Combined Group Research Articles

Comparative Effects of Crude Extracts and Bioactive Compounds from Bidens pilosa and Bidens alba on Nonspecific Immune Responses and Antibacterial Activity Against Vibrio sp. in Coculture with Lactic Acid Bacteria in Hybrid Grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂).

This study investigated the effect of substances on nonspecific immune responses of head kidney leukocytes, the antimicrobial activity against Vibrio sp., as well as the time-kill of Vibrio sp. by combining the substances with lactic acid bacteria (LAB) and Pediococcus sp. The substances are B. pilosa hot water extract, B. pilosa powder extract, B. pilosa methanol extract, B. pilosa ethanol extract, B. alba hot water extract, B. alba powder extract, B. alba methanol extract, B. alba ethanol extract, and bioactive compounds, namely cytopiloyne, flavonoid, phenol, ethyl caffeate, luteolin, chlorogenic acid, butein, and linoleic acid. The results showed that some of them were nontoxic to the head kidney leukocytes, which can increase the phagocytic rate, phagocytic index, and respiratory burst. These substances were able to inhibit the growth of Vibrio sp.; they can even completely kill the pathogenic bacteria. The largest of the inhibition zone formed from the EC group at a concentration range of 5-50 µg/mL against V. parahaemolyticus, V. alginolyticus, and V. harveyi with a value of 19.7 ± 0.56, 19.3 ± 1.53, and 20.6 ± 1.53 mm. Furthermore, the time-kill studies showed that the LAB and P. acidilactici can completely kill the Vibrio sp. at 6 h incubation time, mainly in the group of combination with EC.

Chinese expert consensus on management of antifungal-resistant dermatophytoses (2024 edition).

Antifungal-resistant dermatophytes (ARD) infection is a hotspot issue in clinical microbiology and the dermatology field. Trichophyton indotineae as the dominant species of dermatophyte with terbinafine-resistance or multidrug resistance, is easy to be missed detection clinically, which brings severe challenges to diagnosis and treatment. ARD infection cases have emerged in China, and it predicts a risk of transmission among human. Based on the existing medical evidence and research data, the Mycology Group of Combination of Traditional and Western Medicine Dermatology and Chinese Antifungal⁃Resistant Dermatophytoses Expert Consensus Group organized experts to make consensus on the management of the infection. Here, the consensus formulated diagnosis and treatment recommendations, to raise attention to dermatophytes drug resistance problem, and expect to provide reference information for the clinical diagnosis, treatment, prevention and control.

Efficacy and safety of first-line anti-tuberculosis drugs combined with Linezolid for the treatment of pediatric tuberculous meningitis in real-word practice

Objective: To evaluate the efficacy and safety of first-line anti-tuberculosis (TB) drugs combined with linezolid in treatment of children with tuberculous meningitis (TBM). Methods: A retrospective cohort study design was performed. Eight-nine Children diagnosed as TBM during January 1st 2016 and December 31st 2023 in Department of Infectious Disease, Children's Hospital of Chongqing Medical University were enrolled in the study. According to different treatment regimens, children were divided into a group of first-line anti-tuberculous drugs (isoniazid, rifampicin, pyrazinamide, ethambutol (HRZE)) and a group of HRZE and linezolid combination (HRZEL). The efficacy and safety of the 2 regimens were compared and the relationship between linezolid drug concentration and adverse reactions were analyzed. Comparisons between groups were performed using χ2 test and Mann-Whitney U test. Results: The 89 children with TBM included 53 males and 36 females with an onset age of 4.6 (1.4, 9.6) years. There were 27 cases in the HZREL group and 62 cases in the HRZE group. Before treatment, positive rate of interferon-gamma release assays (IGRA) in HRZEL group was lower than that in HRZE group (64% (16/25) vs.92% (55/60), χ2=9.82, P<0.05), but protein level of cerebrospinal fluid (CSF) was higher than that in HRZE group (1.2 (1.0, 2.0) vs.0.8 (0.4,1.4) g/L, Z=0.32, P<0.05). By the end of the intensive phase, there were no significant differences of rates of CSF improvement and etiology negativity between HRZEL group and HRZE group (both P>0.05).The 44 TBM children with high CSF protein (>1 g/L) included 25 males and 19 females with an onset age of 6.7 (3.0, 11.8) years. There were 21 cases in the HZREL group and 23 cases in the HRZE group accordingly. Before treatment, there were no significant differences of positive rate of IGRA test and CSF protein level between the 2 groups (62% (13/21) vs. 87% (20/23), 1.7 (1.1, 2.2) vs. 1.5 (1.2, 1.9) g/L, χ2=3.67, Z=0.23, both P>0.05). There were no significant differences in CSF indicators, etiology negativity or imaging remission between the two groups by the end of intensive phase (all P>0.05). Higher frequencies of granulocytopenia, gastrointestinal symptoms as well as withdrawal or change of drugs were found in HRZEL group when compared to those in HRZE group (44% (12/27) vs. 19% (12/62), 7% (2/27) vs. 0, 33% (9/27) vs. 3% (2/62), χ2=6.01, 4.70, 15.74, all P<0.05). Conclusions: The efficacy of HRZEL regimen is similar to conventional HRZE regimen in children with TBM, but with higher adverse effect. Prudentially evaluating the pros and cons of linezolid in the usage of drug-susceptible TB and carefully monitoring of linezolid associated adverse effects is suggested.

