Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics.

BACKGROUND: Gastric Cancer (GC) characteristically exhibits heterogeneous responses to treatment, particularly in relation to immuno plus chemo therapy, necessitating a precision medicine approach. This study is centered around delineating the cellular and molecular underpinnings of drug resistance in this context. METHODS: We undertook a comprehensive multi-omics exploration of postoperative tissues from GC patients undergoing the chemo and immuno-treatment regimen. Concurrently, an image deep learning model was developed to predict treatment responsiveness. RESULTS: Our initial findings associate apical membrane cells with resistance to fluorouracil and oxaliplatin, critical constituents of the therapy. Further investigation into this cell population shed light on substantial interactions with resident macrophages, underscoring the role of intercellular communication in shaping treatment resistance. Subsequent ligand-receptor analysis unveiled specific molecular dialogues, most notably TGFB1-HSPB1 and LTF-S100A14, offering insights into potential signaling pathways implicated in resistance. Our SVM model, incorporating these multi-omics and spatial data, demonstrated significant predictive power, with AUC values of 0.93 and 0.84 in the exploration and validation cohorts respectively. Hence, our results underscore the utility of multi-omics and spatial data in modeling treatment response. CONCLUSION: Our integrative approach, amalgamating mIHC assays, feature extraction, and machine learning, successfully unraveled the complex cellular interplay underlying drug resistance. This robust predictive model may serve as a valuable tool for personalizing therapeutic strategies and enhancing treatment outcomes in gastric cancer.

Anti-PD-1/Her2 Bispecific Antibody IBI315 Enhances the Treatment Effect of Her2-Positive Gastric Cancer through Gasdermin B-Cleavage Induced Pyroptosis.

The majority of patients with human epidermal growth factor receptor 2 (Her2)-positive gastric cancer develop refractory to Her2-targeted therapy, where upregulation of immune checkpoints plays an essential role. Herein, a recombinant fully human IgG1 bispecific antibody IBI315 targeting both PD-1 and Her2 is developed  and its antitumor efficacy as well as the underlying mechanism is investigated. IBI315 crosslinks the physical interaction between Her2-positive tumor cells and PD-1-positive T cells, resulting in significantly enhanced antitumor effects compared to each parent antibody or their combination, both in vitro and in vivo mouse tumor models reconstituted with human immune cells using patient-derived xenografts and organoids. Moreover, IBI315 treatment also induces the recruitment and activation of immune cells in tumors. Mechanistically, IBI315 triggers gasdermin B (GSDMB)-mediated pyroptosis in tumor cells, leading to the activation and recruiments of T cells. The activated T cells secret IFNγ, enhancing GSDMB expression and establishing a positive feedback loop of T cell activation and tumor cell killing. Notably, GSDMB is found to be elevated in Her2-positive gastric cancer cells, providing a rationale for IBI315's efficacy. IBI315 is supported here as a promising bispecific antibody-based immunotherapy approach for Her2-positive gastric cancer in preclinical studies, broadening the therapeutic landscape of this patient population.

Heterotopic pancreas in Meckel's diverticulum in an adult man with lower gastrointestinal bleeding: a case report and literature review.

Background: Meckel's diverticulum is a blind-end true diverticulum that contains all of the layers, which is normally found in the ileum. Prevalence of Meckel's diverticulum is around 2% in the general population, and even rare among adults. Gastrointestinal (GI) bleeding is a common complication of Meckel's diverticulum in children and in most cases, caused by peptic ulceration, due to ectopic gastric mucosa, while in minority cases, pancreatic tissue would also appear consisting around 6% of all Meckel's diverticulum patients. Case Description: Herein, we reported a 45-year-old man presented with recurrent hematochezia for over one-month without other remarkable symptoms or past medical history or signs on physical examination. Laboratory examinations showed hemoglobin of 114 g/L and ++++ in stool occult blood test without red blood cell. Contrasted abdominopelvic computerized tomography (CT) were normal and Meckel's electroconvulsive therapy (ECT) for identification was also negative. Considering gastroscopy and colonoscopy were both unremarkable in local hospital, double balloon enteroscopy was adopted and revealed double duct sign at about 100 cm proximal to the ileocecal valve and thus indicated existence of diverticulum. Further, ulceration was found at the far-end bottom of the blind-ending tube. The patient then underwent laparoscopic resection of Meckel's diverticulum and pathology study showed heterotopic pancreas in Meckel's diverticulum. The patient started feeding two days after surgery and was discharged on regular out-patient follow-up two weeks later. Till now, no reappear of hematochezia episode was observed. Conclusions: Heterotopic pancreas in Meckel's diverticulum is relative rare clinical condition in adult which can cause recurrent lower GI bleeding. Thus, special attention should be paid in cases with unexplained lower GI bleeding in adult.

