Upregulation of nuclear-enriched abundant transcript 1 confers oxaliplatin resistance to gastric cancer.

The present study aims to investigate the roles of nuclear-enriched abundant transcript 1 (NEAT1) in the regulation of oxaliplatin resistance to gastric cancer (GC). Oxaliplatin-resistant cell lines were constructed using stepwise selection. NEAT1 knockdown and overexpression of NEAT1 were performed. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and colony formation assays were used to evaluate cell proliferation. Propidium iodide (PI) and annexin V staining were used to evaluate cell apoptosis. A dual-luciferase reporter assay was used to evaluate the molecular interactions. Quantitative polymerase chain reaction (qPCR) was used to determine messenger RNA (mRNA) expression. Western blotting was used to determine the protein expression. Kaplan-Meier's analysis was performed to evaluate the relationship between NEAT1 and poor prognosis in GC. NEAT1 was upregulated in oxaliplatin-resistant GC cells and associated with poor prognosis in GC patients. NEAT1 knockdown suppressed oxaliplatin resistance, whereas overexpression of NEAT1 induced oxaliplatin resistance. In addition, the expressions of NEAT1 were negatively associated with miR-26 expressions. Overexpression of NEAT1 attenuated the inhibitory effects of miR-26 on the enhancer of zeste homolog 2 (EZH2). The roles of NEAT1 in the regulation of oxaliplatin resistance to GC are in part by ameliorating the inhibitory effect of miR-26 on EZH2.

miR-100-3p inhibits cell proliferation and induces apoptosis in human gastric cancer through targeting to BMPR2.

BACKGROUND: miR-100 has been reported to closely associate with gastric cancer (GC) initiation and progression. However, the underlying mechanism of miR-100-3p in GC is still largely unclear. In this study, we intend to study how miR-100-3p regulates GC malignancy. METHODS: The expression levels of miR-100-3p in vitro (GES-1 and GC cell lines) and in vivo (cancerous and normal gastric tissues) were examined by quantitative real-time PCR (qRT-PCR). MTT and PE/Annexin V analyses were responsible for measurement of the effects of miR-100-3p on GC cell proliferation and apoptosis. Transwell assay with or without matrigel was used to examine the capacity of migration and invasion in GC cells. The interaction of miR-100-3p with bone morphogenetic protein receptor 2 (BMPR2) was confirmed through transcriptomics analysis and luciferase reporter assay. qRT-PCR and Western blot analyses were applied to determine the expression of ERK/AKT and Bax/Bcl2/Caspase3, which were responsible for the dysfunction of miR-100-3p. RESULTS: miR-100-3p was down-regulated in GC cell lines and cancerous tissues, and was negatively correlated with BMPR2. Loss of miR-100-3p promoted tumor growth and BMPR2 expression. Consistently, the effects of miR-100-3p inhibition on GC cells were partially neutralized by knockdown of BMPR2. Over-expression of miR-100-3p simultaneously inhibited tumor growth and down-regulated BMPR2 expression. Consistently, over-expression of BMPR2 partially neutralized the effects of miR-100-3p over-expression. Further study demonstrated that BMPR2 mediated the effects downstream of miR-100-3p, which might indirectly regulate ERK/AKT and Bax/Bcl2/Caspase3 signaling pathways. CONCLUSION: miR-100-3p acted as a tumor-suppressor miRNA that down-regulated BMPR2, which consequently inhibited the ERK/AKT signaling and activated Bax/Bcl2/Caspase3 signaling. This finding provided novel insights into GC and could contribute to identify a new diagnostic and therapeutic target.

MiR-876-3p regulates cisplatin resistance and stem cell-like properties of gastric cancer cells by targeting TMED3.