Effect of the Combined Treatment of Taoren Chengqi Decoction with Laser Photocoagulation on Diabetic Retinopathy

This study investigates the therapeutic effect of the combined treatment of Taoren Chengqi decoction with laser photocoagulation on DR. In animal experiments, A total of 18 rats were used and randomly divided into blank groups, model groups, and treatment groups. The rats in the model group and treatment group were intraperitoneally injected with 60 mg/kg streptozotocin. Moreover, the TCT group was gavaged with Tao-ren Cheng-qi decoction, while the other groups received an equivalent volume of normal saline once daily for 8 weeks. Fasting blood glucose (FBG) and serum interleukin (IL)-6 and IL-1β were determined. In the clinical trial, a total of 80 patients with DR were divided into a laser group (treated with laser photocoagulation) and a combination group (treated with laser photocoagulation+Taoren Chengqi decoction). The central macular thickness (CMT), best-corrected visual acuity (BCVA), and serum levels of high-density lipoprotein cholesterol, low-density-lipoprotein cholesterol, total cholesterol, triglycerides, glycated hemoglobin, and hypoxia-inducible factor 1α were measured in the patients. In animal experiments, we observe that Tao-ren Cheng-qi decoction can effectively reduce the levels of FBG, IL-6, and IL-1β in rats models with DR. Clinical studies revealed that the combination of Taoren Chengqi decoction with laser photocoagulation reduced the levels of blood glucose and lipid-related indices, and improved the inflammatory state, BCVA, and CMT. Therefore, this study suggests that the combined treatment of laser surgery and Taoren Chengqi decoction can be considered an optimal therapeutic approach for patients with DR.

Evaluation of the Therapeutic Effect of Preventive External Application of Traditional Chinese Medicine Gel Combined with Psychological Care in Tumor Patients with Radiation Dermatitis

Radiation dermatitis (RD) caused by radiation therapy has brought pain to patients. Therefore, we aim to investigate the efficacy of preventive external application of Traditional Chinese medicine (TCM) gel in conjunction with psychological care for the prevention of RD in patients with malignant tumors. A total of 130 patients who underwent radiotherapy in our hospital from January 2021 to December 2022 were selected as the research objects. The patients were divided into two groups based on their nursing modes: the conventional group received TCM gel treatment for Radiation Therapy Oncology Group (RTOG) grade II skin damage, while the combination group received preventive external application of TCM gel before radiotherapy along with psychological care support. The incidence of RD, quality of life, negative emotional changes, and satisfaction with nursing care were recorded and compared between the two groups. Our results demonstrated a significant reduction in the incidence of RTOG grade III–IV skin damage, an obvious improvement in patient’s quality of life and negative emotions, and a higher satisfaction in the combination group compared to the conventional group (P &lt; 0.05). In conclusion, this study suggests that the preventive external application of traditional Chinese medicine combined with psychological care during radiotherapy holds significant potential in preventing RD in patients with malignant tumors. Furthermore, it is proposed that the observed efficacy of the Chinese medicine gel in preventing radiation dermatitis may be attributed to its anti-inflammatory properties, primarily mediated by key active ingredients such as berberine and obacunone.

Clinicopathological features of kidney injury in patients receiving immune checkpoint inhibitors (ICPi) combined with anti-vascular endothelial growth factor (anti-VEGF) therapy

BackgroundImmune checkpoint inhibitor (ICPi) combined with anti-vascular endothelial growth factor (VEGF) therapy has increasingly become a promising strategy in various malignancies. However, the combination might be associated with increased risk...

The influence of monosodium glutamate on the development of oxidative-nitrosative stress in the large cerebral hemispheres of rats under the combination of a change in the “light-dark” cycle and a systemic inflammatory response

Today, the issue of the consequences of disrupting the normal “light-dark” cycle is becoming increasingly important, and the link between the development of a systemic inflammatory response (SIR) and circadian rhythm disorders has been confirmed. The effect of monosodium glutamate on the human body is being actively studied. The aim of the work was to find out the influence of monosodium glutamate on the development of oxidative-nitrosative stress in the homogenate of the large cerebral hemispheres of rats with a combination of acute desynchronosis (AD), SIR and administration of monosodium glutamate. Material and methods. The research was carried out on 72 white Wistar rats weighing 150–200 of different sexes, divided into 5 groups: control (n = 15), AD (n = 13), SIR (n = 15), a combination of SIR and AD (n = 14), a combination of SIR, AD, and glutamate (n = 15). To simulate AD, a normal “light-dark” cycle (12 hours of light, 12 hours of darkness) was formed for 3 weeks, and the next 3 days the “light-dark” phases were shifted back by 6 hours. SIR was reproduced by intraperitoneal injection of Salmonella typhi lipopolysaccharide in the first week at a dose of 0.4 μg/kg 3 times per week, the following seven weeks – once a week. Sodium glutamate was administered intragastrically for 20 days at a dose 30 mg/kg, dissolved in 0.5 ml of distilled water. In a 10 % homogenate of the large cerebral hemispheres, we determined the rate of superoxide anion radical (SAR) production, the content of products that react with thiobarbituric acid (TBA-reactants), their increase, activity of catalase, superoxide dismutase (SOD), ornithine decarboxylase (ODC), concentration of nitrites, peroxynitrites, total activity of NO-synthase (NOS), its constitutive (cNOS) and inducible (iNOS) isoforms. Results. In the group of SIR, AD and glutamate combination, compared to the control, the following was noted: an increase in the rate of basic production of SAR by 175.8 %, by the microsomal pathway by 20.0 %, by the mitochondrial pathway by 51.2 %, the concentration of TBA-reactants by 83.4 %, their increase – by 61.7 %, decrease in the activity of SOD by 57.1 %, catalase – by 38.1 %; an increase in peroxynitrite content by 116.7 %, ODC activity by 161.5 %, total NOS activity by 25.6 % and iNOS by 27.4 %, a decrease in cNOS activity by 15.0 % and nitrite concentration by 35.0 % in brain tissues. Conclusions. Sodium glutamate administration in combination with AD and SIR leads to increased oxidative-nitrosative stress, inhibition of antioxidant protection; contributes to the activation of the general activity of NO-synthase and iNOS, suppresses the activity of cNOS.