Patient-derived xenograft models for gastrointestinal tumors: A single-center retrospective study.

Background: Patient-derived xenograft (PDX) models have shown a great efficiency in preclinical and translational applications. Gastrointestinal (GI) tumors have a strong heterogeneity, and the engraftment rate of PDX models remarkably vary. However, the clinicopathological and molecular characteristics affecting the engraftment rate still remain elusive. Methods: A total of 312 fresh tumor tissue samples from patients with GI cancer were implanted into immunodeficient mice. The median follow-up time of patients was 37 months. Patients' characteristics were compared in terms of PDX growth and overall survival. PDX models of 3-6 generations were used for drug evaluation. Results: In total, 171 (54.8%, 171/312) PDX models were established, including 85 PDX models of colorectal cancer, 21 PDX models of esophageal cancer, and 65 PDX models of gastric cancer. Other than tumor site, histology, differentiation degree, and serum alpha-fetoprotein (AFP) level, no significant differences were found between transplantation of xenografts and patients' characteristics. For patients who had undergone neoadjuvant therapy, the incidence of tumor formation was higher in those with progressive disease (PD) or stable disease (SD). In gastric cancer, the results showed a higher transplantation rate in deficient mismatch repair (dMMR) tumors, and Ki-67 could be an important factor affecting the engraftment rate. The gene mutation status of RAS and BRAF, two important molecular markers in colorectal cancer, showed a high degree of consistency between patients' tumors and PDXs. However, no significant effects of these two mutations on PDX engraftment rate were observed. More importantly, in this study although KRAS mutations were detected in two clinical cases, evident tumor inhibition was still observed after cetuximab treatment in both PDX models and patients. Conclusion: A large-scale PDX model including 171 cases was successfully established for GI tumors in our center. The relationship between clinicopathological and molecular features and engraftment rates were clarified. Furthermore, this resource provides us with profound insights into tumor heterogeneity, making these models valuable for PDX-guided treatment decisions, and offering the PDX model as a great tool for personalized treatment and translation research.

Efficacy and safety of neoadjuvant sintilimab, oxaliplatin and capecitabine in patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: early results of a phase 2 study.

Immune checkpoint inhibitors have greatly improved the prognoses of diverse advanced malignancies, including gastric and gastroesophageal junction (G/GEJ) cancer. However, the role of anti-programmed cell death protein-1 treatment in the neoadjuvant setting remains unclear. This phase 2 study aimed to evaluate sintilimab plus CapeOx as a neoadjuvant regimen in patients with advanced resectable G/GEJ adenocarcinoma. Eligible patients with resectable G/GEJ adenocarcinoma stage cT3-4NanyM0 were enrolled. Patients received neoadjuvant treatment with sintilimab (3 mg/kg for cases <60 kg or 200 mg for those ≥60 kg on day 1) plus CapeOx (oxaliplatin at 130 mg/m2 on D1 and capecitabine at 1000 mg/m2 two times per day on D1-D14) every 21 days, for three cycles before surgical resection, followed by adjuvant treatment with three cycles of CapeOx with the same dosages after surgical resection. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included objective response rate, tumor regression grade per Becker criteria, survival and safety. As of July 30, 2020, 36 patients were enrolled. Totally 7 (19.4%) patients had GEJ cancer, and 34 (94.4%) patients were clinical stage III cases. A total of 35 (97.2%) patients completed three cycles of neoadjuvant treatment, and 1 patients received two cycles due to adverse events. All patients underwent surgery and the R0 resection rate was 97.2%. In this study, pCR and major pathological response were achieved in 7 (19.4%, 95% CI: 8.8% to 35.7%; 90% CI: 10.7% to 33.1%) and 17 (47.2%, 95% CI: 31.6% to 64.3%) patients, respectively. Thirty-one patients received adjuvant treatment. By December 20, 2021, three patients died after disease relapse, and two patients were alive with relapse. Median disease-free survival (DFS) and overall survival (OS) were not reached. The 1-year DFS and OS rates were 90.3% (95% CI: 80.4% to 100.0%) and 94.1% (95% CI: 86.5% to 100.0%), respectively. The most common (>1 patient) grade 3 treatment-related adverse events during neoadjuvant treatment were anemia and neutropenia (n=5 each, 13.9%). No serious adverse events (AEs) or grade 4-5 AEs were observed. Sintilimab plus oxaliplatin/capecitabine showed promising efficacy with encouraging pCR rate and good safety profile in the neoadjuvant setting. This combination regimen might present a new option for patients with locally advanced, resectable G/GEJ adenocarcinoma. Trial registration; NCT04065282.

