622 (TNFRSF1B) in the response to anti-TNF alpha treatment in Tunisian IBD patients. Methods We conducted a prospective study including patients followed for IBD and treated with anti-TNF alpha. We classified these patients into two groups: responders and non-responders to anti-TNF alpha. Genomic DNA was purified from peripheral blood leucocytes using the salting-out method. Subjects were genotyped for polymorphisms TNF (rs 1799724), TNFRSF1A (rs767455) and TNFRSF1B (rs1061622) using a variant of allele-specific PCR, Mutagenically Separated PCR (MS-PCR). Genotypic and allelic frequencies were compared between the two groups of patients. Results We included 61 IBD patients with a mean age of 38,9 years [18-64 years]. Forty six patients (75.4%) had CD and 15 (24.6%) had UC. In the CD group, 35 (76.1%) patients were treated with infliximab and 11(23.9%) with Adalimumab. Nineteen were responders to treatment (41,3%) and 27 (58.7%) experienced treatment failure: primary failure in 4 and loss of response in 23. Genetic analysis did not show any association between the response to anti TNF alpha treatment and SNPs rs1799724 (TNF alpha) (P= 0,12 ; OR = 1,9) and rs1061622 (TNFRSF1B) (P= 0,9; OR= 1,06). Although, the CT genotype of rs767455 (TNFRSF1A) was associated with non-response (OR= 3.5 with a 95% CI [0.98-12.4], p=0.049). In the UC group, 14 patients were treated with Infliximab and only one patient treated with Adalimumab. Seven patients responded to anti-TNF therapy (46.7%) and 8 were non-responders (53.3%) with 5 cases of primary failure and 3 cases of loss of response. We didn’t find any association between the SNPs rs1799724 (TNF alpha), rs767455 (TNFRSF1A), and rs1061622 (TNFRSF1B) and response to anti TNF alpha in the UC patients. Conclusion Among the three SNPs studied, only the rs767455 (TNFRSF1A) was shown to be associated with non-response to anti-TNF in chrohn’s disease patients. However, our results need to be validated in a larger sample of patients.

Self-assembled HO-1i-Pt(IV) nanomedicine targeting p38/MAPK and MDR pathways for cancer chemo-immunotherapy.

Platinum(II)-based antitumor drugs are widely used in clinics but limited by severe side effects and resistance. Multi-target Platinum(IV) complexes are emerging as ideal alternatives. Heme oxygenase-1 (HO-1) works as a rate-limiting step in heme degradation and is overexpressed in malignant tumors. Herein, HO-1i-based Platinum(IV) prodrugs are prepared and candidate complex 15 is further developed into self-assembled nanoparticles (15-NPs). 15 and 15-NPs significantly increase cytotoxicity, particularly in HepG2 (74.77- and 96.14-fold increases) and A549cisR (38.6- and 47.24-fold increases), while reducing toxicity towards normal cells compared to cisplatin. In vitro experiments show 15 and 15-NPs activated multiple pathways, including p38/MAPK- and MDR-related proteins, achieving multi-target synergistic chemosensitization and anti-resistance, further verified by RNA-sequencing analysis. In vivo tests demonstrate that 15 and 15-NPs efficiently inhibit tumor growth and systemic toxicity, especially 15-NPs with optimal tumor-inhibition rate and survival (80 % and 100 %), superior to cisplatin (40 % and 50 %), attributing to its extra endocytosis, EPR effect, and precisely tumor-targeted release besides the advantage of a free HO-1i-Pt(IV) prodrug. Additionally, 15 and 15-NPs distinctly regulate T-cell and macrophage functions, thereby exhibiting a chemoimmuno-combined action. This study highlights that multi-functional Platinum(IV) prodrug target-delivered to tumors via carrier-free nanoparticles may represent an effective modality for improving cancer therapy.

Lactoferrin-functionalized PEGylation liposomes loaded with norcantharidin acid for targeted therapy of hepatocellular carcinoma.