BACKGROUND AND AIM: Gastric cancer (GC), a prevalent tumor, exerts a major economic burden, and we aimed to explore miR-876-3p's effects on GC and related mechanisms. METHODS: Cell viability was analyzed via CCK-8 and colony formation assay. Stem cell-like properties were examined via spheroid colony formation assay. mRNA abundance of key genes was analyzed via quantitative polymerase chain reaction. Protein level of TMED3 and stem cell markers was examined by western blot. TargetScan, luciferase, and biotin-miRNA pulldown assay were used to identify miR-876-3p's target. RESULTS: MiR-876-3p was downregulated in GC, and its mRNA level had negative relationship with cisplatin resistance of GC. Moreover, decreased miR-876-3p expression level suggested poor prognosis of GC patients. MiR-876-3p inhibited drug resistance of cisplatin-resistant cell line SGC-7901/DDP and MKN-45/DDP, as shown by decreased cell viability, IC50 , and colony formation ability. MiR-876-3p inhibited stem cell-like features and downregulated the expressions of Sox-2, Oct-4, CD133, and CD44 in GC cells. Luciferase and biotin-miRNA pulldown assay confirmed that TMED3 was miR-876-3p's direct target. TMED3 siRNA inhibited miR-876-3p's effects on cisplatin resistance and stem cell-like features of SGC-7901/DDP cells. CONCLUSION: MiR-876-3p enhanced cisplatin sensitivity and restricted stem cell-like features of GC through targeting TMED3.

Stromal fibroblast activation protein alpha promotes gastric cancer progression via epithelial-mesenchymal transition through Wnt/ ß-catenin pathway.

BACKGROUND: To investigate the influence of fibroblast activation protein alpha (FAP) derived from cancer-associated fibroblasts (CAFs), as well as potential mechanism of epithelial mesenchymal transition (EMT), on gastric cancer (GC) progression. METHODS: Correlation between CAFs-derived FAP and clinical results has been studied by using 60 GC cases. To confirm this relationship, SGC7901 cells were co-cultured with pre-established FAP-overexpressed fibroblasts in vitro and the characteristics including proliferation, migration, invasion and apoptosis abilities were detected subsequently. Meanwhile, SGC and GES1 cells cocultured with FAP-overexpressed fibroblasts were treated with cis-platinum for apoptotic analysis. The underlying EMT was detected by analyzing expression level of E-cadherin, ZO-1, N-cadherin, Vimentin, α-SMA, DKK1 and LEF-1 through western blot and immunofluorescence staining assay. Finally, the tumor-promoting ability of FAP was investigated by utlizing a xenograft gastric cancer nude mouse model. RESULTS: It show that FAP has a high-risk correlation with the malignant level of clinical outcomes in GC patients. FAP promotes the ability of proliferation, migration, invasion, apoptosis-inhibition of SGC7901 cells and induces apoptosis of GES1 cells in vitro. The mechanism study shows that epithelial markers have been down-regulated and mesenchymal markers and Wnt/ß-catenin signal pathway related proteins have been up-regulated. Animal assay suggests that tumor burden has been enhanced by FAP significantly in vivo. CONCLUSIONS: Stromal FAP could be a potential prognostic biomarker in GC by promoting cancer progression via EMT through Wnt/ ß-catenin signal pathway.

Quantum dots-based tissue and in vivo imaging in breast cancer researches: current status and future perspectives.

As the most common malignant tumor for females, breast cancer (BC) is a highly heterogeneous disease regarding biological behaviors. Precisely targeted imaging on BC masses and biomarkers is critical to BC detection, treatment, monitoring, and prognostic evaluation. As an important imaging technique, quantum dots (QDs)-based imaging has emerged as a promising tool in BC researches owe to its outstanding optical properties. However, few reviews have been specifically devoted to discussing applications of QDs-based imaging in BC researches. This review summarized recent promising works in QDs-based tissue and in vivo imaging for BC studies. Physicochemical and optical properties of QDs and its potential applications were briefly described first. Then QDs-based imaging studies in BC were systematically reviewed, including tissue imaging for studying biomarkers interactions, and evaluating prognostic biomarkers, in vivo imaging for mapping axillary lymphatic system, showing BC xenograft tumor, and detecting BC metastases. At last, the future perspectives with special emphasis on the potential clinical applications have also been discussed. Potential applications of QDs-based imaging on clinical BC in the future are mainly focused on tissue study, especially in BC molecular pathology due to its optimal optical properties and quantitative information capabilities on multiple biomarkers.