Revealing the transcriptional heterogeneity of organ-specific metastasis in human gastric cancer using single-cell RNA Sequencing.

BACKGROUND: Deciphering intra- and inter-tumoural heterogeneity is essential for understanding the biology of gastric cancer (GC) and its metastasis and identifying effective therapeutic targets. However, the characteristics of different organ-tropism metastases of GC are largely unknown. METHODS: Ten fresh human tissue samples from six patients, including primary tumour and adjacent non-tumoural samples and six metastases from different organs or tissues (liver, peritoneum, ovary, lymph node) were evaluated using single-cell RNA sequencing. Validation experiments were performed using histological assays and bulk transcriptomic datasets. RESULTS: Malignant epithelial subclusters associated with invasion features, intraperitoneal metastasis propensity, epithelial-mesenchymal transition-induced tumour stem cell phenotypes, or dormancy-like characteristics were discovered. High expression of the first three subcluster-associated genes displayed worse overall survival than those with low expression in a GC cohort containing 407 samples. Immune and stromal cells exhibited cellular heterogeneity and created a pro-tumoural and immunosuppressive microenvironment. Furthermore, a 20-gene signature of lymph node-derived exhausted CD8+ T cells was acquired to forecast lymph node metastasis and validated in GC cohorts. Additionally, although anti-NKG2A (KLRC1) antibody have not been used to treat GC patients even in clinical trials, we uncovered not only malignant tumour cells but one endothelial subcluster, mucosal-associated invariant T cells, T cell-like B cells, plasmacytoid dendritic cells, macrophages, monocytes, and neutrophils may contribute to HLA-E-KLRC1/KLRC2 interaction with cytotoxic/exhausted CD8+ T cells and/or natural killer (NK) cells, suggesting novel clinical therapeutic opportunities in GC. Additionally, our findings suggested that PD-1 expression in CD8+ T cells might predict clinical responses to PD-1 blockade therapy in GC. CONCLUSIONS: This study provided insights into heterogeneous microenvironment of GC primary tumours and organ-specific metastases and provide support for precise diagnosis and treatment.

Host miRNAs-microbiota interactions in gastric cancer.

It is widely acknowledged that gastric cancer seriously affects the quality of life and survival of patients. The correlation between the microbiota and gastric cancer has attracted extensive attention in recent years, nonetheless the specific mechanism of its impact on gastric cancer remain largely unclear. Recent studies have shown that in addition to its role in the host's inflammatory and immune response, the microbiota can also affect the occurrence and development of gastric cancer by affecting the expression of miRNAs. This paper brings together all currently available data on miRNAs, microbiota and gastric cancer, and preliminarily describes the relationship among them.

A novel genomic classification system of gastric cancer via integrating multidimensional genomic characteristics.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer deaths with high heterogeneity. There is currently a paucity of clinically applicable molecular classification system to guide precise medicine. METHODS: A total of 70 Chinese patients with GC were included in this study and whole-exome sequencing was performed. Unsupervised clustering was undertaken to identify genomic subgroups, based on mutational signature, copy number variation, neoantigen, clonality, and essential genomic alterations. Subgroups were characterized by clinicopathological factors, molecular features, and prognosis. RESULTS: We identified 32 significantly mutated genes (SMGs), including TP53, ARID1A, PIK3CA, CDH1, and RHOA. Of these, PREX2, PIEZO1, and FSIP2 have not been previously reported in GC. Using a novel genome-based classification method that integrated multidimensional genomic features, we categorized GC into four subtypes with distinct clinical phenotypes and prognosis. Subtype 1, which was predominantly Lauren intestinal type, harbored recurrent TP53 mutation and ERBB2 amplification, high tumor mutation burden (TMB)/tumor neoantigen burden (TNB), and intratumoral heterogeneity, with a liver metastasis tendency. Subtype 2 tended to occur at an elder age, accompanying with frequent TP53 and SYNE1 mutations, high TMB/TNB, and was associated with poor prognosis. Subtype 3 and subtype 4 included patients with mainly diffuse/mixed type tumors, high frequency of peritoneal metastasis, and genomical stability, whereas subtype 4 was associated with a favorable prognosis. CONCLUSIONS: By integrating multidimensional genomic characteristics, we proposed a novel genomic classification system of GC associated with clinical phenotypes and provided a new insight to facilitate genome-guided risk stratification and disease management.

