Tumour cell-derived serglycin promotes IL-8 secretion of CAFs in gastric cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs)-derived IL-8 plays important roles in chemoresistance, immunosuppression, and lymph node metastasis of gastric cancer. However, the mechanisms underlying IL-8 production in CAFs remains unclear. METHODS: DNA pulldown assay was performed to identify the transcription factors responsible for IL-8 expression in CAFs, which was further verified using CHIP-qPCR and DNA agarose gel electrophoresis assays. The cellular localisation of IL-8 was analysed using multiplex immunofluorescence (MxIF). RESULTS: MxIF demonstrated that IL-8 was mainly produced by CAFs in gastric cancer. Lysine[K]-specific demethylase 5B (KDM5B) was identified as an IL-8 transcription factor in CAFs, and the binding of KDM5B to phosphorylated RB1 limited the transcriptional regulation of IL-8 in gastric cancer cells. Serglycin (SRGN) secreted by tumour cells activated the CD44/c-Myc pathway to upregulate KDM5B expression, thereby promoting IL-8 production in CAFs. Furthermore, tumour-associated neutrophils (TANs)-derived regenerating family member 4 (REG4) upregulates SRGN expression by activating cAMP-responsive element binding protein 1 (CREB1) in gastric cancer cells. Thus, the SRGN-IL-8-TANs-SRGN loop, which facilitates tumour progression, has been explored in gastric cancer. CONCLUSIONS: This study revealed the mechanisms of the preferential production of IL-8 by CAFs in gastric cancer, and paves the way for potential new therapeutic strategies for gastric cancer.

REEP3 is a potential diagnostic and prognostic biomarker correlated with immune infiltration in pancreatic cancer.

Receptor Expression-Enhancing Protein 3 (REEP3) serves as a pivotal enzyme crucial for endoplasmic reticulum (ER) clearance during mitosis and is implicated in the advancement of diverse malignancies. Nonetheless, the biological role and mechanisms of REEP3 in pancreatic cancer patients, along with its interplay with immune infiltration, remain inadequately elucidated. In this study, we initially analyzed the differential expression of REEP3 between pancreatic cancer tissues and normal pancreas tissues using the Cancer Genome Atlas (TCGA), GTEx and Gene Expression Omnibus (GEO) databases. Subsequently, we utilized Kaplan-Meier analysis, Cox regression and ROC curve to determine the predictive value of REEP3 for the clinical outcomes of pancreatic cancer patients. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA), were conducted to explore the potential signaling pathways and biological functions associated with pancreatic cancer. Furthermore, we investigated the PPI network, miRNA, RBP and transcription factor interactions of REEP3 using databases such as GeneMania, STRING, StarBase, KnockTK, ENCODE, Jaspar and hTFtarget. Lastly, the "ssGSEA" algorithm and TIMER database were employed to investigate the correlation between REEP3 expression and immune infiltration as well as immune checkpoints. The expression of REEP3 in pancreatic cancer showed a significantly higher level compared to that in normal tissues. ROC curve analysis indicated that REEP3 holds substantial diagnostic potential for pancreatic cancer patients. Elevated REEP3 expression correlated with unfavorable outcomes in terms of both overall survival and relapse-free survival, establishing it as a notable adverse prognostic marker in pancreatic cancer. Moreover, both univariate and multivariate Cox regression analyses demonstrated that REEP3 maintained an independent association with overall survival. Functional enrichment analyses revealed pathways significantly linked to REEP3, including cytoplasmic translation, wound healing, viral processes, regulation of cellular component size and actin filament organization. Additionally, REEP3 expression displayed a significant positive correlation with CD8+ T cells, B cells, natural killer cells, dendritic cells and macrophages. REEP3 is a potential diagnostic, prognostic marker and immunotherapeutic target for pancreatic cancer.

A Fe(III) intercalated clay nanoplatform for combined chemo/chemodynamic therapy.

A Fe(III) intercalated montmorillonite nanoplatform (Fe-MMT) was engineered for doxorubicin (DOX) loading. The constructed Fe-MMT/DOX nanoplatform could not only improve the production of H2O2 to enhance chemodynamic therapy but interfere with DNA damage repair to amplify the efficacy of DOX, proving an ideal combination of chemotherapy and chemodynamic therapy.

Circulating biomarkers of airflow limitation across the life span.