Collagen as a double-edged sword in tumor progression.

It has been recognized that cancer is not merely a disease of tumor cells, but a disease of imbalance, in which stromal cells and tumor microenvironment play crucial roles. Extracellular matrix (ECM) as the most abundant component in tumor microenvironment can regulate tumor cell behaviors and tissue tension homeostasis. Collagen constitutes the scaffold of tumor microenvironment and affects tumor microenvironment such that it regulates ECM remodeling by collagen degradation and re-deposition, and promotes tumor infiltration, angiogenesis, invasion and migration. While collagen was traditionally regarded as a passive barrier to resist tumor cells, it is now evident that collagen is also actively involved in promoting tumor progression. Collagen changes in tumor microenvironment release biomechanical signals, which are sensed by both tumor cells and stromal cells, trigger a cascade of biological events. In this work, we discuss how collagen can be a double-edged sword in tumor progression, both inhibiting and promoting tumor progression at different stages of cancer development.

Impact of neoadjuvant chemotherapy on lymphocytes and co-inhibitory B7-H4 molecule in gastric cancer: low B7-H4 expression associates with favorable prognosis.

Little is known on the immune response after neoadjuvant chemotherapy (NACT) in gastric cancer (GC). The present study aimed to investigate the effects of NACT on tumor cells and tumor-infiltrating lymphocytes (TILs) in patients with GC. Expressions of CD4+ and CD8+ TILs and identified co-inhibitory B7-H4 molecule were examined by immunohistochemical staining in GC tissues of 56 patients who received NACT (NACT group) and 46 patients who did not receive NACT (nNACT group). These markers, clinicopathological features, and overall survival (OS) time between both groups were compared. Results showed that the clinicopathological features of patients were not significantly associated with NACT (P > 0.05), but the rate of low expression of B7-H4 (78.6 vs. 47.8 %, P = 0.005) and rate of high expression of CD4+ TILs (58.9 vs. 39.1 %, P = 0.048) and CD8+ TILs (92.9 vs. 56.5 %, P < 0.001) were both significantly higher in NACT group than that in nNACT group. Further, Kaplan-Meier analysis indicated that there was no significant difference in OS time between the groups. However, in NACT group, those with low B7-H4 expression had significantly longer OS (P = 0.031). The study findings suggest that low expression of B7-H4 could serve as a candidate biomarker for predicting response to NACT and could provide favorable prognostic information in GC.

High expression of transform growth factor beta 1 in gastric cancer confers worse outcome: results of a cohort study on 184 patients.

BACKGROUND/AIMS: Transform growth factors beta (TGFbeta) plays different roles at different stages of tumor development. TGFbeta1 is one isoform of TGFbeta, with complex secretion mechanism and bidirectional functions. This study was to investigate TGFbeta1 expression and its clinical significance in different clinicopathological subgroups of gastric cancer (GC) patients. METHODOLOGY: Tumor and peritumoral tissues from 184 GC patients were constructed into three tumor tissue microarrays. The expression of TGFbeta1 was analyzed by immunohistochemistry methods. RESULTS: TGFbeta1 was mainly expressed in the cytoplasm and membrane of GC cells. Low TGFbeta1 expression was observed in 82 (44.6%) tumor and 28 (68.3%) peritumoral tissues, and high expression was observed in 102 (55.4%) tumor and 13 (31.7%) peritumoral tissues. TGFbeta1 expression was significantly higher in tumor than peritumoral tissues (chi2 = 7.554, P = 0.006). The high expression of TGFbeta1 was related to worse overall survival (OS) (P = 0.040). TGFbeta1 expression was higher in the old and intestinal type GC than in the young (P = 0.017) and in diffuse type GC (P = 0.015), respectively. Patients with high TGFbeta1 expression had a worse survival in young people, female, diffuse type GC, poor differentiation, and lymph nodes metastasis. Multivariate Cox proportional hazards analysis showed that age, pathological grading, serosal invasion and TGFbeta1 expression were independent risk factors. CONCLUSIONS: High TGFbeta1 expression may indicate poor prognosis of GC patients and warrant more active treatment against TGFbeta1.