Whole-exome sequencing of alpha-fetoprotein producing gastric carcinoma reveals genomic profile and therapeutic targets.

Alpha-fetoprotein producing gastric carcinoma (AFPGC) is a rare and aggressive subtype of gastric cancer. However, little is known about the genomic features of this disease. We perform whole-exome sequencing analysis of AFPGC, and identify 34 significantly mutated genes. Somatic copy number alterations analysis reveals several significant focal amplifications (e.g. 19q12, 17q12) and focal deletions (e.g. 1p36.11, 9p21.3), and some of these negatively affect the patient prognosis. Comparative analyses reveal that AFPGC has distinct genomic features from gastric cancer of The Cancer Genome Atlas as well as four molecular subtypes. Several frequently altered genes with potential as therapeutic targets are identified in AFPGC. Further analysis reveals that AFPGC with amplification of CCNE1 at 19q12 and/or ERBB2 at 17q12 show poorer survival and more aggressive. Subsequently, based on our established patient-derived xenograft models for AFPGC, translational research is performed and the therapeutic value of targeting CCNE1 and ERBB2 is validated. In this work, we provide an understanding of genomic characteristics of AFPGC and propose a platform to explore and validate the genome-guided personalized treatment for this disease.

Identification of genes associated with gastric cancer survival and construction of a nomogram to improve risk stratification for patients with gastric cancer.

The present study aimed to identify genes associated with gastric cancer survival and improve risk stratification for patients with gastric cancer. Transcriptomic and clinicopathological data from 443 gastric cancer samples were retrieved from The Cancer Genome Atlas database. The DESeq R package was applied to screen for differentially expressed genes between Tumor-Node-Metastasis (TNM) stage (I vs. IV) and histological grade (G3 vs. G1 and G2). A total of seven genes were common to both comparisons; spondin 1 (SPON1); thrombospondin 4 (THBS4); Sushi, Von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1); prickle planar cell polarity protein 1 (PRICKLE1); ATP binding cassette subfamily A member 8 (ABCA8); Slit guidance ligand 2 (SLIT2); and EGF containing fibulin extracellular matrix protein 1 (EFEMP1), were selected as candidate survival-associated genes for further analysis. The prognostic value of these genes was assessed according to a literature review and Kaplan-Meier survival analysis. In addition, a multivariate Cox regression analysis revealed PRICKLE1 expression to be an independent prognostic factor for patients with gastric cancer. Furthermore, a predictive nomogram was generated using PRICKLE1 expression, patient age and TNM stage to assess overall survival (OS) rate at 1, 3 and 5 years, with an internal concordance index of 0.65. External validation was conducted in an independent cohort of 59 patients with gastric cancer, and high consistency between the predicted and observed results for OS was exhibited. Overall, the current findings suggest that PRICKLE1 expression may serve as an independent prognostic factor that can be integrated with age and TNM stage in a nomogram able to predict OS rate in patients with gastric cancer.

Prognostic Value of the Combination of CEA and Fibrinogen/Albumin Ratio in Resectable Gastric Cancer.