Synergistic Effect and Long-Term Efficacy of Shilong Jiedu Formula as An Adjuvant Chemotherapy in the Treatment of Diffuse Large B-Cell Lymphoma Patients

Chemotherapy is the main treatment for diffuse large B-cell lymphoma (DLBCL), but the recurrence rate in patients after standard chemotherapy is high. Moreover, there is a significant issue of drug resistance, resulting in low remission rates when retreatment is required. Thus, there is a need to improve the overall efficacy of DLBCL treatment. In order to identify an effective approach to enhance DLBCL treatment outcomes without increasing adverse reactions, this study focused on DLBCL patients who visited our hospital from January to December 2020. The study included 53 patients who received the CHOP treatment plan in the CHOP group, and another 53 patients who received adjuvant chemotherapy with Shilong Jiedu Formula in the combination group. The treatment efficacy, quality of life, changes in molecular markers, and two-year progression-free survival were recorded for all patients, and differences between the two groups were compared. The research results reveal that patients who combined Shilong Jiedu Formula with chemotherapy achieved better remission rates compared to those who only received chemotherapy. Meanwhile, patients who combined Shilong Jiedu Formula with chemotherapy experienced higher quality of life and stronger immune function after treatment, indicating significant improvements (P &lt; 0.05) in these aspects compared to patients who solely received chemotherapy. Importantly, adjuvant chemotherapy with Shilong Jiedu Formula also demonstrated a certain extent of improvement in the progression-free survival rate of DLBCL patients. Therefore, this study suggests that the Shilong Jiedu Formula, primarily consisting of Rehmanniae Radix Praeparata and Cuscutae Semen, holds high value as an adjuvant chemotherapy for the treatment of DLBCL.

Study of Banxia Xiexin Prescription Combined with Diet Nursing on Improving the Clinical Symptoms, Inflammatory Factor Levels and Prognosis of Hospitalized Patients with Peptic Ulcer

Western medicine is the first choice for the clinical treatment of peptic ulcer (PU), which can quickly improve the symptoms of patients. However, the efficacy of western medicine can be influenced by PU patients’ unhealthy lifestyle and other factors, leading to various adverse reactions during and after treatment. Therefore, it is necessary to actively find ways to increase the efficacy of PU patients without increasing adverse reactions. Traditional Chinese Medicine (TCM) treatment for PU focuses on warming and tonifying deficiencies and alleviating urgency. The medicinal composition of Banxia Xiexin Decoction is Pinellia, Scutellaria baicalensis, Zingiberis rhizoma, fried licorice, Rhizoma coptidis and jujube, etc. β-sitosterol, 6-gingerol and berberine, the active components of Pinellia, Zingiberis rhizoma and Rhizoma coptidis, have been proved to have anti-ulcer effects. In this study, a rat model of PU was established in the animal experiment, and it was found that Banxia Xiexin prescription could effectively reduce the levels of ET-1 and NO in PU rats (P &lt; 0.05). In the clinical trial, the Western Medicine convention (W-Con) group consisted of 61 PU patients who were hospitalized in our facility from 2020.01 to 2022.12 and received conventional western medicine treatment, while the Banxia combination (B-Com) group included PU patients who received Banxia xiexin decoction along with dietary care during the same period. The analysis of treatment outcomes between the two groups revealed that patients treated with Banxia Xiexin decoction combined with dietary care exhibited more significant improvements in clinical symptoms and inflammatory state compared to those relying solely on traditional western medicine (P &lt; 0.05). In addition, we found that combined diet care helped to improve the prognosis of patients (P &lt; 0.05). Therefore, this study suggests that Banxia Xiexin decoction combined with diet nursing can be used as an optimal treatment for PU patients. Banxia Xiexin decoction can effectively treat PU, which may be the main active ingredients in Banxia Xiexin decoction, such as β-sitosterol, 6-gingerol and berberine, which have anti-ulcer effects.