BACKGROUND: Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life. OBJECTIVES: This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children. METHODS: This study used data from 3 adult cohorts (TESAOD [Tucson Epidemiological Study of Airway Obstructive Disease], SAPALDIA [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults], LSC [Lovelace Smoker Cohort]) and 1 birth cohort (TCRS [Tucson Children's Respiratory Study]) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV1/forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life. RESULTS: After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV1/FVC and FEV1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV1 % predicted in all adult cohorts (meta-analyzed FEV1 decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; P = 2.4 × 10-16). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV1 and FEV1/FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV1 and FEV1/FVC (P = .01 and .001). CONCLUSIONS: A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease.

Acetylshikonin induces apoptosis through the endoplasmic reticulum stress-activated PERK/eIF2α /CHOP axis in oesophageal squamous cell carcinoma.

Acetylshikonin (AS) is an active component of Lithospermum erythrorhizon Sieb. et Zucc that exhibits activity against various cancers; however, the underlying mechanisms of AS against oesophageal squamous carcinoma (ESCC) need to be elusive. The research explores the anti-cancer role and potential mechanism of AS on ESCC in vitro and in vivo, providing evidences for AS treatment against ESCC. In this study, we firstly demonstrated that AS treatment effectively inhibits cell viability and proliferation of ESCC cells. In addition, AS significantly induces G1/S phage arrest and promotes apoptosis in ESCC cell lines. Further studies reveal that AS induces ER stress, as observed by dose- and time-dependently increased expression of BIP, PDI, PERK, phosphorylation of eIF2α , CHOP and splicing of XBP1. CHOP knockdown or PERK inhibition markedly rescue cell apoptosis induced by AS. Moreover, AS treatment significantly inhibits ESCC xenograft growth in nude mice. Elevated expression of BIP and CHOP is also observed in xenograft tumours. Taken together, AS inhibits proliferation and induces apoptosis through ER stress-activated PERK/eIF2α /CHOP pathway in ESCC, which indicates AS represents a promising candidate for ESCC treatment.

A modified Blumgart anastomosis with a simple and practicable procedure after laparoscopic pancreaticoduodenectomy: our center's experience.

BACKGROUND: Laparoscopic pancreaticoduodenectomy(LPD) has become the goal of lots of minimally invasive surgical centers in recent years. Postoperative pancreatic fistula(POPF) is still the barrier to attaining the above goal. Thus, improving anastomosis techniques to reduce the rate of POPF has been a hotspot of surgery. Blumgart pancreaticojejunostomy is considered one of the best anastomosis procedures, with low rates of POPF. However, the original Blumgart pancreaticojejunostomy method is not easy for laparoscopic operation. In consequence, we modified a Blumgart pancreaticojejunostomy technique with a simple and practicable procedure and applied to LPD. METHODS: We collected and retrospectively analyzed the perioperative clinical data of patients who underwent modified Blumgart anastomosis from February 2017 to September 2022. The above patients included 53 cases in open pancreaticojejunostomy(OPD) and 58 cases in LPD. After propensity score matching, 44 cases were included for comparison in each group. RESULTS: After propensity score matching, the average time for pancreaticojejunostomy was about 30 min in the LPD group. The Clinically relevant POPF(CR-POPF) rate was 9.1%. The length of postoperative hospitalization was 13.1 days. Compared with the OPD group, The CR-POPF rate in the LPD group are not significant differences. But the postoperative length of hospital stay was significantly shorter in the LPD group. Besides, there were no other severely postoperative complications between two groups. CONCLUSION: The modified Blumgart anastomosis technique applied to LPD in our Center not only has simple and convenient properties but also low rate of CR-POPF. And this method may be a good choice for surgeons to begin to carry out LPD.

Identification and validation of molecular subtypes' characteristics in bladder urothelial carcinoma based on autophagy-dependent ferroptosis.