Long term follow up and retrospective study on 533 gastric cancer cases.

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer death in China and the outcome of GC patients is poor. The aim of the research is to study the prognostic factors of gastric cancer patients who had curative intent or palliative resection, completed clinical database and follow-up. METHODS: This retrospective study analyzed 533 GC patients from three tertiary referral teaching hospitals from January 2004 to December 2010 who had curative intent or palliative resection, complete clinical database and follow-up information. The GC-specific overall survival (OS) status was determined by the Kaplan-Meier method, and univariate analysis was conducted to identify possible factors for survival. Multivariate analysis using the Cox proportional hazard model and a forward regression procedure was conducted to define independent prognostic factors. RESULTS: By the last follow-up, the median follow-up time of 533 GC patients was 38.6 mo (range 6.9-100.9 mo), and the median GC-specific OS was 25.3 mo (95% CI: 23.1-27.4 mo). The estimated 1-, 2-, 3- and 5-year GC-specific OS rates were 78.4%, 61.4%, 53.3% and 48.4%, respectively. Univariate analysis identified the following prognostic factors: hospital, age, gender, cancer site, surgery type, resection type, other organ resection, HIPEC, LN status, tumor invasion, distant metastases, TNM stage, postoperative SAE, systemic chemotherapy and IP chemotherapy. In multivariate analysis, seven factors were identified as independent prognostic factors for long term survival, including resection type, HIPEC, LN status, tumor invasion, distant metastases, postoperative SAE and systemic chemotherapy. CONCLUSIONS: Resection type, HIPEC, postoperative SAE and systemic chemotherapy are four independent prognostic factors that could be intervened for GC patients for improving survival.

Short-Term Safety Evaluation of Albumin-Bound Paclitaxel in Intraoperative and Postoperative Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer.

PURPOSE: To evaluate the short-term safety of albumin-bound paclitaxel in hyperthermic intraperitoneal chemotherapy (HIPEC) during and after gastric cancer (GC) surgery. METHODS: A retrospective analysis of clinical data was conducted for GC surgery patients at Zhongnan Hospital of Wuhan University, from January 2020 to September 2022. The study group (n = 120) received HIPEC and the control group (n = 268) did not receive albumin-bound paclitaxel. Short-term safety indicators including intraoperative complications, hematological toxicity, liver and kidney function, and gastrointestinal function recovery were compared between the two groups. RESULTS: There were no statistically significant differences between the two groups regarding intraoperative complications, hematological toxicity, liver and kidney function, and gastrointestinal function recovery time (P > 0.05 for all). In the study group, patients were further divided into subgroups based on dose and timing. Subgroup analysis revealed no significant differences among the different dose subgroups. However, when focusing on timing subgroups, the postoperative subgroup exhibited significantly higher white blood cell counts and bilirubin levels compared to the intraoperative subgroup, while the intraoperative subgroup had significantly higher bilirubin levels compared to both postoperative and intraoperative plus postoperative subgroups. CONCLUSION: Albumin-bound paclitaxel demonstrates good safety and tolerability in HIPEC during and after GC surgery, without increasing the risk of intraoperative complications.

Combined features based on MT1-MMP expression, CD11b + immunocytes density and LNR predict clinical outcomes of gastric cancer.

