Intrinsic and evasive antiangiogenic drug (AAD) resistance is frequently developed in cancer patients, and molecular mechanisms underlying AAD resistance remain largely unknown. Here we describe AAD-triggered, lipid-dependent metabolic reprogramming as an alternative mechanism of AAD resistance. Unexpectedly, tumor angiogenesis in adipose and non-adipose environments is equally sensitive to AAD treatment. AAD-treated tumors in adipose environment show accelerated growth rates in the presence of a minimal number of microvessels. Mechanistically, AAD-induced tumor hypoxia initiates the fatty acid oxidation metabolic reprogramming and increases uptake of free fatty acid (FFA) that stimulates cancer cell proliferation. Inhibition of carnitine palmitoyl transferase 1A (CPT1) significantly compromises the FFA-induced cell proliferation. Genetic and pharmacological loss of CPT1 function sensitizes AAD therapeutic efficacy and enhances its anti-tumor effects. Together, we propose an effective cancer therapy concept by combining drugs that target angiogenesis and lipid metabolism.

Accumulating evidence indicates that gut microbiota participates in the pathogenesis and progression of liver diseases. The severity of immune-mediated liver injury is associated with different microbial communities. Akkermansia muciniphila can regulate immunologic and metabolic functions. However, little is known about its effects on gut microbiota structure and function. This study investigated the effect of A. muciniphila on immune-mediated liver injury and potential underlying mechanisms. Twenty-two C57BL/6 mice were assigned to three groups (N = 7–8 per group) and continuously administrated A. muciniphila MucT or PBS by oral gavage for 14 days. Mouse feces were collected for gut microbiota analysis on the 15th day, and acute liver injury was induced by Concanavalin A (Con A, 15 mg/kg) injection through the tail vein. Samples (blood, liver, ileum, colon) were assessed for liver injury, systemic inflammation, and intestinal barrier function. We found that oral administration of A. muciniphila decreased serum ALT and AST and alleviated liver histopathological damage induced by Con A. Serum levels of pro-inflammatory cytokines and chemokines (IL-2, IFN-γ, IL-12p40, MCP-1, MIP-1a, MIP-1b) were substantially attenuated. A. muciniphila significantly decreased hepatocellular apoptosis; Bcl-2 expression increased, but Fas and DR5 decreased. Further investigation showed that A. muciniphila enhanced expression of Occludin and Tjp-1 and inhibited CB1 receptor, which strengthened intestinal barriers and reduced systemic LPS level. Fecal 16S rRNA sequence analysis indicated that A. muciniphila increased microbial richness and diversity. The community structure of the Akk group clustered distinctly from that of mice pretreated with PBS. Relative abundance of Firmicutes increased, and Bacteroidetes abundance decreased. Correlation analysis showed that injury-related factors (IL-12p40, IFN-γ, DR5) were negatively associated with specific genera (Ruminococcaceae_UCG_009, Lachnospiraceae_UCG_001, Akkermansia), which were enriched in mice pretreated with A. muciniphila. Our results suggested that A. muciniphila MucT had beneficial effects on immune-mediated liver injury by alleviating inflammation and hepatocellular death. These effects may be driven by the protective profile of the intestinal community induced by the bacteria. The results provide a new perspective on the immune function of gut microbiota in host diseases.

The use of proton pump inhibitors (PPIs) may potentially predispose to the development of small intestinal bacterial overgrowth (SIBO), but this association is controversial due to conflicting results from studies conducted to date. The aim of this meta-analysis was to evaluate the association between the use of PPIs and the risk of SIBO. We systematically searched the online PubMed, Embase, and Cochrane Library databases and Web of Science for relevant articles published up to November 2016. Two researchers identified and extracted data independent of each other. The pooled analysis was performed using the generic inverse-variance random-effects model. Subgroup and sensitivity analysis were conducted to assess the stability and heterogeneity of the pooled results. The risk of publication bias was evaluated by assessing for funnel plot asymmetry and by Egger's test and Begg's test. A total of 19 articles met the eligibility criteria for the meta-analysis, reporting on 7055 subjects. The pooled odds ratio (OR) showed a statistically significant association between increased risk of SIBO and PPI use (OR 1.71, 95% confidence interval 1.20-2.43). Subgroup analyses demonstrated an association between SIBO and PPI use in studies that employed small bowel aspirates culture and glucose hydrogen breath tests (GHBT) as diagnostic tests for SIBO. Our meta-analysis suggests that the use of PPI moderately increases the risk of SIBO, thereby highlighting the need for appropriate prescribing of PPIs.