PURPOSE: To investigate the prognostic value of combined serum carcinoembryonic antigen (CEA) levels and fibrinogen/albumin ratio (FAR) in patients with resectable gastric cancer (GC). INTRODUCTION: This retrospective study evaluated the CEA, fibrinogen, and albumin levels and other clinicopathological features of GC patients. The prognostic significance of these factors for overall survival (OS) was assessed using Kaplan-Meier curves and univariate and multivariate Cox proportional models. PATIENTS AND METHODS: A total of 267 patients were included. The optimal cutoff values of CEA and FAR were 3.2 ng/mL and 0.086, respectively. Patients were stratified into three groups based on this cutoff value: CEA-FAR=0 (CEA <3.2 ng/mL and FAR <0.086), CEA-FAR=1 (CEA ≥3.2 ng/mL or FAR ≥0.086), and CEA-FAR=2 (CEA ≥3.2 ng/mL and FAR ≥0.086). RESULTS: Higher CEA-FAR was strongly associated with age, tumor size, tumor invasion, lymph node status, and TNM stage (all P<0.05). The OS rates differed significantly between these 3 groups (88.9% vs 65.0% vs 46.9%, P<0.001). Multivariate analysis showed that CEA-FAR was an independent prognostic factor for OS (P<0.001). The area under the curve was larger for CEA-FAR than for either CEA or FAR alone (0.683, 0.644, and 0.669, respectively). CONCLUSION: Preoperative CEA-FAR could be a potential blood marker for predicting tumor progression and the prognosis of GC patients. Patients with a higher CEA-FAR should undergo extensive follow-up.

The Ectopic Expression of SurvivinT34A and FilC Can Enhance the Oncolytic Effects of Vaccinia Virus in Murine Gastric Cancer.

BACKGROUND/AIMS: Anti-tumor vaccines have been shown to be effective in cancer therapeutics ever since the anti-HPV vaccine was developed. Compared to conventional chemotherapy, anti-tumor vaccines can specifically target cancer cells and they have lower side effects. We developed a recombinant vaccinia virus (VACV) (Western Reserve) WR strain, and we tested its anti-tumor effects in an animal model. METHODS: A recombinant VACV WR strain expressing mutant survivin T34A (SurT34A) and FilC was constructed and validated. Its oncolytic effect was tested in vitro using a CCK-8 assay, and its tolerance and anti-tumor effects were tested in a murine gastric cancer model. The proportion of lymphocytes in the spleen and tumor was determined after antibody-mediated immuno-depletion. RESULTS: The recombinant VACV showed a stronger replication ability in tumor cells, and it was safe in vivo, even at high doses. The combination of vv-SurT34A and vv-FilC resulted in a stronger anti-tumor effect compared to either construct alone. However, the inhibitory effect of vv-SurT34A was stronger than the combination. The recombinant VACV activated the host immune response, as indicated by lymphocyte infiltration in the spleen and tumor tissues. CONCLUSION: The recombinant VACV WR strain expressing SurT34A and FilC is a safe and effective anti-tumor vaccine.

LncRNA MIR4435-2HG targets desmoplakin and promotes growth and metastasis of gastric cancer by activating Wnt/ß-catenin signaling.

Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of gastric cancer; however, their mechanisms of action remain largely unknown. The aim of this study was to identify lncRNAs involved in the tumorigenesis of gastric cancer and to investigate the signaling pathways they affect. Using microarray and RT-qPCR analyses, candidate lncRNAs were screened in paired gastric cancer tissues. The analysis revealed MIR4435-2HG to be markedly up-regulated in gastric cancer samples compared to normal stomach specimens. Increased MIR4435-2HG expression was associated with aggressive clinicopathologic features and unfavorable tumor stage. Functional experiments showed that MIR4435-2HG up-regulation enhanced gastric cancer cell proliferation, clonogenicity, and migration and invasion in vitro, as well as tumorigenicity in mice. Using RNA pull-down and mass-spectrometry analyses we found and verified a direct and novel interaction between MIR4435-2HG and desmoplakin (DSP), the most abundant desmosomal protein. Overexpression and knockdown experiments revealed opposing roles for DSP and MIR4435-2HG, unmasking a cascade through which MIR4435-2HG binds to and inhibits DSP, leading to activation of WNT/ß-catenin signaling and epithelial-mesenchymal transition in gastric cancer cells. We propose that the MIR4435-2HG/DSP/WNT axis serves as a critical effector of carcinogenesis and progression of gastric cancer, and could be exploited therapeutically to improve patients' outcomes.

Gut microbiota shifts in patients with gastric cancer in perioperative period.

