OncoVee™-MiniPDX-guided anticancer treatment for HER2-negative intermediate-advanced gastric cancer patients: a single-arm, open-label phase I clinical study.

BACKGROUND: Chemotherapy is the main treatment strategy for patients with advanced HER2-negative gastric cancer (GC); yet, many patients do not respond well to treatment. This study evaluated the sensitivity of a mini patient-derived xenograft (MiniPDX) animal model in patients with HER2-negative intermediate-advanced GC. METHODS: In this single-arm, open-label clinical study, we consecutively recruited patients with HER2-negative advanced or recurrent GC from September 2018 to July 2021. Tumor tissues were subjected to MiniPDX drug sensitivity tests for screening individualized anti-tumor drugs; appropriate drug types or combinations were selected based on drug screening results. The primary endpoints were progression-free survival (PFS) and safety, and the secondary endpoints were overall survival (OS) and objective response rate (ORR). RESULTS: A total of 17 patients were screened, and 14 eligible patients were included.The median follow-up time was 9 (2-34) months. The median PFS time was 14.1 (2-34) months, the median OS time was 16.9 (2-34) months, ORR was 42.9% (6/14), and DCR was 92.9% (13/14). The most common treatment-related adverse events (TRAE) were fatigue (14 (100%)), anorexia (13 (93%)) and insomnia (12 (86%)), and the most common grade 3 or worse TRAE was fatigue (6 (43%)), and anorexia (6 (43%)). The occurrence rate of myelosuppression, nausea and vomiting, abnormal liver enzymes, and other grade 3-4 chemotherapy adverse reactions were relatively low, and no grade 5 treatment-related adverse events occurred. CONCLUSION: Screening HER2-negative medium-advanced GC/GJC chemotherapy regimens and targeted drugs based on MiniPDX animal models showed good tumor activity and safety.

Macrophage-specific autophagy-related gene HSPB8 is involved in the macrophage polarization in atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is a chronic inflammatory disease, as a main cause leading to vascular diseases worldwide. Although increasing studies have focused on macrophages in AS, the exact relating mechanism is still largely unclear. Our study aimed to explore the pathogenic role and diagnostic role of macrophage autophagy related genes (MARGs) in AS. METHODS: All datasets were downloaded from Gene Expression Omnibus database and Human Autophagy Database. The differential expression analysis and cross analysis were performed to identify candidate MARGs. GO and KEGG enrichment analyses were conducted to obtain the functional information. Moreover, we analyzed the correlation between target gene and macrophage polarization in AS. The correlation between target gene and plaque instability, different stages of AS were also analyzed. RESULTS: Compared with normal samples, a total of 575 differentially expressed genes (DEGs) were identified in AS samples. A total of 12 overlapped genes were obtained after cross-analysis of the above 575 DEGs and autophagy related genes (ARGs). Then, 10 MARGs were identified in AS samples, which were significantly enriched in 22 KEGG pathways and 61 GO terms. The expression of HSPB8 was significantly down-regulated in atherosclerotic samples compared with normal samples (with largest fold change). Meanwhile, the proportion of M-CSF in low HSPB8 expression AS group was higher than high expression AS group. Furthermore, the expression of HSPB8 was negatively correlated with most inflammatory factors. CONCLUSION: The downregulation of MARG HSPB8 probably involves in the M2 macrophage polarization in AS samples. HSPB8 is a promising diagnostic marker for AS patients.

Retrospective cohort study on the correlation analysis among peri-procedural factors, complications, and local tumor progression of lung tumors treated with CT-guided microwave ablation.

Background: Despite adherence to guidelines, recurrence of lesions remains possible in lung tumor microwave ablation (MWA) even when termination is enabled by 5-10 mm ground glass changes. Limited evidence exists regarding the correlation between timely management of perioperative complications (including pneumothorax, pleural effusion, hemorrhage, cavity formation, and infection) and local tumor progression. This retrospective study aimed to investigate the relationship among peri-procedural factors, complications, and local tumor progression in 164 cases of lung tumors treated with computed tomography-guided MWA (CT-MWA), and improve the local prognosis and reduce the complication rate of CT-guided lung tumor ablation. Methods: We reviewed 164 consecutive patients who underwent CT-MWA at Fudan University Shanghai Cancer Center's Minimally Invasive Therapy Center for lung cancer from September 2019 to May 2020. Correlative analysis was performed between peri-procedural factors, complications and outcomes (local tumor progression rates). Patients who have had prior surgery or previous MWA were excluded. Ablation was the first treatment of choice, and all patients who have had other treatments were excluded. Patients were followed every 3 months with CT. Outcomes of ablation including complications and local tumor progression were evaluated. Peri-procedural factors included demographical factors, tumor features, ablation parameters, management of intra-procedural pneumothorax, and CT features. Complications included pneumothorax, post-procedural refractory infection, and pleural effusion. Results: The study included 98 males and 68 females, with an average age of 56.1 years. Local tumor progression rate was negatively correlated with intra-procedural management of pneumothorax (R=-0.550, P=0.0003) and Hounsfield unit (HU) difference between HU before and after procedure (R=-0.855, P=0.006), and positively correlated with the average HU value of immediate post-procedural CT at the measurement points (R=0.857, P=0.00002). The correlation analysis results also showed a positive correlation between infection after procedure and pneumothorax (R=0.340, P=0.0001). Conclusions: A greater difference between HU before and after the procedure or a decrease in CT values immediately after ablation may predict a higher rate of local complete ablation. Prompt management of intraoperative pneumothorax may lower local tumor progression rates and decrease incidence of post-procedural infection.