Background: Nowadays, more evidences indicated that autophagy-dependent ferroptosis regulatory molecules (ADFRMs) may be closely related to various tumors. In current study, we intended to establish a prognostic ADFRMs signature and investigated its potential roles in bladder urothelial carcinoma (BLCA). Methods: Two distinct clusters were determined by consensus clustering with expression of 119 identified ADFRMs in BLCA. The tumor microenvironment was investigated through "CIBERSORT" algorithm, and enrichment analyses were utilized to seek molecular characteristics of differentially expressed genes (DEGs) between clusters. Moreover, a 2-ADFRMs prognostic signature including TRIB3 and WIPI1 was identified in TCGA cohort and further evaluated in the GSE13507 cohort. The qRT-PCR was conducted to examine the expression of prognostic genes. Further, the risk score was gained through calculating the level of TRIB3 and WIPI1 expression through the coefficient. The correlations between risk score with clinicopathologica features, tumor microenvironment, and drug sensitivity were explored. Results: Patients in TCGA-BLCA were grouped into two clusters with different expression patterns of ADFRMs. And the overall survival, tumor microenvironment and biological functions were significant different between two clusters. Moreover, a 2-ADFRMs model was constructed, and patients were separated into a low-risk and high-risk group. Survival analysis indicated patients with low risk promised a good prognosis, suggesting the risk score determined with ADFRMs signature exhibited an acceptable capacity for survival prediction in BLCA. Correlation analysis demonstrated risk score had close ties with age, stage, and tumor microenvironment. In vivo, the expression of prognostic genes was identified to be up-regulated in BLCA cell line T24. Conclusion: The constructed 2-ADFRMs signature was a promising model to predict prognosis and correlated with tumor microenvironment, which had latent clinical value in the intervention for BLCA.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastasis (BrM) and a poor prognosis. As the most lethal form of breast cancer, BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis (BCBrM), but the underlying mechanisms are far from being fully elucidated. METHODS: Through analysis of BCBrM transcriptome data from mice and patients, and immunohistochemical validation on patient tissues, we identified and verified the specific down-regulation of retinoic acid receptor responder 2 (RARRES2), a multifunctional adipokine and chemokine, in BrM of TNBC. We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies. Key signaling pathway components were evaluated using multi-omics approaches. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2. RESULTS: We found that down-regulation of RARRES2 is specifically associated with BCBrM, and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue (PTEN)-mammalian target of rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment. CONCLUSIONS: Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM. RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer.

In gastric cancer, lymph node metastasis (LNM) is the major metastasis route, and lymphatic invasion is the precursor of LNM. Tumor-associated neutrophils (TANs) promote LNM. However, the molecular mechanisms underlying TANs-mediated lymphatic invasion and/or LNM remain unclear. Herein, we revealed that high level of TANs was the independent risk factor for lymphatic invasion and LNM respectively, and lymphatic tumor cell-neutrophil clusters were positively correlated with LNM. Crosstalk between neutrophils and tumor cells was required for enhanced tumor cell invasiveness, endowing neutrophils to boost epithelial-to-mesenchymal transition (EMT) of tumor cells and in turn promoting LNM. Mechanically, tumor cells educated neutrophils via TGFß1 to produce more FAM3C through Smad2/3 signaling activation, and FAM3C promoted tumor cell EMT through JNK-ZEB1/Snail signaling pathway. The crosstalk enhanced the affinity of neutrophils with tumor cells through interaction of integrins α6ß1 and α6ß4 with CD151. Furthermore, studies using tumor-bearing mice demonstrated that neutrophils were the important driver for gastric cancer tumorigenesis and invasiveness. The study clearly identifies the functional roles of TANs in promoting tumor invasion, and facilitates a better understanding of novel mechanisms responsible for LNM of gastric cancer, which provides potential targets for developing new strategies to prevent or treat LNM in gastric cancer.

Cytomegalovirus serology in young to mid-adult life and decline of lung function.

INTRODUCTION: Cytomegalovirus (CMV) seropositivity has been recently linked to severity and progression of asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). To date, no longitudinal study has addressed the relation of CMV serology to levels and decline of lung function in the general adult population. METHODS: We evaluated 403 participants from the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) who at enrollment were aged 28-55 years and completed lung function tests. During follow-up, the 403 participants completed on average 7.2 lung function tests per subject for a total of 2908 observations over a mean period of 14.7 years. We tested CMV serology in serum samples from enrollment and categorized participants into low, medium, and high CMV serology based on tertiles. The relation of CMV serology at enrollment to lung function levels and decline during follow-up was tested in multivariate random coefficients models. RESULTS: After full adjustment, participants in the highest CMV serology tertile had faster declines of forced expiratory volume in 1 s (FEV1 ) and FEV1 /forced vital capacity (FVC) compared with subjects in the lowest tertile (by -7.9 ml/year 95% confidence interval [-13.9 ml/year, -1.93 ml/year], and by -0.13%/year [-0.23%/year, -0.026%/year], respectively). These CMV effects were additive with those of cigarette smoking. No associations were found between CMV serology and FVC, indicating specific effects of CMV seropositivity on airflow limitation. CONCLUSION: High CMV serology in young to mid-adult life may be linked to increased COPD risk through an accelerated decline of lung function.

