Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.

In this paper, we propose a novel deep learning architecture for multi-label zero-shot learning (ML-ZSL), which is able to predict multiple unseen class labels for each input instance. Inspired by the way humans utilize semantic knowledge between objects of interests, we propose a framework that incorporates knowledge graphs for describing the relationships between multiple labels. Our model learns an information propagation mechanism from the semantic label space, which can be applied to model the interdependencies between seen and unseen class labels. With such investigation of structured knowledge graphs for visual reasoning, we show that our model can be applied for solving multi-label classification and ML-ZSL tasks. Compared to state-of-the-art approaches, comparable or improved performances can be achieved by our method.

Activities of CD4+ regulatory (TREG) cells restore immune homeostasis during chronic inflammatory disorders. Roles for TREG cells in inflammation-associated cancers, however, are paradoxical. It is widely believed that TREG function in cancer mainly to suppress protective anticancer responses. However, we demonstrate here that TREG cells also function to reduce cancer risk throughout the body by efficiently downregulating inflammation arising from the gastrointestinal (GI) tract. Building on a “hygiene hypothesis” model in which GI infections lead to changes in TREG that reduce immune-mediated diseases, here we show that gut bacteria-triggered TREG may function to inhibit cancer even in extraintestinal sites. Ability of bacteria-stimulated TREG to suppress cancer depends on interleukin (IL)-10, which serves to maintain immune homeostasis within bowel and support a protective antiinflammatory TREG phenotype. However, under proinflammatory conditions, TREG may fail to provide antiinflammatory protection and instead contribute to a T helper (Th)-17-driven procarcinogenic process; a cancer state that is reversible by downregulation of inflammation. Consequently, hygienic individuals with a weakened IL-10 and TREG-mediated inhibitory loop are highly susceptible to the carcinogenic consequences of elevated IL-6 and IL-17 and show more frequent inflammation-associated cancers. Taken together, these data unify seemingly divergent disease processes such as autoimmunity and cancer and help explain the paradox of TREG and inflammation in cancer. Enhancing protective TREG functions may promote healthful longevity and significantly reduce risk of cancer.

Helicobacter pylori infection results in chronic gastritis, which may progress to gastric cancer. In this study, we investigated the efficacy of H. pylori eradication in preventing the progression of gastritis to gastric cancer in H. pylori-infected transgenic INS-GAS mice. H. pylori infection induced severe dysplasia and gastric cancer classified as high-grade and lowgrade gastrointestinal intraepithelial neoplasia (GIN) in INS-GAS mice at 28 weeks postinfection (WPI). H. pylori eradication therapy using omeprazole, metronidazole, and clarithromycin was administered p.o. at 8, 12, or 22 WPI. Compared with untreated infected mice, H. pylori eradication at 8, 12, and 22 WPI significantly reduced the severity of dysplasia (P < 0.01). Moreover, H. pylori eradication at 8 WPI completely prevented the development of GIN (P < 0.001).Although not as effective as early antimicrobial treatment, prevention of progression to high-grade GIN was achieved by H. pylori eradication at 12 and 22 WPI (P < 0.05). Consistent with reduced gastric pathology, H. pylori eradication at all time points significantly down-regulated gastric Interferon-;, tumor necrosis factor-A, inducible nitric oxide synthase, and Reg 1 mRNA levels (P < 0.05) and reduced epithelial proliferation in the corpus (P < 0.01) compared with untreated infected mice. We concluded that H. pylori eradication prevented gastric cancer to the greatest extent when antibiotics are given at an early point of infection, but that eradication therapy given at a later time point delayed the development of severe dysplastic lesions. [Cancer Res 2008;68(9):3540-8]

BACKGROUND: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years. METHODS: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. RESULTS: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age. CONCLUSIONS: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a firstline checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

The mechanisms of melanoma invasion are poorly understood despite extensive inquiry. SRY (sex determining region Y)-box 2 (SOX2) is an embryonic stem cell transcription factor that has recently been discovered to be expressed in human melanoma where it is associated with dermal invasion and primary tumor thickness. To assess the potential role of SOX2 expression in melanoma invasion, we examined patient melanomas and humanized melanoma xenografts, and noted preferential SOX2 expression in cells that interfaced and infiltrated dermal stroma. Experimental knockdown (KD) of SOX2 mRNA and protein in A2058 melanoma cells with high constitutive SOX2 expression resulted in 4.5-fold decreased invasiveness in vitro compared with controls (P<0.0001). Conversely, when G361 cells that normally express low SOX2 were transduced to overexpress SOX2 mRNA and protein, a 3.8-fold increase in invasiveness was observed (P=0.0004). Among 84 invasion-related genes, RT-PCR screening revealed that SOX2 KD resulted in striking decrease in matrix metalloproteinase-3 (MMP-3), an endopeptidase associated with cleavage of the extracellular matrix. Quantitatively, SOX2 KD diminished MMP-3 mRNA by 87.8%. MMP-3 KD in SOX2-expressing A2058 cells served to inhibit invasion, although to a lesser degree than SOX2 KD. Finally, immunostaining of patient and xenograft melanomas revealed coordinate SOX2 and MMP-3 expression in regions of stromal infiltration. These data implicate SOX2 expression in melanoma invasion, and suggest a role for MMP-3 as one potential mediator of this process.

Background and Purpose: Contrast-induced encephalopathy (CIE) is a rare and underrecognized complication after endovascular thrombectomy (EVT) for acute ischemic stroke. This study investigated the incidence and risk factors of CIE in patients who underwent EVT. Methods: Consecutive patients with acute ischemic stroke who received EVT between September 2014 and December 2019 at 2 medical centers were included. CIE was diagnosed on clinical criteria of neurological deterioration or delayed improvement within 24 hours after the procedure that was unexplained by the infarct or hemorrhagic transformation and radiological criterion of edematous change extending beyond the infarct core accompanied by contrast staining. Results: Of 421 patients with acute ischemic stroke who received EVT, 7 (1.7%) developed CIE. The manifestations included worsening of focal neurological signs, coma, and seizure. Patients with CIE were more likely to experience contrast-induced acute kidney injury than were those without CIE, but the volume of contrast medium was comparable between the two groups. The independent risk factors for CIE included renal dysfunction (defined as an estimated glomerular filtration rate <45 mL/min per 1.73 m 2 ; odds ratio, 5.77 [95% CI, 1.37–24.3]; P =0.02) and history of stroke (odds ratio, 4.96 [95% CI, 1.15–21.3]; P =0.03). Patients with CIE were less likely to achieve favorable functional outcomes (odds ratio, 0.09 [95% CI, 0.01–0.87]; P =0.04). Conclusions: CIE should be suspected in patients with clinical worsening after EVT accompanied by imaging evidence of contrast staining and edematous changes, especially in patients with renal dysfunction or history of stroke.

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