The Effects of Different Exercise Types on Cognitive and Physical Functions in Dementia Patients: A Randomized Comparative Study

Purpose: The physical and cognitive effects of aerobic exercise on dementia have been extensively studied. Further investigation of other types of exercise with different physiological effects is still needed. This study aimed to determine cognitive and physical effects of 6-week aerobic, balance, and combined (aerobic-balance) exercise programs on dementia. Materials and Methods: A total of 31 mild to moderate dementia patients aged 65-90 years were divided into three exercise groups. Before and after the 6-week exercise program, mental rotation, spatial orientation, visual memory, and mental status were assessed for cognitive functions, while fall risk, reaction time, lower limb strength, and frailty were assessed for physical functions. Comprehensive cognitive and physical assessments were performed to provide a holistic approach to dementia. Results: When post-exercise values were compared with pre-exercise values, only frailty decreased significantly in the aerobic exercise group (p=0.017). After exercise program in balance and combined exercise groups, mental rotation (p=0.005, p=0.032), spatial orientation (p=0.020, p=0.035), mental status (p=0.007, p=0.014), and lower extremity strength (p=0. 010, p=0.005) increased significantly, while fall risk (p=0.005, p=0.005), reaction time (p=0.028, p=0.016), and frailty (p=0.020, p=0.009) decreased significantly. Moreover, in contrast to combined and aerobic exercise, improvement in visual memory was also observed in the balance exercise group (p=0.016). Conclusions: These findings suggest that balance and combined exercises may have broader effects on dementia than aerobic exercise. It emphasizes the importance of designing exercise programs for dementia patients, considering the cognitive and physical deficits of the patients, and creating a multidimensional treatment approach.

Changes in weight among individuals with psychiatric conditions or socioeconomic disadvantage assigned to smoke very low nicotine content cigarettes.

Nicotine abstinence leads to weight gain, which could be an unintended consequence of a nicotine reduction policy. This secondary analysis used weekly assessments of weight and ratings of "increased appetite/hunger/weight gain" collected in three 12-week, randomized controlled trials evaluating the effects of cigarettes differing in nicotine dose (15.8, 2.4, or 0.4 mg/g) among individuals with affective disorders, opioid use disorder (OUD), and socioeconomically disadvantaged women. Linear mixed models tested differences by dose and time. Analyses first collapsed across populations and then separated out individuals with OUD because biomarkers suggested they used substantially more noncombusted nicotine. Across populations, weight increased significantly over time, averaging 1.03 kg (p < .001), but did not vary by dose nor was there any interaction of dose/time. "Increased appetite/hunger/weight gain" ratings increased significantly as a function of dose, with differences between low and high doses (1.95 and 1.73, respectively, p = .01), but not by time nor any interaction. In the combined group of individuals with affective disorders and socioeconomically disadvantaged women, weight and "increased appetite/hunger/weight gain" ratings increased significantly by dose, with differences between low and high doses (1.43 vs. 0.73 kg, p = .003 and 2.00 vs. 1.76, p = .02, respectively). Among individuals with OUD, there were no significant effects of any kind on either outcome. Individuals with affective disorders and socioeconomically disadvantaged women gained weight and reported more subjective appetite/weight gain when given 0.4, but not 2.4 mg/g cigarettes, despite comparable decreases in nicotine exposure. However, neither change was clinically significant, suggesting minimal short-term adverse consequences of a nicotine reduction policy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Solamargine improves the therapeutic efficacy of anti-PD-L1 in lung adenocarcinoma by inhibiting STAT1 activation

ObjectiveThe effect of solamargine on lung adenocarcinoma and its effect on STAT1 signaling pathway mediated immune escape were studied through network pharmacology and in vitro and in vivo experiments. MethodsThe solamargine targets were screened using the TCMSP and the LUAD targets were screened using the GeneCard, OMIM, PharmGkb, TTD and DrugBank databases. PPI network analysis and target prediction were performed using GO and KEGG. Colony formation assay, EDU staining, wound healing, transwell assay, Hoechst and flow cytometry were used to detect the effects of solamargine on the proliferation, migration and apoptosis of LUAD. Western blotting (WB) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect P-STAT1 and PD-L1 expression. And immunofluorescence was used to detect P-STAT1 expression. In vivo experiments, C57BL/6 mice were divided into control group, low concentration group, high concentration group, positive control group and combination group. Every other day, following seven consecutive doses, the size of the tumor was assessed. Finally, the expressions of P-STAT1, STAT1, PD-L1 and apoptosis index proteins were detected by WB. ResultsThe anti-LUAD effect of solamargine was found by wound healing, colony formation assay, transwell assay, hoechst and EdU staining. The results of network pharmacological analysis showed that solamargine could suppress STAT1 expression level. Further enrichment assay of STAT1 showed that STAT1 was associated with immune-related pathways. In addition, molecular signal analysis by WB and RT-qPCR indicated that solamargine could reduce the expression levels of P-STAT1 and PD-L1 in a concentration-dependent manner. According to the results of in vivo assays, combination of solamargine and immune checkpoint inhibitors (ICIs) durvalumab could significantly inhibit the growth of Lewis transplanted tumors in C57BL/6 mice, and no toxic side effect was recoded. ConclusionThese results indicated that solamargine could inhibit the proliferation and promote the apoptosis of LUAD. It also could reduce the expression level of P-STAT1 protein and inhibit the expression level of PD-L1. At the same time, the combination with the ICIs can better block the expression of PD-L1 in cells, thereby inhibiting the immune escape pathway of tumor cells and achieving anti-tumor effects. This study proposed a novel combined therapeutic approach, involving the inhibition of STAT1 by solamargine in conjunction with ICIs.