BACKGROUND: Given the complexity of tumor microenvironment, no single marker from cancer cells could adequately predict the clinical outcomes of gastric cancer (GC). The objective of this study was to evaluate the prognostic role of combined features including conventional pathology, proteinase and immune data in GC. METHODS: In addition to pathological studies, immunohistochemistry was used to assess membrane-type 1 matrix metalloproteinase (MT1-MMP) expression and CD11b + immunocytes density in three independent GC tissue microarrays containing 184 GC tissues. Separate and combined features were evaluated for their impact on overall survival (OS). RESULTS: We found that traditional factors including tumor size, histological grade, lymph node status, serosa invasion and TNM stage were associated with OS (P < 0.05 for all). Moreover, statistically significant differences in OS were found among lymph node ratio (LNR) subgroups (P < 0.001), MT1-MMP subgroups (P = 0.015), and CD11b + immunocytes density subgroups (P = 0.031). Most importantly, combined feature (MT1-MMP positive, low CD11b + immunocytes density and high LNR) was found by multivariate analysis to be an independent prognostic factors for OS after excluding other confounding factors (HR = 3.818 [95%CI: 2.223-6.557], P < 0.001). In addition, this combined feature had better performance in predicting clinical outcomes after surgery long before recurrence had occurred (Area under the curve: 0.689 [95%CI: 0.609-0.768], P < 0.001). CONCLUSIONS: These findings indicate that better information on GC prognosis could be obtained from combined clinico-pathological factors, tumor cells and the tumor microenvironment.

Evaluation of the staging systems for gastric cancer.

BACKGROUND: Some staging systems for gastric cancer (GC) have been developed as alternatives to the 6th and 7th TNM staging systems, including the Hybrid, tumor-ratio-metastasis (TRM), and Kiel staging systems. This study evaluated the overall performance of these systems for GC. METHODS: A total of 540 GC patients undergoing surgical resection were staged using these five systems. Homogeneity, discrimination power, predictive accuracy, and complexity of these systems were compared. RESULTS: Multivariate analyses showed that all of 7th pT, pN, and pM classifications were independent factors for GC prognosis (P < 0.001 for all). Compared with the other four systems, 7th TNM system had improved stage groups homogeneity (7 of 8 stage groups homogeneous), enhanced discrimination power (4 of 5, 5 of 7, 4 of 7, 3 of 7, and 1 of 4 adjacent stage groups were differentiated by the 6th, 7th TNM, Hybrid, TRM, and Kiel systems, respectively), and better prediction value for GC patients' outcome (AUC = 0.801, P < 0.001). In addition, the 7th TNM system did not increase the staging complexity (9 groups and 21 subgroups). CONCLUSIONS: The 7th TNM staging system represents advancement in GC staging system for better prediction of clinical outcomes.

Coevolution of the tumor microenvironment revealed by quantum dot-based multiplexed imaging of hepatocellular carcinoma.

AIM: This study aimed to provide new insights into the mechanisms of hepatocellular carcinoma (HCC) invasion by simultaneously imaging tumor cells and major components of the tumor microenvironment. MATERIALS & METHODS: Formalin-fixed paraffin-embedded human HCC tissues were studied by conventional immunohistochemistry and quantum dot-based multiplexed imaging to reveal type IV collagen, LOX and tumor angiogenesis. RESULTS: Type IV collagen degradation and repatterning in the extracellular matrix (ECM) was a continuous process, making the ECM harder, although more fragile and less resistant to cancer invasion. The distribution of LOX among cancer nests was heterogeneous, with higher expression in small cancer nests and lower expression in large cancer nests. LOX expression in cancer cells was associated with rigid stroma and tumor angiogenesis. Tumor angiogenesis occurred with type IV collagen presence. At the cancer invasion front, the ECM was hydrolyzed, with the prominent linear reorientation of type IV collagen surrounding cancer nests adjacent to neovessels. CONCLUSION: The visualization of the temporal-spatial relationship between type IV collagen, LOX and tumor angiogenesis revealed the coevolution process of HCC cells and their microenvironment, emphasizing an active role of the ECM during cancer invasion.

In vitro invasive pattern of hepatocellular carcinoma cell line HCCLM9 based on three-dimensional cell culture and quantum dots molecular imaging.