Lycorine weakens tamoxifen resistance of breast cancer via abrogating HAGLR-mediated epigenetic suppression on VGLL4 by DNMT1.

Much is known about the significance of lycorine, a natural alkaloid, in combating various types of cancer, including breast cancer (BC), but whether it participates in regulating tamoxifen (TAM) resistance and its underlying mechanism remain to be elucidated. Tamoxifen-resistant (TAMR) BC cells were first established by continuously exposed to increasing concentrations of TAM. Levels of targeted gene including HOXD antisense growth-associated lncRNA (HAGLR) and Vestigial like family member 4 (VGLL4) were analyzed by qRT-PCR and western blot, respectively. Cell proliferation ability was assessed by MTT and EdU assays. Flow cytometry was carried out to evaluate the apoptosis. VGLL4 promoter methylation was examined using methylation specific PCR (MSP). The role of HAGLR acting on the expression of VGLL4 via DNA hypermethylation was confirmed by RNA immunoprecipitation (RIP). Here, we reported that lycorine administration reduced the survival ratio of TAMR BC cells, decreased the IC50 of TAM, and strengthened TAM-induced apoptosis. HAGLR, observed to be highly expressed in TAMR BC cells, was identified to be a downstream effector of lycorine, of which overexpression abolished lycorine-mediated TAMR inhibition. VGLL4 served as a target of HAGLR in regulating lycorine-mediated suppression on tamoxifen resistance of TAMR BC cells. Mechanistically, HAGLR epigenetically suppressed VGLL4 expression via DNA methyltransferase 1 (DNMT1)-mediated DNA hypermethylation. Taken together, our data highlights the pivotal role of lycorine in TAM resistance of BC, which may provide a potential agent for improving the effectiveness and efficacy of BC resistance.

A Systematic Review of the Therapeutic Potential of Resveratrol During Colorectal Cancer Chemotherapy.

BACKGROUND: The chemotherapy modality is generally used for treating colorectal cancer. However, the clinical application of chemotherapeutic drugs may be limited due to their adverse effects on normal cells/tissues and the development of cancer resistance. Using the combined treatment of chemotherapy drugs and natural bioactive compounds (such as resveratrol) can alleviate adverse drug reactions and induce synergies between the drugs. OBJECTIVE: In the current review, the potential therapeutic impacts of resveratrol during colorectal cancer chemotherapy were studied. METHODS: Based on the PRISMA guideline, we performed a systematic search in different electronic databases up to May, 2021. Following the search, 321 papers were found and then screened for eligibility. Twenty-seven papers were finally included in the present study Results: Compared to the control group, the growth inhibition of cancerous cells treated with chemotherapeutic drugs was considerably higher, and resveratrol co-administration synergistically increased chemotherapy-induced cytotoxicity. Moreover, a reduction in the tumor weight, volume and growth of mice was observed following chemotherapy administration compared to the untreated groups, and these reductions were predominant in animals treated with resveratrol plus chemotherapy. Other findings showed that chemotherapy alone and in combination with resveratrol modulated the cell cycle profile of cancerous cells. Furthermore, chemotherapy treatment induced a set of biochemical and histopathological alterations in cancer cells/tissues, and these changes were synergized following resveratrol co-treatment (in most of the cases), excluding inflammatory mediators. CONCLUSION: In most cases, resveratrol co-administration could sensitize cancerous cells to chemotherapy drugs through its oxidant, apoptosis, anti-inflammatory activities, etc. Nevertheless, suggesting the use of resveratrol during chemotherapy of colorectal cancer patients requires further clinical studies.

