Biomarkers of Pathologic Complete Response to Neoadjuvant Immunotherapy in Mismatch Repair-Deficient Colorectal Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) have become the standard of care for patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer. However, biomarkers of response to ICI are still lacking. EXPERIMENTAL DESIGN: Forty-two patients with dMMR colorectal cancer treated with neoadjuvant PD-1 blockade were prospectively enrolled. To identify biomarkers of pathologic complete response (pCR) to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles based on next-generation sequencing, and immune cell density based on multiplex immunofluorescence (mIF) staining. An integrated analysis of single-cell RNA sequencing from our previous study and GSE178341, as well as mIF was performed to further explore the significance of the tumor microenvironment (TME) on pCR response. RESULTS: The tumor mutation burden of both tumor tissue and plasma blood samples was comparable between the pCR and non-pCR groups, while HLA-DQA1 and HLA-DQB1 were significantly overexpressed in the pCR group. Gene signature enrichment analysis showed that pathways including T-cell receptor pathway, antigen presentation pathway were significantly enriched in the pCR group. In addition, higher pre-existing CD8+ T-cell density was associated with pCR response (767.47 per.mm2 vs. 326.64 per.mm2, P = 0.013 Wilcoxon test). Further integrated analysis showed that CD8+ T cells with low PD-1 expression (PD-1lo CD8+ T cells) expressing high levels of TRGC2, CD160, and KLRB1 and low levels of proliferated and exhausted genes were significantly associated with pCR response. CONCLUSIONS: Immune-associated transcriptomic features, particularly CD8+ T cells were associated with pCR response to ICI in dMMR colorectal cancer. Heterogeneity of TME within dMMR colorectal cancer may help to discriminate patients with complete response to neoadjuvant ICI.

Tumor stroma Siglec15 expression is a poor prognosis predictor in colon adenocarcinoma.

Sialic acid binding Ig-like lectin 15 (Siglec15) is considered a novel immune checkpoint and an emerging target for next-generation cancer immunotherapy. However, the significance of Siglec15 and its relationship with programmed death-ligand 1 (PD-L1) in colon adenocarcinoma (COAD) remain unknown. In this study, we analyzed Siglec15 expression within stromal area (SA) and tumor area (TA), and its relationship with tumor-infiltrating lymphocytes (TILs) in COAD and mismatch repair-proficient (MMR-p) COAD. Siglec15 expression was significantly higher in COAD tissues than in normal tissues, and elevated Siglec15(SA) expression, rather than Siglec15(TA) and Siglec15 (whole) expression, was correlated with poor prognosis and inversely correlated with the density of CD8+ T cell, both in COAD and MMR-p COAD. Moreover, there were no correlations between Siglec15(SA) and PD-L1(SA), and between Siglec15(TA) and PD-L1(TA), whereas there was positive correlation between Siglec15(whole) and PD-L1(whole). A new immune classification based on the Siglec15(SA)/PD-L1(SA) expression, indicated that patients with Siglec15(SA)Low/PD-L1(SA)+ status had the longest survival times in COAD. Our study highlights that Siglec15(SA) is an independent predictor of poor prognosis and has an immunosuppressive role in COAD and MMR-p COAD tissues. These findings may provide insights into improving responses to immunotherapy-included comprehensive treatments for COAD in the future.

Association of Procedure Time With Clinical and Procedural Outcome in Patients With Basilar Occlusion Undergoing Embolectomy.

BACKGROUND AND OBJECTIVES: Previous studies have demonstrated the association between the procedure time (PT) and outcomes for patients with proximal large vessel occlusion; however, whether the relationship remains for patients with acute basilar artery occlusion (ABAO) was not clear. We aimed to characterize the association between PT and other procedure-related variables on clinical outcomes among patients with ABAO who underwent endovascular treatment (EVT). METHODS: Patients with ABAO who underwent EVT with a documented PT in the EVT for Acute Basilar Artery Occlusion (BASILAR) study from January 2014 to May 2019 among 47 comprehensive centers in China were included. Multivariable analysis was performed to reveal the association between PT and 90-day modified Rankin Scale score, mortality, complications, and all-cause death at 1 year. RESULTS: Of the 829 patients from the BASILAR registry, 633 eligible patients were included. Longer PT were associated with a lower rate of favorable outcome (by 30 minutes, adjusted OR 0.82 [95% CI 0.72-0.93], p = 0.01). In addition, a PT ≤ 75 minutes was associated with a favorable outcome (adjusted OR 2.03 [95% CI 1.26-3.28]). The risk of complications and mortality increased by 0.5% and 1.5% with every 10 minutes increase in PT, respectively (R2 = 0.64 and R2 = 0.68, p < 0.01). The cumulative rates of favorable outcomes and successful recanalization plateaued after 120 minutes (2 attempts). Restricted cubic spline regression analysis for the probability of favorable outcomes had an L-shape association (p nonlinearity = 0.01) with PT with significant benefit loss before 120 minutes and then appeared relatively flat. DISCUSSION: For patients with ABAO, procedures that exceeded 75 minutes were associated with an increased risk of mortality and lower odds of a favorable outcome. A careful assessment of futility and the risks of continuing the procedure should be made after 120 minutes.