This study aimed to establish a new in vitro three-dimensional (3D) cell culture and use quantum dots (QDs) molecular imaging to examine the invasive behaviors of hepatocellular carcinoma (HCC) cells. Each well of the 24-well cell culture plate was cover-slipped. Matrigel diluted with serum-free DMEM was added and HCCLM9 cells were cultured on the Matrigel. The cell morphological and cell growth characteristics were observed by inverted microscopy and laser confocal microscopy at different culture time. Cell invasive features were monitored by QDs-based real-time molecular imaging techniques. The results showed that on this 3D cell culture platform, HCCLM9 cells exhibited typical multi-step invasive behaviors, including reversion of cell senescence, active focal proliferation and dominant clones invasion. During the process, cells under 3D cell culture showed biological behaviors of spatio-temporal characteristics. Cells first merged on the surface of matrix, then gradually infiltrated and migrated into deep part of matrix, presenting polygonal morphology with stretched protrusions, forming tubular, annular and even network structure, which suggested that HCC cells have the morphological basis for vasculogenic mimicry. In addition, small cell clones with their edges well-circumscribed in early stage, progressed into a large irregular clone with ill-defined edge, while the other cells developed invadopodia. And QDs probing showed MT1-MMP was strongly expressed in the invadopodia. These findings indicate that a novel 3D cell culture platform has been successfully established, which can mimic the in vivo tumor microenvironment, and when combined with QDs-based molecular imaging, it can help to better investigate the invasive behaviors of HCC cells.

Gut microbiota: key facilitator in metastasis of colorectal cancer.

Colorectal cancer (CRC) ranks third in terms of incidence among all kinds of cancer. The main cause of death is metastasis. Recent studies have shown that the gut microbiota could facilitate cancer metastasis by promoting cancer cells proliferation, invasion, dissemination, and survival. Multiple mechanisms have been implicated, such as RNA-mediated targeting effects, activation of tumor signaling cascades, secretion of microbiota-derived functional substances, regulation of mRNA methylation, facilitated immune evasion, increased intravasation of cancer cells, and remodeling of tumor microenvironment (TME). The understanding of CRC metastasis was further deepened by the mechanisms mentioned above. In this review, the mechanisms by which the gut microbiota participates in the process of CRC metastasis were reviewed as followed based on recent studies.

Significance of Siglec-15 expression in colorectal cancer: association with advanced disease stage and fewer tumor-infiltrating lymphocytes.

Siglec-15, a novel immune suppressor, is upregulated in many human cancers. The aim of this study was to explore the expression of Siglec-15 in colorectal cancer (CRC), and investigate whether Siglec-15 could be a potential target for cancer immunotherapy in patients with CRC. We performed immunohistochemical analyses of Siglec-15 on a cohort of 805 patients with CRC and made comparisons between clinicopathological characteristics, PD-L1 expression, CD3, CD8, CD45RO tumor-infiltrating lymphocytes (TILs), and prognosis. We found that Siglec-15 expression was commonly detected in tumor cells (48.3%) and tumor-associated stromal cells (33.4%), and was more frequently observed than PD-L1 expression in tumor cells. In contrast, Siglec-15 expression was weakly and scarcely found in normal mucosa (13%). Siglec-15 overexpression in tumor cells was associated with advanced TNM stage (p = 0.020). Co-expression of Siglec-15 and PD-L1 in tumor cells was found in 14.4% of patients, and Siglec-15 expression was detected in almost half of PD-L1 negative cases. Elevated Siglec-15 expression in tumor and stromal cells was associated with sparser CD45RO and CD8 TILs (p = 0.035 and p = 0.004, respectively). The expression of Siglec-15 did not have prognostic significance. In summary, compared to PD-L1, Siglec-15 protein expression is more prevalent in CRC and is associated with advanced disease stage and fewer TILs. These findings support Siglec-15 as a potential cancer immunotherapy target, in addition to PD-1/PD-L1 inhibitors, in patients with CRC.

Laparoscopy-assisted gastrectomy for advanced gastric cancer patients with situs inversus totalis: Two case reports and review of literature.