The optimal neoadjuvant chemotherapy regimen for locally advanced gastric and gastroesophageal junction adenocarcinoma: a systematic review and Bayesian network meta-analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) for locally advanced gastric and gastroesophageal junction adenocarcinoma (LAGC) has been recommended in several guidelines. However, there is no global consensus about the optimum of NAC regimens. We aimed to determine the optimal NAC regimen for LAGC. METHODS: A systematic review and Bayesian network meta-analysis was performed. The literature search was conducted from inception to June 2022. The odds ratio (OR) value and 95% confidence interval (95% CI) were used for assessment of R0 resection rate and pathological complete response rate (pCR) as primary outcomes. The hazard ratio (HR) value and 95% CI were interpreted for the assessment of overall survival (OS) and disease-free survival (DFS) as second outcomes. The risk ratio (RR) value and 95% CI were used for safety assessment. RESULTS: Twelve randomized controlled trials were identified with 3846 eligible participants. The network plots for R0 resectability, OS, and DFS constituted closed loops. The regimens of TPF (taxane and platinum plus fluoropyrimidine), ECF (epirubicin and cisplatin plus fluorouracil), and PF (platinum plus fluoropyrimidine) showed a meaningful improvement of R0 resectability, as well as OS and/or DFS, compared with surgery (including surgery-alone and surgery plus postoperative adjuvant chemotherapy). Importantly, among these regimens, TPF regimen showed significant superiority in R0 resection rate (versus ECF regimen), OS (versus ECF regimen), DFS (versus PF and ECF regimens), and pCR (versus PF regimen). CONCLUSIONS: The taxane-based triplet regimen of TPF is likely the optimal neoadjuvant chemotherapy regimen for LAGC patients.

Association of serum Interleukin-8 level with lymph node metastasis and tumor recurrence in gastric cancer.

The level of pretherapeutic serum interleukin-8 (sIL-8) has been demonstrated to correlate with chemoresistance in gastric cancer. However, its clinicopathological significance of sIL-8 in gastric cancer remains unknown. Herein, a total of 335 patients diagnosed with gastric adenocarcinoma were enrolled. The clinicopathological features were collected, and the sIL-8 levels were measured using enzyme-linked immunosorbent assay. The sIL-8 levels ranged from 1.48 pg/ml to 1025.22 pg/ml with > 15.41 pg/ml defined as high according to the receiver operating characteristic analysis. sIL-8 levels were strongly associated with Lauren classification and tumor recurrence. High sIL-8 correlated with lymph node metastasis (LNM) in the intestinal- and diffuse-type tumors and acted as an independent risk factor for LNM in both types. Patients with high sIL-8 levels had worse relapse-free survival than those with low sIL-8 levels. High sIL-8 level was associated with tumor relapse in the intestinal- and diffuse-type tumors, and was also an independent risk factor in the intestinal- and mixed-type tumors. Further analysis revealed that sIL-8 levels were positively associated with LNM and tumor relapse in patients with negative carcinoembryonic antigen (CEA), but not in those with elevated serum CEA levels. In conclusion, this retrospective study demonstrated that the pretherapeutic sIL-8 level has predictive value for LNM and tumor recurrence, and may serve as a potential tumor marker in gastric cancer.

The Effect of SBIRT on Harmful Alcohol Consumption in the Community Health Centers of Shanghai, China: A Randomized Controlled Study.

OBJECTIVE: The present study was a randomized controlled trial with a longitudinal design aimed at examining the effectiveness of Screening, Brief Intervention and Referral to Treatment (SBIRT) on harmful alcohol use in the community health centres in Shanghai, China, and further compared the effects of a multi-session brief intervention (MBI) and a single-session brief intervention (SBI). METHODS: A total of 362 participants were recruited from four districts of Shanghai and randomly assigned to MBI, SBI and routine care (RC) groups. The MBI group received the brief intervention twice. Follow-up assessments were conducted at 1 and 3 months after the intervention. RESULTS: Compared with the SBI and the RC groups, the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) scores (F = 6.422, P = 0.002), SDS scores (F = 5.779, P = 0.003) and SAS scores (F = 4.004, P = 0.019) were significant improved in the MBI group at 1and 3-month follow-up assessment. In the SBI group, the SDS scores decreased significantly compared with the RC group, and there were no significant differences in ASSIST scores, drinking knowledge scores and SAS scores 1-month follow-up assessment. CONCLUSION: The findings suggested that SBIRT with two sessions of BI had considerable effects on individuals with harmful alcohol use. It provided clinical evidence for future use in China and other Asian countries with similar situations.