Gastric cancer (GC) is one of the common malignant tumors in China, with a high morbidity and mortality. With the development and application of high-throughput sequencing technologies and metagenomics, a great quantity of studies have shown that gastrointestinal microbiota is closely related to digestive system diseases. Although some studies have reported the effect of long-term follow-up after subtotal gastrectomy on intestinal flora changes in patients with GC. However, the features of gut microbiota and their shifts in patients with GC in perioperative period remain unclear.This study was designed to characterize fecal microbiota shifts of the patients with GC before and after the radical distal gastrectomy (RDG) during their hospital staying periods. Furthermore, fecal microbiota was also compared between the GC patients and healthy individuals.Patients who were diagnosed with advanced gastric adenocarcinoma at distal stomach were enrolled in the study. The bacterial burden within fecal samples was determined using quantitative polymerase chain reaction. To analyze the diversity and composition of gut microbiota from fecal DNA of 20 GC patients and 22 healthy controls, amplicons of the 16S rRNA gene from all subjects were pyrosequenced. To study gut microbiota shifts, the fecal microbiota from 6 GC patients before and after RDG was detected and subsequently analyzed. Short-chain fatty acids were also detected by chromatography spectrometer in these 6 GC patients.RDG had a moderate effect on bacterial richness and evenness, but had pronounced effects on the composition of postoperative gut microbiota compared with preoperative group. The relative abundances of genera Akkermansia, Esherichia/Shigella, Lactobacillus, and Dialister were significant changed in perioperative period. Remarkably, higher abundances of Escherichia/Shigella, Veillonella, and Clostridium XVIII and lower abundances of Bacteroides were observed in gut microbiota of overall GC patients compared to healthy controls.This study is the first study to characterize the altered gut microbiota within fecal samples from GC patients during perioperative period, and provide a new insights on such microbial perturbations as a potential effector of perioperative period phenotype. Further research must validate these discoveries and may evaluate targeted microbiota shifts to improve outcomes in GC patients.

Long-term survival of an elderly female with metastatic colon cancer after treated with capecitabine monotherapy: A case report.

RATIONALE: Colorectal cancer (CRC) is one of the most common cancers all over the world, and approximately 70% of the newly diagnosed patients are over 65 years old. Due to the aging of society, there will be more and more elderly patients of CRC in the future. Treatment of CRC in elderly patients is much more challenging thanks to multiple factors including disabling comorbidities as well as declines in organs function, especially in advanced or metastatic settings. PATIENT CONCERNS: An 82-year-old female without history of disease was admitted to the emergency room because of abdominal pain in December 2009. A computed tomography (CT) scan of the abdomen was performed immediately, which revealed bowel obstruction. DIAGNOSES: The histopathological examination of the resected specimen confirmed well-to-moderately differentiated colonic adenocarcinoma with a stage of IIIB (T3N1M0) based on the NCCN tumor-node-metastasis (TNM) classification system. INTERVENTIONS: The patient underwent emergency surgery and rejected adjuvant chemotherapy, but was diagnosed with multiple liver metastases 3 months later. Then she received capecitabine monotherapy as first-line treatment. OUTCOMES: The efficacy achieved complete response (CR) when 8 cycles were completed and the agent was continued as maintenance treatment until totally 16 cycles were completed. Up to the latest follow-up, the disease remained CR and the progression-free survival (PFS) has achieved approximately 87 months. She is still alive and has good quality of life. LESSONS: Capecitabine monotherapy may be an effective treatment in advanced or metastatic colorectal cancer (mCRC) for elderly patients.

BP­1­102 exerts an antitumor effect on the AGS human gastric cancer cell line through modulating the STAT3 and MAPK signaling pathways.

BP­1­102, a novel inhibitor of signal transducer and activator of transcription 3 (STAT3), exhibits significant antitumor effects in several malignancies in vitro and in vivo. However, its role in gastric cancer (GC) remains to be elucidated. In the present study, the effect and potential molecular mechanisms of BP­102 in human GC cell lines were investigated. The results showed that BP­1­02 dose­dependently inhibited the proliferation of AGS cells, whereas it had little effect on HGC­27 cells. Flow cytometric analysis indicated that BP­1­102 induced apoptosis, but had minimal effect on cell cycle distribution. In addition, cells treated with BP­1­102 demonstrated markedly suppressed migration and invasion capacities. Western blot analysis revealed that BP­1­102 inhibited the phosphorylation of STAT3 and its target genes, including c­Myc, cyclin D1 and survivin, in a time­ and dose­dependent manner. Furthermore, it was found that BP­1­102 induced the phosphorylation of c­Jun N­terminal kinase and p38 mitogen­activated protein kinase (MAPK) and inhibited the activation of extracellular signal­related kinases. Taken together, these results demonstrated that BP­1­102 may be a potent antitumor agent that acts through modulating the STAT3 and MAPK signaling pathways in GC cells.

miR-129-5p attenuates cell proliferation and epithelial mesenchymal transition via HMGB1 in gastric cancer.