Objective: To investigate the clinical significance of IL-10 þ tumor-associated macrophages (TAMs) in gastric cancer. Background: Due to the plasticity and diversity of TAMs, it is necessary to phenotypically and functionally classify subsets of TAMs to better understand the critical role of TAMs in cancer progression. TAMs expressing interleukin-10 (IL-10) have been found to facilitate immune evasion in many malignancies, but the role of IL-10 þ TAMs in gastric cancer remains obscure. Methods: Four hundred and sixty-eight tumor tissue microarray specimens, 52 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, and data of 298 gastric cancer patients from the Cancer Genome Atlas (TCGA) were analyzed. IL-10 þ TAM level and immune contexture were examined by CIBERSORT, immunohistochemistry, and flow cytometry. Clinical outcomes were analyzed by Kaplan-Meier curves and Cox model. Results: Gastric cancer patients with high IL-10 þ TAM infiltration exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. IL-10 þ TAM infiltration yielded an immunoevasive tumor microenvironment featured by regulatory T cell infiltration and CD8 þ T cell dysfunction. The combinational analysis of IL-10 þ TAM and CD8 þ T cell infiltration stratified patients into distinct risk groups with different clinical outcomes. Moreover, IL-10 þ TAM infiltration was correlated with tumor-intrinsic characteristics including EBV status, PD-L1 expression, and genome stability in gastric cancer. Conclusions: This study revealed that IL-10 þ TAMs might drive an immunoevasive microenvironment and determine poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy,indicating IL-10 þ TAMs could be applied as a potential target for immunotherapeutic approach in gastric cancer.

Pyogenic liver abscess (PLA) is a common intra-abdominal infection in adults. In this study, we aim to explore demographic and clinical characteristics of PLA focusing on Klebsiella pneumoniae (K. pneumoniae) induced PLA (KP-PLA) in mainland China. A retrospective review of medical records from all patients with KP-PLA admitted to a tertiary teaching hospital over a 21-year period (1994–2015) was performed. Among 296 PLA cases with confirmed culture-positive data, K. pneumoniae was revealed as the predominant pathogen (n = 189, 63.9%), followed by Escherichia coli (n = 39, 13.2%). Strikingly, KP-PLA patients had a higher incidence of metabolic disorders, such as diabetes mellitus (49.7% vs. 36.4%, P = 0.027; odds ratio (OR): 1.725; 95% confidence interval (CI): 1.061–2.805), hypertension (38.1% vs. 19.6%, P = 0.001; OR: 2.520; 95% CI: 1.439–4.413), and fatty liver (32.3% vs. 14.0%, P = 0.001; OR: 2.923; 95% CI: 1.564–5.462) than those with non-K. pneumoniae induced PLA (non-KP-PLA). Moreover, patients with KP-PLA had higher susceptibility to septic metastatic infection at distant sites compared to those with non-KP-PLA (10.6% vs. 3.7%, p = 0.038). Our results indicate that K. pneumoniae is the predominant pathogen of PLA in mainland China. KP-PLA is frequently diagnosed in patients with metabolic diseases and has a higher risk for septic metastatic infection.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.DesignTwo unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33–ST2–CXCL3–CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.ResultsIL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33–ST2–MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3–CXCR2 signalling. Type III collagen was identified as the CXCL3–CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.ConclusionsOur work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.

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BackgroundThe morbidity and mortality of pancreatic cancer vary considerably around the world. The aim of this study was to characterize and evaluate recent changes in incidence and incidence-based mortality in the USA.MethodsIncidence and incidence-based mortality data were based on the 18 Surveillance, Epidemiology, and End Results (SEER) registries through SEER*Stat software. We adopted joinpoint regression to analyze the temporal trends stratified by age, gender, ethnicity, stage, tumor site, and size.ResultsBased on 18 SEER data sets, the age-adjusted incidence of pancreatic cancer increased from 11.85/100,000 in 2000 to 14.70/100,000 in 2014, increasing by an average annual percentage change (AAPC) of 1.6 (95% CI 1.5–1.8, p<0.05). The incidence-based mortality also increased, from 9.96/100,000 in 2001 to 12.96/100,000 in 2014, increasing by an AAPC of 1.9 (95% CI 1.3–2.5, p<0.05). However, we observed a deceleration in mortality since 2005, with the annual percentage change decreasing from 4.1 (2001–2005) to 1.0 (2005–2014). These increasing trends in pancreatic cancer were observed in most subgroups (stratified by age, gender, ethnicity, stage, tumor site, and size).ConclusionThe incidence and mortality rates of pancreatic cancer in the USA have increased significantly since 2000, highlighting the need for increased preventive, screening, and surveillance efforts.