Abstract 4039: Enhanced anti-cancer efficacy of the AhR Inhibitor DA-4505 in combination with anti-PD-1 treatment: Attenuation of lung metastasis and elimination of tumor

Abstract Background: The Aryl hydrocarbon receptor (AhR) is one of the most predominant regulators of cancer metabolism. AhR plays a crucial role in inhibiting the activation of immune cells and promoting the growth of tumor cells. Here, we propose that a best-in-class AhR inhibitor, DA-4505, improves anti-tumor efficacy in combination with anti-PD-1. Methods: To explore the anti-tumor effects, DA-4505 was administered at a daily dose of 10 mg/kg either alone or in combination with anti-PD-1 (10 mg/kg) in a syngeneic mouse model. Tumor volume, survival rates, and metastasis were measured, and immune profiles were evaluated using mIHC, flow cytometry, and scRNAseq. Results: The synergistic anti-tumor effects of the DA-4505 and aPD-1 combination therapy were observed across four mouse tumor models (CT26, 4T1, LLC, TC1). The combination group demonstrated a significant improvement in anti-tumor efficacy compared to the monotherapy groups. Despite the moderate response of aPD-1 in the CT26 colon tumor model, the combination group displayed heightened anti-tumor effects through increase in CD8 T cell activity (P&amp;lt;0.05). In the LLC and TC1 lung cancer models, the combination therapy demonstrated improved anti-tumor effects and survival rates (P&amp;lt;0.001). Notably, the LLC model exhibited a significant increase in M1-type macrophages, while the TC1 model showed a significant augmentation in functional markers of CD3+ T cells within the combination group (P&amp;lt;0.05). In both models, there was a significant reduction in the ratio of immunosuppressive M-MDSC and PMN-MDSC in the combination group. Immune depletion assays elucidated that DA-4505 mediated anti-tumor effects by increase in CD8+ T cells, NK cells, and macrophages in the CT26 model. In contrast, the LLC model exhibited the contribution of macrophages and CD4+ T cells to anti-tumor effects in the combination group (P&amp;lt;0.05). To assess the impact on metastasis inhibition, an orthotopic model of 4T1 mouse tumor was established, revealing a significantly increased anti-tumor effects and survival rate in the combination group, accompanied by a reduced lung metastasis ratio. H&amp;E staining confirmed diminished migration of tumor tissue to adjacent areas. scRNAseq analysis of CT26 tumor samples indicated consistent changes at the gene expression level, reflecting a decrease in metastasis-related MMP and VEGF genes in the combination group and an increasing trend in cytotoxicity-related genes following DA-4505 treatment. Conclusion: The AhR inhibitor, DA-4505, has demonstrated enhanced anti-tumor efficacy when administered in combination with anti-PD-1. Furthermore, it not only promoted tumor elimination but also demonstrated significant efficacy in inhibiting metastasis. This study highlights the potential of combining AhR inhibitors with immunotherapies for clinical treatment. Citation Format: Dong Kwon Kim, Sujeong Baek, Seung Min Yang, Young Taek Kim, Joon Yeon Hwang, Seul Lee, Seong-san Kang, Mi hyun Kim, Heekyung Han, Kwangmin Na, Chai Young Lee, Yu Jin Han, Taedong Han, Hyounmie Doh, Jongho Cho, Dajeong Kim, Daewon Cha, Jae Hwan Kim, Youngseon Byeon, Young Seob Kim, Mi Ran Yun, Jii Bum Lee, Min Hee Hong, Sun Min Lim, Kyoung-Ho Pyo, Byoung Chul Cho. Enhanced anti-cancer efficacy of the AhR Inhibitor DA-4505 in combination with anti-PD-1 treatment: Attenuation of lung metastasis and elimination of tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4039.

Abstract 4038: TU2218 (TGFβRI/VEGFR2 dual inhibitor) maximizes the benefit of cancer immunotherapies

Abstract Approved anti-PD-1 antibodies play a pivotal role in driving innovative clinical outcomes through combination with cytotoxic agents, targeted therapies, or other immune checkpoint inhibitors in various cancers. Anti-PD-1 antibody-based combination therapies have led to a paradigm shift in cancer treatment from cytotoxic agents or targeted therapy to immunotherapy. Considering this change in the regimen, the clinical development of TU2218 aims to accelerate approval and clinical application by improving the efficacy and safety of clinically proven combination therapies. TU2218 is characterized by the following four mechanisms of action: 1) improvement of T lymphocyte activity, 2) suppression of Treg, 3) improvement of costimulatory signal defects, and 4) overcoming endothelial cell anergy. Based on the mechanisms of action, TU2218 is expected to show significant clinical effects when combined with immune checkpoint inhibitors by lowering the intensity of immune evasion and changing more favorably to immune checkpoint inhibitors. To test the feasibility of various combination options based on TU2218, in vivo efficacy studies were conducted in 4T1, MC38, and CT26 syngeneic tumor models. In the 4T1 of TNBC type, a level of tumor reduction was significant to p&amp;lt;0.001 on TU2218 and anti-PD-1 antibody combination group compared to vehicle, whereas anti-PD-1 antibody alone or anti-PD-1 antibody and paclitaxel combination group was not significant. Combination therapy with anti-CTLA4 antibody and anti-PD-1 antibody has been approved for some cancers but has therapeutic limitations due to safety issues such as immune-related toxicity and needs improvement. In the MC38, the effectiveness of a dose-sparing strategy of anti-CTLA4 antibody was evaluated by adding TU2218 to the anti-CTLA4 antibody and anti-PD-1 antibody combination regimen to improve safety concerns. In the anti-CTLA4 antibody sparing group, co-administration of TU2218 maintained the anti-tumor activity despite reducing 90% or 60% of the original anti-CTLA4 antibody dose. In effect, the difference in anti-tumor activity between the group with a reduced dose of anti-CTLA4 antibody and the group without was not statistically significant. In CT26, the efficacy of Lenvatinib and anti-PD-1 antibody combination therapy was compared with the combination of Lenvatinib, anti-PD-1 antibody, and TU2218. The efficacy of the Lenvatinib anti-PD-1 antibody, and TU2218 combination group was superior to that of TGI 99% and CR 67% than the Lenvatinib and anti-PD-1 antibody combination group of TGI 76% and CR 17%. Moreover, a statistical difference in anti-tumor activity between the two groups was significant at p&amp;lt;0.001. Collectively, the combination therapies using TU2218 not only improved efficacy but also showed high safety profiles without weight loss or any toxicity signs, supporting the feasibility of the combination strategy of TU2218. Citation Format: Jihyun Lee, Nam-Hoon Kim, Jeong Su Park, Jihyun Noh, Sowon Bae, Hun-Taek Kim. TU2218 (TGFβRI/VEGFR2 dual inhibitor) maximizes the benefit of cancer immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4038.