BACKGROUND: Situs inversus totalis (SIT) is a rare condition in which the positions of abdominal and thoracic organs present a "mirror image" of the normal ones in the median sagittal plane. Although minimally invasive surgery has evolved to achieve laparoscopic gastrectomy for gastric cancer (GC) patients with SIT, it is difficult to perform lymphadenectomy (LND) in such a transposed anatomical condition. Herein, we report the cases of two patients with SIT who successfully underwent laparoscopy-assisted gastrectomy (LAG) with D2 LND. CASE SUMMARY: Case 1: A 65-year-old man was admitted for intermittent abdominal pain and distension, occasional belching, and acid reflux for 4 mo. He was diagnosed with GC (cT3N1-2M0) with SIT. Before surgery, he had undergone four cycles of neoadjuvant chemotherapy and immunotherapy. Then, the patient was evaluated as having a partial response, and laparoscopy-assisted distal gastrectomy with D2 LND and Billroth II reconstruction were performed. The operation was performed successfully within 240 min with an estimated blood loss of 50 mL and no severe complications. The patient was discharged on postoperative day (POD) 9. Case 2: A 55-year-old man was admitted for upper abdominal distension with pain and discomfort after eating for 3 mo. He was diagnosed with GC (cT3N1M0) with SIT. He had a history of hypertension for more than 10 years; however, his blood pressure was well-controlled via regular medication. We performed laparoscopy-assisted total gastrectomy with D2 LND and Roux-en-Y reconstruction. The operation was performed successfully within 168 min with an estimated blood loss of 50 mL and no severe complications. The patient was discharged on POD 10. CONCLUSION: LAG with D2 LND could be considered an accessible, safe, and curative procedure for advanced GC patients with SIT.

Upregulation of LINC00501 by H3K27 acetylation facilitates gastric cancer metastasis through activating epithelial-mesenchymal transition and angiogenesis.

BACKGROUND: The molecular mechanism of the significant role of long noncoding RNAs (lncRNAs) in the progression and metastasis of gastric cancer (GC) remains largely elusive. Our objective is to detect overexpressed lncRNA in GC and investigate its role in promoting epithelial-mesenchymal transition and tumour microenvironment remodel. METHODS: LncRNA differential expression profile in GC was analysed using RNA microarrays. The level of LINC00501 was evaluated in both GC patient tissues and GC cell lines by quantitative reverse transcription PCR and large-scale (n = 304) tissue microarray. To explore the biological role and regulatory driver of LINC00501 in GC, various experimental techniques including Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) assay, dual luciferase assays were performed. RESULTS: Clinically, it was observed that LINC00501 level was abnormal overexpression in GC tissue and was associated with GC progression and distant metastasis. Gain and loss molecular biological experiments suggested that LINC00501, promoted EMT process and angiogenesis of GC. Mechanically, the enrichment of H3K27 acetylation in LINC00501 promoter region contributed to the increase of LINC00501 in GC. LINC00501 transactivated transcription of SLUG, by recruiting hnRNPR to its promoter. The growth of GC was inhibited both in vitro and in vivo by suppressing the level of LINC00501 using pharmacological intervention from the histone acetyltransferase (HAT) inhibitor -C646. CONCLUSIONS: This study suggests that LINC00501 promotes GC progression via hnRNPR/SLUG pathway, which indicates a promising biomarker and target for GC.

Efficacy of Warfarin Therapy Guided by Pharmacogenetics: A Real-world Investigation Among Han Taiwanese.