Individualized therapy based on the combination of mini-PDX and NGS for a patient with metastatic AFP-producing and HER-2 amplified gastric cancer.

Mini-patient-derived xenograft (mini-PDX) is a novel, rapid and accurate method used to assess in vivo drug susceptibility. In the present study, a mini-PDX combined with next-generation sequencing (NGS) was used to guide the individualized treatment of a patient with metastatic a-fetoprotein-producing and human epidermal growth factor receptor 2 (HER-2) amplified gastric cancer (GC). Tumor cells were isolated from the tumor tissue obtained from gastroscopic biopsy, transferred into capsules and implanted into severe combined immunodeficiency mice to determine their sensitivity to various drug regimens. NGS was also performed to assess the mutation spectrum of the cells. The results were analyzed to select the most appropriate treatment regimen for the patient. The mini-PDX model confirmed that the patient's tumor was sensitive to a combination regimen of irinotecan and tegafur-gimeracil-oteracil (S-1). Fluorescence in situ hybridization assay of the tumor tissue confirmed HER-2 amplification. The NGS results indicated ERBB2 amplification, and tumor protein P53 [c.659A>G (p.Y220C)], ataxia-telengiectasia mutated [c.125A>G (p.H42R)] and MutS homolog 6 [c.3254C(8>7) (p.F1088Sfs*2)] mutation, in which UGT1A1*28, TA6/7 (rs8175347) was a mutant heterozygote. After six courses of treatment with a regimen comprising 300 mg irinotecan on day 1 + 40 mg S-1 twice daily on days 2-15 + 350 mg trastuzumab once-every 3 weeks, the patient continued with S-1 treatment for 4 courses and trastuzumab for 1 year. The patient retained progression-free survival status at the 32-month follow-up. Thus, the mini-PDX model combined with the NGS rapidly assessed drug sensitivity in a patient with GC and revealed key genetic mutations. However, the proposed technique requires further research to confirm its potential in the individualized treatment of patients with refractory malignancies.

Efficacy of bivalent CEACAM6/4-1BBL genetic vaccine combined with anti-PD1 antibody in MC38 tumor model of mice.

We used mouse CRC cell line (MC38) to establish a heterotopic mouse model, and applied [89Zr]-labeled PD-L1 antibody KN035 for PET imaging. Attenuated Salmonella typhimurium 3261 was used as an anti-tumor vaccine, and the combined anti-tumor immunotherapy with bivalent genetic vaccine and anti-PD1 antibody Nivolumab was conducted. MicroPET was performed to observe the changes of tumor tissues and expression of PD-L1. We found that the recombinant double-gene plasmids were stably expressed in COS7 cells. Study results showed the combined immunotherapy improved the effectiveness over genetic vaccine alone. This study supports that combination of genetic vaccines and anti-immunocheckpoint immunotherapy can inhibit MC38 tumor growth.

Corrigendum: Potential Mechanisms of Action of Chinese Patent Medicines for COVID-19: A Review.

[This corrects the article DOI: 10.3389/fphar.2021.668407.].

Potential Mechanisms of Action of Chinese Patent Medicines for COVID-19: A Review.

Coronavirus disease 2019 (COVID-19) is an emergent infectious pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is highly contagious and pathogenic. COVID-19 has rapidly swept across the world since it was first discovered in December 2019 and has drawn significant attention worldwide. During the early stages of the outbreak in China, traditional Chinese medicines (TCMs) were involved in the whole treatment process. As an indispensable part of TCM, Chinese patent medicines (CPMs) played an irreplaceable role in the prevention and treatment of this epidemic. Their use has achieved remarkable therapeutic efficacy during the period of medical observation and clinical treatment of mild, moderate, severe, and critical cases and during convalescence. In order to better propagate and make full use of the benefits of TCM in the treatment of COVID-19, this review will summarize the potential target of SARS-CoV-2 as well as the theoretical basis and clinical efficacy of recommended 22 CPMs by the National Health Commission and the Administration of TCM and local provinces or cities in the treatment of COVID-19. Additionally, the study will further analyze the drug composition, potential active ingredients, potential targets, regulated signaling pathways, and possible mechanisms for COVID-19 through anti-inflammatory and immunoregulation, antiviral, improve lung injury, antipyretic and organ protection to provide meaningful information about the clinical application of CPMs.