Abstract 3263: VEGFA mediates traditional EGFR-TKI resistance in non-small cell lung cancer with EGFR exon 20 insertions

Abstract Background: Epidermal growth factor receptor (EGFR) exon 20 insertions (Ex20ins) accounted for 4%-12% of EGFR mutations and showed primary resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) which is an urgent issue to be solved. In our previous studies, we found that antiangiogenetic therapy had certain advantages for patients with Ex20ins in the real-world practice. Previous research showed the tumor microenvironment has been associated with resistance to targeted therapy in sensitive mutations. However, the mechanism of resistance of EGFR-TKIs and the advantage of antiangiogenetic therapy in patients with EGFR Ex20ins were still unclear. Methods: In this study, patients with EGFR exon 19 deletion (19del), exon 21 p.L858R (21L858R), and Ex20ins were collected to identify the efficacy of EGFR-TKIs. Stable cell lines expressing were established and used to compare signaling pathway activation. Matrigel angiogenesis assay was conducted in different cell lines. Next, we evaluated the efficacy of various treatments combined with antiangiogenetic agents or not in mouse models. Results: We collected 23 patients with EGFR sensitive mutations and Ex20ins, respectively, and found Ex20ins presented primary resistance to TKIs and poor survival outcomes. Based on the RNA sequence of stable cell lines, it was found that Ex20ins had a higher level of VEGFA expression and enriched in MAPK pathway compared to EGFR 19del and 21L858R. Immunohistochemical studies also revealed that a higher level of VEGFA expression was observed in a cohort of NSCLC patients with Ex20ins mutation compared with 19del or L858R. Matrigel angiogenesis assay has shown consistent result that Ex20ins promoted angiogenesis in vivo. Further experiments in mouse models identified that in the group of Osimertinib, mobocertinib alone, chemotherapy alone, mobocertinib or chemotherapy combination with bevacizumab, Osimertinib achieved the worst efficacy and additional utility of antiangiogenetic agents had a more favorable efficacy. Conclusion: Our study highlights the potential of VEGFA as a mechanism of resistance to EGFR-TKIs and induces immunosuppression microenvironment in NSCLC with Ex20ins. Furthermore, the findings suggested that antiangiogenetic therapy could be a promising therapeutic approach. Keywords: VEGFA, targeted therapy, resistance, EGFR exon 20 insertions, non-small cell lung cancer Citation Format: Yaning Yang, Chengming Liu, Guangjian Yang, Haiyan Xu, Siyu Lei, Yan Wang. VEGFA mediates traditional EGFR-TKI resistance in non-small cell lung cancer with EGFR exon 20 insertions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3263.

Abstract 6698: Tumor microbiota associated with immune enrichment in breast tumor