Human Urinary Kallidinogenase Pretreatment Inhibits Myocardial Inflammation and Apoptosis after Coronary Microembolization by Activating PI3K/Akt/FoxO1 Axis.

BACKGROUND: As a fatal cardiovascular complication, coronary microembolization (CME) results in severe cardiac dysfunction and arrhythmia associated with myocardial inflammation and apoptosis. Human urinary kallidinogenase (HUK) can provide a protective function for cardiomyocytes by improving microcirculation. However, the therapeutic effects and underlying mechanisms of HUK in CME-induced myocardial injury remain unclear. AIMS: We evaluated the effect of HUK on cardiac protection in a rat model of CME and whether it could restrain myocardial inflammation and apoptosis, and alleviate CME-induced myocardial injury. METHODS: We established the CME model by injecting 42 µm inert plastic microspheres into the left ventricle of rats in advance, then the rats were randomly and equally divided into CME, CME + HUK (the dose of HUK at 0.016 PNA/kg/day), CME + HUK + LY (the dose of LY294002 at 10 mg/kg, 30 minutes before modeling), and Sham operation groups. Cardiac function, the serum levels of myocardial injury biomarkers, myocardial inflammation and apoptosis-related genes were measured; and the myocardial histopathological examination was performed at 12 h after the operation. RESULTS: The results revealed that HUK effectively reducing myocardial inflammation, apoptosis, and myocardial infarction area; and improving CME-induced cardiac injury by activating the PI3K/Akt/FoxO1 axis. In addition, these cardioprotective effects can be reduced by the PI3K specific inhibitor LY294002, suggesting that the aforementioned protective effects may be related to activation of the PI3K/Akt/FoxO1 axis. CONCLUSIONS: HUK seems to control inflammatory infiltration and cardiomyocyte apoptosis significantly to improve CME-induced cardiac injury via regulating the PI3K/Akt/FoxO1 axis.

Visible-light-responsive photocatalytic inactivation of ofloxacin-resistant bacteria by rGO modified g-C3N4.

The visible light responsive graphitic nitride (g-C3N4) mediated photocatalysis has drawn extensive attention in water treatment field. Carbon doping could improve the photocatalytic activity of g-C3N4 in promoting charge separation efficiency, visible-light utilization, etc. In this paper, the g-C3N4 (as MC) was modified by barbituric acid (as MCB0.07) and further treated by reduced graphene oxide (rGO) (as n%GCN) and then applied to inactivate ofloxacin-resistant bacteria (OFLA) under light irradiation at UVA-visible wavelength. The results showed that the n%GCN presented strong photocatalytic activity when the GO mass ratio was 7.5% (as 7.5%GCN). The inactivation efficiencies of OFLA by MC, MCB0.07, and 7.5%GCN were 5.77 log, 8.48 log, and 8.25 log, respectively, under UVA-visible wavelength (λ > 305 nm), compared to 4.83 log, 5.56 log, and 6.08 log, respectively, within 16 h under visible wavelength (λ > 400 nm). The rGO-doping obviously improved the inactivation efficiency of MCB0.07 on OFLA under visible wavelength. Furthermore, the photoreactivation and dark repair phenomena of OFLA were examined after MC, MCB0.07, and 7.5%GCN treatment, respectively, and it was found that all approaches led to permanent damage to OFLA of which the regrowth was not observed after 24-48 h. Based on the quenching test, reactive oxygen species of O2-• and hole (h+) exhibited dominant roles in the photocatalytic inactivation of OFLA, which may result in oxidative stress and damage to the cell membrane. This study could shed light on the inactivation of OFLA under visible light radiation by rGO modified g-C3N4.

Influence of the request and purchase of television advertised foods on dietary intake and obesity among children in China.

BACKGROUND: This study aims to examine the effects of the request and purchase of Television (TV) advertised foods on children's dietary intake, overweight and obesity in China. METHODS: Data from 1417 children (aged 6-17 years) in the 2011 China Health and Nutrition Survey were analysed. The request and purchase of TV advertised foods were assessed through the frequency of children's requests to purchase TV advertised foods and the frequency of parents' purchases of these advertised foods, as well as the frequency of children's purchases of TV advertised foods. The height and weight of children were measured. Logistic regression models were used to identify the associations between the request and purchase of TV advertised foods and overweight/obesity of children. RESULTS: The request and purchase of TV advertised foods were positively associated with children's dietary intake of energy, protein, fat and carbohydrates. After adjusting for potential confounding factors, children's request and purchase of TV advertised foods and parent's purchase of TV advertised foods were positively associated with children's overweight/obesity: odds ratio (OR) and 95% confidence interval (CI) for overweight/obesity were: 1.46 (1.01-2.11) for children purchasing advertised foods ≥1 time/week, 1.59 (1.15-2.18) for parents purchasing advertised foods for their children ≥1 time/week and 1.39 (1.00-1.95) for children requesting advertised foods ≥1 time/week. CONCLUSIONS: The request and purchase of TV advertised foods are associated with children's dietary intake. Moreover, the request and purchase of TV advertised foods can increase the risk of overweight and obesity of children. Health education involving children's request and purchase of TV advertised foods and parents' purchase of TV advertised foods should be considered in China.