Tumor-derived IL-8 facilitates lymph node metastasis of gastric cancer via PD-1 up-regulation in CD8+ T cells.

BACKGROUND: The pretherapeutic serum interleukin-8 (sIL-8) levels have been revealed to be increased in about half of patients with locally advanced gastric cancer. However, the roles of IL-8 in lymph node metastasis (LNM) and the underlying mechanisms remain unclear. METHODS: 146 patients with primary gastric carcinoma were enrolled in this study. ELISA was used to measure IL-8 levels. The CD4/CD8 ratio and programmed cell death-1 (PD-1) expression of T cells in primary tumor tissues, tumor-draining lymph nodes (TDLNs) and non-draining lymph nodes (NDLNs) were assayed with flow cytometry. Protein expression of the molecules was determined with immunohistochemistry, western blotting or immunoprecipitation. The gastric cancer mouse tumor model with LNM was utilized to determine the role of IL-8 in regulation of tumor metastasis and progression. RESULTS: The elevated sIL-8 levels were associated with LNM and poor prognosis in gastric cancer. Furthermore, sIL-8 was identified to be prominently produced by gastric cancer-associated fibroblasts (CAFs). Elevated IL-8 can up-regulate PD-1 expression in CD8+ T cells, resulting in immunosuppression in primary tumors and TDLNs, which enhances LNM of gastric cancer. Molecularly, IL-8 increases PD-1 expression through JAK2/STAT3 signaling activation, and inhibits its ubiquitination via Fbxo38 down-regulation. In addition, the in vivo studies in mouse gastric cancer model demonstrated that IL-8 promotes LNM via PD-1 up-regulation in CD8+ T cells. CONCLUSION: The present study elucidates the pro-metastatic role of elevated IL-8 in gastric cancer, and provides novel insights to enhance immune checkpoint blockade therapy for anti-PD-1 in gastric cancer.

Club cell secretory protein and lung function in children with cystic fibrosis.

BACKGROUND: Club cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF). METHODS: We used longitudinal data from CF children (EPIC Study) with no positive cultures for Pseudomonas aeruginosa prior to enrollment. Circulating levels of CC16 and an inflammatory score (generated from CRP, SAA, calprotectin, G-CSF) were compared between participants with the lowest and highest FEV1 levels in adolescence (LLF and HLF groups, respectively; N = 130-per-group). Single nucleotide variants (SNVs) in the SCGB1A1, EHF-APIP loci were tested for association with circulating CC16 and with decline of FEV1 and FEV1/FVC% predicted levels between ages 7-16 using mixed models. RESULTS: Compared with the HLF group, the LLF group had lower levels of CC16 (geometric means: 8.2 vs 6.5 ng/ml, respectively; p = 0.0002) and higher levels of the normalized inflammatory score (-0.21 vs 0.21, p = 0.0007). Participants in the lowest CC16 and highest inflammation tertile had the highest odds for having LLF (p<0.0001 for comparison with participants in the highest CC16 and lowest inflammation tertile). Among seven SNVs associated with circulating CC16, the top SNV rs3741240 was associated with decline of FEV1/FVC and, marginally, FEV1 (p = 0.003 and 0.025, respectively; N = 611 participants, 20,801 lung function observations). CONCLUSIONS: Serum CC16 deficits are strongly associated with severity of CF lung disease and their effects are additive with systemic inflammation. The rs3741240 A allele is associated with low circulating CC16 and, possibly, accelerated lung function decline in CF.

Docetaxel and 5-FU enhanced the inhibitory effects of apatinib and ramucirumab on growth and migration of gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors in the world. The clinical benefit of anti-angiogenic strategy as a single drug is limited. Some studies showed that the combination of anti-angiogenic therapy and chemotherapy exhibited synergistic effect and reduced the side effects of chemotherapy drugs. We investigated the combined effects of these two types of drugs in gastric cancer cells in vitro and in vivo. METHODS: cell viability, migration, invasion, and apoptosis were evaluated by CCK-8, wound-healing, transwell, and Annexin V-FITC/PI assay, respectively. In vivo anti-cancer efficacy was tested for the cell proliferation and metastasis in cell line derived tumor xenograft (CDX) model and patient derived tumor xenografted (PDX) model based on Tg (fli-1: EGFP) zebrafish embryos; RESULTS: In the cell experiments, the combination of the two types of drugs could inhibit the proliferation and metastasis of gastric cancer cells and promote apoptosis through VEGFR-2/AKT/ERK1/2 signal. In the zebrafish CDX (zCDX) model and zebrafish PDX (zPDX) model, the combination of the two treatment also showed a synergistic effect in inhibiting gastric cancer cell metastasis and cell proliferation. CONCLUSIONS: Apatinib/ramucirumab targeted therapy combined with docetaxel or 5-fluorouracil (5-FU) may serve as an effective treatment strategy for patients with advanced gastric cancer.