Abstract Asian cancer patients have enriched immune profiles when compared to Caucasians. This is associated with improved overall survival and potentially better response to immunotherapy. Yet the reason behind enriched Asian immune profiles is unclear. This study investigated microbes found in Malaysian breast tumors in association with immune profiles. We used an existing dataset of RNA-seq data from fresh frozen breast tumor tissue (n=978). Sequencing reads were trimmed and filtered to remove human reads. Non-human reads were mapped to Kraken2 and relative abundance was estimated using Bracken. Microbiome analysis was conducted on R following Microbiome OMA guidebook. The top five genera found in the Malaysian Breast Cancer (MyBrCa) cohort were Pseudomonas, Siphoviridae, Bacillus, Escherichia and Klebsiella. Alpha diversity of basal subtype microbiota was significantly higher than Her2 subtype (Shannon index, p=0.027) whilst the other subtypes were more homogenous. MyBrCa patients with low immune scores were significantly different from high immune scores while controlling for age, stage, grade, ethnicity and PAM50 subtype (PERMANOVA, F-statistic = 1.656, p=0.05). Differential abundance analysis revealed Sulfidibacter and Priestia to be significantly different in abundance between high vs low IFNg groups (FDR-adjusted p-value &amp;lt; 0.05) using ALDEx2, ANCOM-BC2 and ZicoSeq and LinDA algorithms. Sulfidibacter was significantly different between high vs low immune group for Bindea combined immune score and ESTIMATE score groups (FDR-adjusted p-value &amp;lt;0.05). An independent breast cancer cohort (n=419) was used as validation where Sulfidibacter and Priestia were also significantly different in abundance for immune high vs low groups. Machine learning using Random Forest model predicted immune group with an AUC of 0.79 (CI = 0.74, 0.83; p-value &amp;lt; 0.01). The top five most important features contributing to the random forest model were Sulfidibacter, Prestia, Cutibacterium, Acinetobacter and Rhizobium. This study is the largest to date that characterize the tumor microbiota of an Asian cohort of breast cancers, where Sulfidibacter and Priestia, both relatively new and uncharacterized bacteria, were differentially abundant among patients with high vs low immune scores. Citation Format: Li-Fang Yeo, Bernard KB Lim, Tania Islam, Li-Ying Teoh, Suniza Jamaris, Mee-Hoong See, Lai-Meng Looi, Nur Aishah Mohd Taib, Cheng-Har Yip, Pathmanathan Rajadurai, Soo-Hwang Teo, Jia Wern Pan. Tumor microbiota associated with immune enrichment in breast tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6698.

Effects of mindful breathing training combined with diary-based rehabilitation guidance in lung cancer patients undergoing surgery: A randomized controlled trial

Background and purposeLung cancer surgery patients experience severe physical and mental symptoms, which seriously affect their quality of life and prognosis. Mindful breathing training is a promising strategy to improve their symptoms, but its effectiveness is affected by training compliance, and diary-based rehabilitation instruction has been shown to help improve training compliance. Therefore, the aim of this study was to evaluate the effects of mindful breathing training combined with diary-based rehabilitation guidance on improving perioperative outcomes in lung cancer surgery patients. Materials and methodsThis single-center, assessor-blinded, prospective, three-arm randomized controlled trial was conducted from November 1, 2021 to November 1, 2022. Patients diagnosed with primary non-small cell lung cancer and scheduled for thoracoscopic surgery were randomly allocated to the combined intervention group, the mindful breathing group or the control group, with 34 patients in each group. The control group received routine care, while the mindful breathing group received mindful breathing training and routine care. The combined intervention group received both mindful breathing training and diary-based rehabilitation guidance, along with routine care. ResultsThe per-protocol analysis revealed that patients in the mindful breathing group experienced statistically significant improvements in dyspnea, fatigue and anxiety. Patients in the combined intervention group had statistically significant improvements in dyspnea, fatigue, anxiety, depression, exercise self-efficacy and training compliance. ConclusionThis study provides evidence that mindful breathing training combined with diary-based rehabilitation guidance can be effective in improving perioperative outcomes in lung cancer patients. It can be applied in clinical practice in the future.

Anlotinib plus docetaxel vs. docetaxel alone for advanced non-small-cell lung cancer patients who failed first-line treatment: A multicenter, randomized phase II trial

ObjectivesGiven the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in combination with docetaxel compared to docetaxel monotherapy as a second-line therapy for patients with advanced NSCLC. Materials and MethodsIn this phase II study, patients with advanced NSCLC experiencing failure with first-line platinum-based regimens were randomized in a 1:1 ratio to receive either anlotinib plus docetaxel or docetaxel alone. Primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints. ResultsA total of 83 patients were randomized. The combination of anlotinib and docetaxel significantly extended median PFS to 4.4 months compared to 1.6 months for docetaxel alone (hazard ratio [HR] = 0.38, 95 % confidence interval [CI]: 0.23–0.63, P = 0.0002), and also demonstrated superior ORR (32.5 % vs. 9.3 %, P = 0.0089) and DCR (87.5 % vs. 53.5 %, P = 0.0007). Median OS was observed at 12.0 months in the combination group vs. 10.9 months in the monotherapy group (HR = 0.82, 95 % CI: 0.47–1.43, P = 0.4803). For patients previously treated with immunotherapy, the median PFS was notably longer at 7.8 vs. 1.7 months (HR = 0.22, 95 % CI: 0.09–0.51, P = 0.0290). The incidence of grade ≥ 3 treatment-related adverse events, predominantly leukopenia (15.0 % vs. 7.0 %) and neutropenia (10.0 % vs. 5.0 %), was manageable across both groups. ConclusionAnlotinib plus docetaxel offers a viable therapeutic alternative for patients with advanced NSCLC who failed first-line platinum-based treatments.

Mid-term surgical success after transscleral ab interno glaucoma gel stent implantation.