PURPOSE: The anticoagulation activity of warfarin in populations with CYP2C9, VKORC1, and CYP4F2 variants differs between individuals and is correlated with poor international normalized ratio (INR) control. Pharmacogenetics-guided warfarin dosing has been successfully developed for patients with genetic variations in recent years. However, few real-world data have been used to investigate the INR and warfarin dosage and the time to target INR. This study examined the largest collection of genetic and clinical real-world data related to warfarin to provide further evidence supporting the benefits of pharmacogenetics in clinical outcomes. METHODS: We retrieved a total of 69,610 INR-warfarin records after the index date from 2,613 patients in the China Medical University Hospital database between January 2003 and December 2019. Each INR reading was obtained from the latest laboratory data after the hospital visit date. Patients with a history of malignant neoplasms or pregnancy before the index date were excluded, as were patients without data on INR measurements after the fifth day of prescription, genetic information, or gender variables. The primary outcomes were the INR and warfarin dosage during days 7, 14, 28, 56, and 84 after prescription. The secondary outcome was the time required to reach the INR ranges of 1.5 to 3.0 and >4.0. FINDINGS: A total of 59,643 INR-warfarin records from 2188 patients were retrieved. The average INR was higher for homozygous carriers of the minor allele at CYP2C9 and VKORC1 during the first 7 days (1.83 [1.03] [CYP2C9*1] and 2.46 [1.44] [CYP2C9*3], P < 0.001; 1.39 [0.36] [rs9923231 G/G], 1.55 [0.79] [rs9923231 G/A], and 1.96 [1.13] [rs9923231 A/A], P < 0.001) than for the wild-type allele. These patients with variants required lower warfarin doses than those with the wild-type allele during the first 28 days. CYP4F2 variant patients seemed to require higher doses of warfarin than those in the wild-type group; however, no significant difference in the average INR was observed (1.95 [1.14] [homozygous V433 carriers], 1.78 [0.98] [heterozygous V433M carriers], and 1.66 [0.91] [homozygous M433 carriers], P = 0.016). IMPLICATIONS: Our study indicates that genetic variants in the Han population may enhance warfarin responsiveness, which holds clinical relevance. An increased warfarin dosage was not linked to a shorter time to therapeutic INR between CYP4F2 variant patients and those with a wild-type allele. Assessing CYP2C9 and VKORC1 genetic polymorphisms before initiating warfarin treatment in real-world practice is essential for potentially vulnerable patients and is likely to optimize therapeutic dosing.

Cathepsin B cleavable novel prodrug Ac-Phe-Lys-PABC-ADM enhances efficacy at reduced toxicity in treating gastric cancer peritoneal carcinomatosis: an experimental study.

BACKGROUND: Doxorubicin (Adriamycin) is effective in gastric cancer treatment, but with severe dose-dependent toxicities. A novel prodrug of doxorubicin (Ac-Phe-Lys-PABC-ADM) is designed to deliver free doxorubicin relying on cathepsin B and reduce side effects. The authors examined the antitumor effect and toxicities of Ac-Phe-Lys-PABC-ADM against gastric cancer peritoneal carcinomatosis. METHODS: SGC-7901 gastric cancer cell line was used for the study. The in vitro study investigated the effects of doxorubicin and Ac-Phe-Lys-PABC-ADM on cell growth dynamics and cell cycle. The in vivo study investigated the efficacy and toxicity of Ac-Phe-Lys-PABC-ADM on a nude mice model of peritoneal carcinomatosis, with doxorubicin as positive control. RESULTS: In the in vitro study, Ac-Phe-Lys-PABC-ADM had a lower dose-dependent inhibitory effect on SGC-7901 cells. In the in vivo study of control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups, the median experimental peritoneal carcinomatosis indexes were 6, 1.5, and 1, respectively (P = .004); the body weights were 24.32 ± 1.40 g, 18.40 ± 2.97 g, and 23.61 ± 0.80 g, respectively (P = .000). Biochemical studies showed that Ac-Phe-Lys-PABC-ADM had significantly lower toxicities on the bone marrow, liver, kidney, and particularly heart. Histopathological studies of the control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups found significant myocardium toxicities in 3, 7, and 4 animals, respectively. CONCLUSIONS: Ac-Phe-Lys-PABC-ADM could be an effective molecular targeting drug to treat gastric cancer peritoneal carcinomatosis with enhanced efficacy and reduced toxicity.