Effects of WD­3 on tumor growth and the expression of integrin αvß3 and ERK1/2 in mice bearing human gastric cancer using the 18F­RGD PET/CT imaging system.

Activation of the vitronectin receptor αvß3 and the phosphorylation of extracellular signal­regulated kinase (ERK)1/2 are critical events during tumor development and progression. The aim of the present study was to investigate the effects of WD­3, a formula used in traditional Chinese medicine, on integrin αvß3 and ERK1/2 expression in vivo using a nude mouse­human gastric cancer xenograft model combined with non­invasive, real­time 18F­Arg­Gly­Asp (RGD) positron emission tomography (PET)/computerized tomography (CT) imaging methods. SGC­7901 human gastric cancer cells were subcutaneously injected into BALB/c nude mice. Following tumor development, animals were randomly assigned into the following 4 groups (n=6 mice/group): Control group (CG), Chinese medicine group (CMG), Western medicine group (WMG) and Chinese and Western medicine combination group (CMG + WMG). Mice in the CG and CMG received daily intragastric injections of 0.5 ml saline and 0.5 ml WD­3, respectively. Mice in the WMG received an intravenous injection of albumin­bound paclitaxel (25 mg/kg) on days 0, 2 and 4 Mice in the CMG + WMG received combination therapy of WD­3 and albumin­bound paclitaxel. Tumor growth was monitored using standard caliper technique and via PET imaging. 18F­RGD PET/CT analysis was performed on days 3, 7, 18 and 24 following drug administration. Radioactivity uptake was measured and expressed as the percentage of injected dose (ID) per tissue weight (%ID/g) ​​ and the standardized uptake value (SUV). Animals were sacrificed at 30 days following treatment and tumor weight was measured. Immunohistochemistry was used to detect the expression of phosphorylated (p)­ERK1/2 protein in tumor tissue samples. No statistically significant differences were observed in %ID/g and SUV among the various groups prior to treatment. At the end of treatment, mice in the CMG, WMG and CMG + WMG exhibited significantly reduced tumor mass when compared with mice in the CG. In addition, mice in the CMG and CMG + WMG demonstrated reduced %ID/g and SUV when compared with mice in the CG. Conversely, mice in the WMG exhibited no significant difference in %ID/g and SUV compared with the CG. Furthermore, p­ERK1/2 expression was significantly reduced in mice from all treatment groups when compared with those in the CG. The results of the present study suggest that the traditional Chinese formula WD­3 may inhibit gastric tumor growth, potentially via the downregulation of integrin αvß3 and the inhibition of ERK1/2 phosphorylation in vivo.

Recombinant Salmonella-based CEACAM6 and 4-1BBL vaccine enhances T-cell immunity and inhibits the development of colorectal cancer in rats: In vivo effects of vaccine containing 4-1BBL and CEACAM6.

The present study aimed to determine the effect of recombinant Salmonella (SL3261)-based CEACAM6 and 4-1BB ligand (4-1BBL) vaccine on the development of colorectal cancer in rats and the potential immune mechanisms involved. Attenuated Salmonella typhimurium (vaccine strain)­carrying plasmids pIRES-CEACAM6, pIRES­4­1BBL and pIRES-CEACAM6-4-1BBL were constructed. The rats were administered subcutaneous injections of 1,2-dimethyl-hydrazine (DMH) once a week for 18 weeks. Eight weeks after the first injection, the rats were divided into the pIRES/SL3261, pIRES-4-1BBL/SL3261, pIRES-CEACAM6/SL3261 and pIRES-CEACAM6-4-1BBL/SL3261 groups, and fed with corresponding vaccine strains. The rats were then sacrificed, the number of colon tumors were recorded, and the Dukes' stage were evaluated. CD3, CD4, CD8, CD56, FOXP3 and CEACAM6 expression in tumor tissues was determined by immunohistochemical staining. Compared with the expression levels in the pIRES/SL3261 group, similar levels of CD3+, CD8+ and CD56+ expression were identified for the pIRES-CEACAM6/SL3261 group of rats. Additionally, a comparable number of tumors was detected in the pIRES-4-1BBL/SL3261 and pIRES-CEACAM6/SL3261 groups. By contrast, a significantly fewer number of tumors, albeit with a higher density of CD3+CD8+, CD56+ and a lower density of Foxp3+ tumor-infiltrating lymphocyte (TIL) cells was detected in the pIRES-CEACAM6-4-1BBL/SL3261 group of rats. The results indicated that vaccination with recombinant attenuated Salmonella harboring the CEACAM6 and 4-1BBL gene efficiently increased the number of CD3+CD8+ TIL and NK cells, decreased the number of FOXP3 cells and inhibited the development of DMH-induced colorectal cancer in rats.