To investigate the surgical success and efficacy of XEN45 implantation (XEN45 μm, AbbVie Inc., USA) with and without combined cataract surgery up to the first 5 years. In a prospective observational monocentric trial, 192 eyes of 157 patients with open-angle glaucoma received either XEN45 implants only (solo surgery group) or combined surgery/cataract surgeries (combined surgery group). Surgical success (qualified and full success; IOP-limit: ≤12, 15, 18, 21 mmHg), time to secondary IOP-lowering procedure, IOP and number of IOP-lowering medications were analysed for 1, 2, 3, 4 and 5 years. Compared to baseline, IOP (24.1 ± 8.1 to 12.6 ± 2.8 mmHg, -48%, p < 0.001) and the number of IOP-lowering medications (3.0 ± 1.0 to 1.5 ± 1.2, -50%, p < 0.001) decreased significantly at 5 years. Although no differences between IOP and the number of IOP-lowering medication courses between the groups were detected at 5 years (p > 0.11), the combined procedure (63%, 37%) showed better success rates compared to the solo procedure (36%, 13%) in the definition IOP ≤18 and ≤12 mmHg (p = 0.035, 0.028). Solo XEN45 procedures had a higher rate of secondary IOP-lowering procedures compared to combined XEN45 cataract procedures (hazard ratio: 2.02, 95%CI: 1.03-3.97, p = 0.04). Twenty per cent of the eyes, including both procedures, required a secondary IOP-lowering procedure within 5 years. The XEN45 implant is effective in lowering IOP and the number of IOP-lowering medications in patients with open-angle glaucoma in the mid-term. Comparing XEN45 implant results with the results of trabeculectomy available in current literature, we speculate that there might be a higher surgical success rate without medications in favour of trabeculectomy.

Effect and mechanism of acupuncture on airway smooth muscle relaxation during acute asthma attack in rats.

To explore the effect and mechanism of acupuncture at "Feishu" (BL 13) and "Dingchuan" (EX-B 1), and "Kongzui" (LU 6) and "Yuji" (LU 10) for relaxing the airway smooth muscle in the rats during acute asthma attack and compare the effect among the two pairs of acupoints and the acupoints combination. Forty SD male rats with SPF grade were randomly divided into a blank group, a model group, a pair-point A group (acupuncture at "Feishu" [BL 13] and "Dingchuan" [EX-B 1]), a pair-point B group (acupuncture at "Kongzui" [LU 6] and "Yuji" [LU 10]) and a point combination group (acupuncture at "Feishu" [BL 13] , "Dingchuan" [EX-B 1], "Kongzui" [LU 6] and "Yuji" [LU 10]), with 8 rats in each group. Except the rats in the blank group, the model of acute asthma attack was induced by ovalbumin (OVA) combined with aluminum hydroxide gel in the rest groups. Started on the 15th day of modeling, except in the blank group and the model group, acupuncture was delivered in the other groups, 30 min in each intervention, once daily, for 14 days. In each group, the latent period of asthma inducing was measured; the lung resistance (LR) and dynamic lung compliance (Cdyn) were determined using lung function detector; the levels of endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in serum and bronchoalveolar lavage fluid (BALF) were measured by ELISA; with Masson staining and electron microscopy adopted, the morphology and ultrastructure of airway smooth muscle of the rats were observed; the mRNA and protein expressions of ET-1 and beta-2 adrenergic receptor (β2-AR) were detected by quantitative real-time fluorescence and Western blot, respectively. Compared with the blank group, the latent period of asthma inducing was shortened (P<0.05), RL increased and Cdyn decreased (P<0.05) with the different concentrations of methacholine (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg) in the model group. In the pair-point A group, the pair-point B group and the point combination group, the latent period of asthma inducing was prolonged (P<0.05), RL decreased and Cdyn increased (P<0.05) with different concentrations of methacholine when compared with those in the model group; and the latent period of asthma inducing in the point combination group was longer than that in the pair-point A group (P<0.05). Compared with the blank group, the levels of ET-1, TNF-α and cGMP in the serum and BALF were elevated (P<0.05), and those of cAMP reduced (P<0.05) in the model group. The levels of ET-1, TNF-α and cGMP in the serum and BALF were reduced (P<0.05), and those of cAMP elevated (P<0.05) in the pair-point A group, the pair-point B group and the point combination group when compared with those in the model group. In the blank group, the lung tissue was normal structurally. In the model group, the collagen fibers were proliferated increasingly, the smooth muscle was thickened, the mitochondria were swollen, and their cristae disrupted and reduced massively. In the pair-point B group, the collagen fibers were proliferated, the smooth muscle was thicker compared with that in the blank group, the mitochondria were mildly swollen and their cristae disrupted partially. In the pair-point A group and the point combination group, the lung tissue changes were obviously alleviated in comparison with the model group, the mitochondria were slightly swollen and their cristae disrupted occasionally. Compared with the blank group, the mRNA and protein expression of ET-1 increased and that of β2-AR decreased in the lung tissue of the model group (P<0.05). In the pair-point A group, the pair-point B group and the point combination group, the mRNA and protein expression of ET-1 was reduced and that of β2-AR elevated in the lung tissue when compared with those in the model group (P<0.05). In comparison with the pair-point A group, the mRNA expression of β2-AR was elevated in the point combination group (P<0.05). When compared with the pair-point B group, the mRNA expression of β2-AR increased, the protein expression of ET-1 decreased (P<0.05) in the point combination group. Acupuncture at "Feishu" (BL 13) and "Dingchuan" (EX-B 1), "Kongzui" (LU 6) and "Yuji" (LU 10), two pairs of acupoints relieves the airway smooth muscle spasm in the rats during acute asthma attack, which may be related to inhibiting the mRNA and protein expression of ET-1 to reduce the excretion of ET-1 and TNF-α; while enhancing the mRNA and protein expression of β2-AR to balance the levels of cAMP and cGMP. The effect is optimal when acupuncture is delivered at two pairs of acupoints simultaneously.