Norcantharidin (NCTD), an antitumor agent with an increased leukocyte function, has been used for the treatment of hepatocellular carcinoma (HCC) in clinical. However, the clinical application of NCTD is limited due to its inadequate hydrophilicity and lipophilicity, short half-life (t1/2), as well as adverse effects such as vascular irritation, cardiotoxicity, and nephrotoxicity. Herein, a lactoferrin (Lf) and DSPE-mPEG2000 functionalized liposomes loaded with norcantharidic acid (NCA), an active metabolite of NCTD, was constructed for the targeted therapy of HCC. In this study, blank PEGylated liposomes were prepared using the film hydration method, and the NCA was loaded by calcium acetate active loading method to increase the encapsulation efficiency (EE). Subsequently, lactoferrin was covalently coupled to DSPE-PEG2000-COOH activated by EDC and NHS. In addition, the in vivo pharmacokinetics and pharmacodynamics were investigated in Sprague-Dawley (SD) rats and H22 tumor-bearing BALB/c mice, respectively. As expected, the encapsulation efficiency measurement showed that the encapsulation efficiency of the NCA liposomes was 89.3±1.25 %, and the coupling efficiency of lactoferrin was more than 65.97 %. Additionally, the variations in both the dynamic size and encapsulation efficiency of norcantharidic acid liposomes in long-term storage stability and serum stability studies did not exceed 10 %. Furthermore, the pharmacokinetics and pharmacodynamics results showed that, the NCA-Lips-Lf were able to significantly improve antitumor activity by enhancing tumor-targeting accumulation and prolonging circulation time in the body compared to the sodium demethylcantharidate for injection (Na2DCA). Notably, the AUC0-48 and the t1/2 of NCA-Lips-Lf increased 4.28-time and 5.17-time in comparison to those of NCA-sol, respectively. The tumor inhibition rate of NCA-Lips-Lf (85.29 %) was significantly higher than that of sodium demethylcantharidate for injection (Na2DCA) (59.13 %), without obvious vascular irritation, cardiotoxicity and nephrotoxicity. In conclusion, NCA-Lips-Lf have the potential to eliminate hepatocellular carcinoma more effectively with fewer side effects than Na2DCA, which further advances the clinical application of norcantharidin-related drugs.

Mannose functionalized small molecule nanodrug self-assembled from amphiphilic prodrug connected by disulfide bonds for synergistic cancer chemotherapy and photodynamic/photothermal therapy.

Compared to conventional nanocarrier-based drug delivery technology, small-molecule-assembled nanomaterials provide various advantages, including higher drug loading efficiency, lower excipient-related toxicity, and a simpler formulation process. Our research constructed a mannonse-modified small-molecule-assembled nanodrug for synergistic photodynamic/chemotherapy against A549 cancer cells. The hydrophobic hypoxic-activated agent tirapazamine (TPZ) and a hydrophilic fluorescence probe Cyanine 3 (Cy3) constitute this amphiphilic prodrug via a glutathione (GSH)-responsive linkage, which could self-assemble into stable nanoparticles (NPs) and encapsulate a newly synthesized photosensitizer (SeBDP). To enhance the tumor targeting capability, we introduced a tumor-targeted nanodrug SeBDP@TPZ-S-S-Cy/Man NPs by co-assembling mannose-modified lipid (DSPE-PEG-Man). The GSH-responsive linkage of TPZ-S-S-Cy can be rapidly cleaved by GSH to release the therapeutic agents and fluorescent molecule. The released SeBDP generate reactive oxygen species (ROS) to specifically kill cancer cells and elevate hypoxia, thereby enhancing the cytotoxicity of TPZ. SeBDP@TPZ-S-S-Cy/Man NPs exhibited high selectivity and efficiency for in vivo combination therapy without adverse effects to normal tissues. Our findings demonstrate that SeBDP@TPZ-S-S-Cy/Man NPs have great potential for enhancing cancer treatment both in vitro and in vivo by combining an oxygen depletion prodrug with a hypoxia-activated antitumor agent. Thus, the GSH-sensitive self-assembled nanodrug from an amphiphilic hypoxia-activated prodrug, could serve as a potential drug carrier in targeted synergistic cancer therapy.

Inherent differential microbial assemblages and functions associated with corals exhibiting different thermal phenotypes.

Certain coral individuals exhibit enhanced resistance to thermal bleaching, yet the specific microbial assemblages and their roles in these phenotypes remain unclear. We compared the microbial communities of thermal bleaching-resistant (TBR) and thermal bleaching-sensitive (TBS) corals using metabarcoding and metagenomics. Our multidomain approach revealed stable distinct microbial compositions between thermal phenotypes. Notably, TBR corals were inherently enriched with microbial eukaryotes, particularly Symbiodiniaceae, linked to photosynthesis, and the biosynthesis of antibiotic and antitumor compounds and glycosylphosphatidylinositol-anchor proteins, crucial for cell wall regulation and metabolite exchange. In contrast, TBS corals were dominated by bacterial metabolic genes related to nitrogen, amino acid, and lipid metabolism. The inherent microbiome differences between TBR and TBS corals, already observed before thermal stress, point to distinct holobiont phenotypes associated to thermal bleaching resistance, offering insights into mechanisms underlying coral response to climate-induced stress.