Efficacy and Safety of Oblique Lumbar Interbody Fusion Versus Transforaminal Lumbar Interbody Fusion for Degenerative Lumbar Spondylolisthesis: A Systematic Review and Meta-Analysis.

OBJECTIVE: We critically evaluated the efficacy and safety of oblique lumbar interbody fusion (OLIF) versus transforaminal lumbar interbody fusion (TLIF) for degenerative lumbar spondylolisthesis (DLS). METHODS: PubMed, Embase, Cochrane Library, the Web of Science Core Collection, Chinese Biomedical Literature, China National Knowledge Infrastructure, Wanfang Digital Periodicals, and Chinese Science and Technology Periodicals were searched from their inception to February 2021. Randomized controlled trials and retrospective or prospective cohort studies (CSs) comparing OLIF and TLIF for DLS were included. A meta-analysis was conducted, if possible. RESULTS: Ten studies were included in the statistical analysis. The pooled results of the CSs showed no statistically significant differences (P > 0.05) in pain relief at 3 or 6 months of follow-up and functional improvement at 1 or 3 months of follow-up in DLS patients between those who had undergone OLIF versus TLIF. The pooled results of the CSs showed that OLIF could significantly improve the degree of lumbar lordosis, foraminal height, and disc height and decrease the intraoperative blood loss, postoperative drainage volume, operative duration, bed rest time, and hospital length of stay (P < 0.05) compared with TLIF. The incidence of adverse events was not significantly different statistically between OLIF and TLIF. CONCLUSIONS: The results from the present study suggest that pain relief and functional improvement were not significantly different between OLIF and TLIF. Nevertheless, the use of OLIF might improve radiological outcomes and reduce intraoperative blood loss, postoperative drainage volume, operative duration, bed rest duration, and hospital length of stay compared with TLIF. Additional high-quality randomized controlled trials are still required to confirm these findings.

Cancer-associated fibroblasts-derived HAPLN1 promotes tumour invasion through extracellular matrix remodeling in gastric cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are the most principal cells of depositing and remodeling extracellular matrix (ECM) within solid tumours. Both CAFs and ECM have been demonstrated to play critical roles in tumour development. However, the functional roles of CAFs-associated ECM or ECM remodeling in the pathogenesis of gastric cancer remain unclear. METHODS: Bioinformatics analysis of the differentially expressed genes between CAFs and corresponding normal fibroblasts (NFs) in gastric cancer was performed. The clinical relevance of hyaluronan and proteoglycan link protein 1 (HAPLN1) was investigated using TCGA data and human gastric cancer specimens. Spheroid cell invasion assay and nude mouse xenograft model were introduced to assay cell invasion. Second harmonic generation (SHG) was used to image and analyze the changes of collagen fibers in ECM. RESULTS: HAPLN1 was identified as the most significantly up-regulated gene in CAFs of gastric cancer, and higher HAPLN1 levels were associated with shorter overall survival. HAPLN1 was prominently produced by CAFs, and its levels were correlated positively with tumor T staging (P < 0.0001), lymph node metastasis (P = 0.0006) and TNM stage (P = 0.0063). Mechanically, gastric cancer cells activate fibroblasts to up-regulate HAPLN1 expression via activation of TGF-ß1/Smad2/3 signaling, which in turn promotes tumour migration and invasion. Importantly, SHG assays with mouse xenograft models and human samples further demonstrated CAFs-derived HAPLN1 increased tumour invasiveness through ECM remodeling. CONCLUSIONS: This study sheds light on the role of CAFs-derived HAPLN1 in the pathogenesis of gastric cancer, and provides insights for the development of novel strategies for prevention and treatment of gastric carcinoma.