BACKGROUND: The miR-129-5p has been reported to be aberrant expression and exert vital roles in tumor progression of various malignancies. However, the effects on EMT in gastric cancer and its precise molecular mechanism in gastric cancer remain unclear. METHODS AND MATERIALS: RT-qPCR was performed to evaluate the expression level of miR-129-5p and HMGB1 in cell lines. Cell proliferation was detected via CCK-8. The epithelial mesenchymal transition (EMT) related proteins and the expression of HMGB1 were detected by western blot analysis. Luciferase assays were used to validate binding seeds between miR-129-5p and HMGB1. RESULTS: miR-129-5p was downregulated in gastric cancer cells compared with GES-1. At the same time EMT was promoted in gastric cancer cells compared to GES-1. Overexpression of miR-129-5p inhibited EMT and proliferation. MiR-129-5p negatively and directly targeted HMGB1. HMGB1 was upregulated in gastric cancer cells and HMGB1 knocked-down inhibited EMT and cell proliferation. CONCLUSION: Taken together, upregulation of miR-129-5p associated with gastric cancer proliferation and EMT, and serves as a potential diagnostic and therapeutic target via miR-129-5p/HMGB1 pathway in gastric cancer.

Regeneration of a Bioengineered Thyroid Using Decellularized Thyroid Matrix.

BACKGROUND: Hypothyroidism is a common hormone deficiency condition. Regenerative medicine approaches, such as a bioengineered thyroid, have been proposed as potential therapeutic alternatives for patients with hypothyroidism. This study demonstrates a novel approach to generate thyroid grafts using decellularized rat thyroid matrix. METHODS: Isolated rat thyroid glands were perfused with 1% sodium dodecyl sulfate to generate a decellularized thyroid scaffold. The rat thyroid scaffold was then recellularized with rat thyroid cell line to reconstruct the thyroid by perfusion seeding technique. As a pilot study, the decellularized rat thyroid scaffold was perfused with human-derived thyrocytes and parathyroid cells. RESULTS: The decellularization process retained the intricate three-dimensional microarchitecture with a perfusable vascular network and native extracellular matrix components, allowing efficient reseeding of the thyroid matrix with the FRTL-5 rat thyroid cell line generating three-dimensional follicular structures in vitro. In addition, the recellularized thyroid showed successful cellular engraftment and thyroid-specific function, including synthesis of thyroglobulin and thyroid peroxidase. Moreover, the decellularized rat thyroid scaffold could further be recellularized with human-derived thyroid cells and parathyroid cells to reconstruct a humanized bioartificial endocrine organ, which maintained expression of critical genes such as thyroglobulin, thyroid peroxidase, and parathyroid hormone. CONCLUSION: These findings demonstrate the utility of a decellularized thyroid extracellular matrix scaffold system for the development of functional, bioengineered thyroid tissue, which could potentially be used to treat hypothyroidism.

HJC0152, a novel STAT3 inhibitor with promising anti-tumor effect in gastric cancer.

BACKGROUND: Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) is frequently seen in patients with gastric cancer (GC), and is generally associated with worse prognosis. HJC0152, a novel STAT3 inhibitor, has shown significant anti-tumor effects in several cancers, although its role in GC remains to be clarified. METHODS: The effect of HJC0152 on STAT3 signaling pathway and the biological behaviors of GC cells were evaluated through in vitro and/or in vivo experiments. Meanwhile, RNA sequence analysis was used to further explore its potential anti-tumor mechanisms. RESULTS: HJC0152 inhibited the expression of activated STAT3 and its downstream target genes (c-Myc and clyclinD1) in GC cells, and restrained tumor growth in vivo. HJC0152 treatment induced apoptosis in the STAT3 hyper-activated AGS and MKN45 cell lines, along with down-regulation of survivin and Mcl1, and up-regulation of cleaved-poly(ADP-ribose) polymerase. Moreover, HJC0152 markedly inhibited migration and invasion of these cells. Finally, RNA sequence analysis and protein expression analyses showed that in addition to STAT3 suppression, HJC0152 also exerts its anti-tumor effects at least partly via the mitogen-activated protein kinases pathway. CONCLUSION: Our findings highlight that HJC0152 is a promising therapeutic agent for GC.