Influx of activated neutrophils into the lungs is the histopathologic hallmark of acute lung injury (ALI) after intestinal ischemia/reperfusion (I/R). Neutrophils can release DNA and granular ...proteins to form cytotoxic neutrophil extracellular traps (NETs), which promotes bystander tissue injury. However, whether NETs are responsible for the remote ALI after intestinal I/R and the mechanisms underlying the dissemination of harmful gut-derived mediators to the lungs are unknown. In the C57BL/6J mouse intestinal I/R model, DNase I-mediated degradation and protein arginine deiminase 4 (PAD4) inhibitor-mediated inhibition of NET treatments reduced NET formation, tissue inflammation, and pathological injury in the lung. High-mobility group protein B1 (HMGB1) blocking prevented NET formation and protected against tissue inflammation, as well as reduced cell apoptosis and improved survival rate. Moreover, recombinant human HMGB1 administration further drives NETs and concurrent tissue toxic injury, which in turn can be reversed by neutrophil deletion via anti-Ly6G Ab i.p. injection. Furthermore, global MyD88 deficiency regulated NET formation and alleviated the development of ALI induced by intestinal I/R. Thus, HMGB1 released from necroptotic enterocytes caused ALI after intestinal I/R by inducing NET formation. Targeting NETosis and the HMGB1 pathway might extend effective therapeutic strategies to minimize intestinal I/R-induced ALI.
Immune checkpoint blockade has demonstrated remarkable efficacy in hepatocellular carcinoma (HCC) but is also commonly accompanied by immune‐related adverse events (irAEs). However, the association ...between irAEs and antitumor efficacy in HCC patients remains unknown. All patients with HCC treated with anti‐PD‐1 antibodies from July 2018 to November 2019 were analyzed and divided into different groups according to their irAEs' status. In total, 101 HCC patients, including 21 (20.8%) patients who presented with irAEs (irAEs+), were enrolled. Among the adverse events, rash (n = 9, 8.9%) was the most frequent irAE, followed by mucositis (n = 3, 3.0%) and thyroiditis (n = 3, 3.0%). Patients in the irAEs+ group showed a higher tumor response rate than those in the irAEs− group (overall response rate: 28.6% vs 6.3%, P = .011; disease control rate: 85.7% vs 60.0%, P = .028). The median progression‐free survival (PFS) times were 14.8 months in the irAEs+ group and 4.1 months in the irAEs− group (P < .001). Further analysis based on the presence or absence of rash showed that the PFS of the patients in the irAEs+/rash+ group was better than that of those in the irAEs+/rash− or irAEs− group (all P < .05). Multivariate analysis showed that irAEs were an independent prognostic factor for PFS (hazard ratio HR: 0.22, P = .002). Thus, the occurrence of irAEs, especially rash, was associated with markedly improved PFS. Awareness of irAEs may help classify the subtype of HCC patients with an unprecedented survival benefit from anti‐PD‐1 antibodies.
What's new?
While anti‐program death receptor‐1 (anti‐PD‐1) antibodies produce clinical responses in patients with hepatocellular carcinoma (HCC), variations in efficacy and in the occurrence of adverse events present significant challenges in the clinical management of HCC. In the present study, the authors show that in HCC patients treated with anti‐PD‐1 antibodies, the development of immune‐related adverse events (irAEs), notably rash, is associated with improved progression‐free survival. The marked association between irAEs and treatment response suggests that irAEs could be used to predict survival in anti‐PD‐1 antibody‐treated HCC patients and could facilitate HCC subtype classification in patients who experience striking survival benefits.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Time-varying linear matrix equations and inequations have been widely studied in recent years. Time-varying Sylvester-transpose matrix inequation, which is an important variant, has not been fully ...investigated. Solving the time-varying problem in a constructive manner remains a challenge. This study considers an exp-aided conversion from time-varying linear matrix inequations to equations to solve the intractable problem. On the basis of zeroing neural network (ZNN) method, a continuous-time zeroing neural network (CTZNN) model is derived with the help of Kronecker product and vectorization technique. The convergence property of the model is analyzed. Two discrete-time ZNN models are obtained with the theoretical analyses of truncation error by using two Zhang et al.’s discretization (ZeaD) formulas with different precision to discretize the CTZNN model. The comparative numerical experiments are conducted for two discrete-time ZNN models, and the corresponding numerical results substantiate the convergence and effectiveness of two ZNN discrete-time models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing ...intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor‐interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain‐like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo. Furthermore, necroptosis was specifically blocked by the RIP1 kinase inhibitor necrostatin‐1. In addition, the combined treatment of necrostatin‐1 and the pan‐caspase inhibitor Z‐VAD acted synergistically to protect against intestinal I/R injury, and these two pathways can be converted to one another when one is inhibited. In vitro, necrostatin‐1 pre‐treatment reduced the necroptotic death of oxygen‐glucose deprivation challenged intestinal epithelial cell‐6 cells, which in turn dampened the production of pro‐inflammatory cytokines (tumour necrosis factor‐α and interleukin‐1β), and suppressed high‐mobility group box‐1 (HMGB1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB1 into the supernatant, thus decreasing the activation of Toll‐like receptor 4 and the receptor for advanced glycation end products. Collectively, our study reveals a robust RIP1/RIP3‐dependent necroptosis pathway in intestinal I/R‐induced intestinal injury in vivo and in vitro and suggests that the HMGB1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Microvascular invasion (MVI) is a risk factor for tumor recurrence after hepatectomy in hepatocellular carcinoma (HCC) patients.
Objective
This study aimed to investigate the efficacy and ...safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with the FOLFOX regimen for HCC patients with MVI.
Methods
In this prospective, phase III, randomized, open-label, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either one to two cycles of adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), while secondary endpoints were overall survival (OS) and safety.
Results
Between June 2016 and April 2019, 127 patients were randomly assigned to the AT group (
n
= 63) or FU group (
n
= 64). Clinicopathological characteristics of the two groups were well-balanced. The 6-, 12-, and 18-month OS rates for the AT group were 100.0%, 97.7%, and 97.7%, respectively, and 94.5%, 89.6%, and 78.5% for the FU group, respectively. The 6-, 12-, and 18-month DFS rates for the AT and FU groups were 84.7%, 61.8%, and 58.7%, and 62.9%, 48.1%, and 38.6%, respectively. OS and DFS were significantly better in the AT group than in the FU group (
p
= 0.037 and 0.023, respectively). No patients in the AT group experienced grade 3 or more severe adverse events.
Conclusions
Adjuvant TAI after hepatectomy may bring survival benefits to HCC patients with MVI.
Trial registration
Trial number: NCT03192618.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Vessels that encapsulate tumor clusters (VETC) is a novel described vascular pattern different from microvascular invasion (MVI) for patients with hepatocellular carcinoma (HCC). The ...prognostic value of integrating VETC and MVI (VETC-MVI model) in HCC patients after resection remains unclear.
Methods
From January 2013 to December 2016, 498 HCC patients who underwent curative resection were enrolled from five academic centers and stratified into different groups according to their VETC and MVI statuses. Overall survival (OS), disease-free survival (DFS), and early and late recurrence rates were evaluated.
Results
The patients were divided into four subgroups: VETC
−
/MVI
−
(
n
= 277, 55.6%), VETC
−
/MVI
+
(
n
= 110, 22.1%), VETC
+
/MVI
−
(
n
= 53, 10.6%), and VETC
+
/MVI
+
(
n
= 58, 11.6%). The patients in the VETC
+
/MVI
−
and VETC
−
/MVI
+
groups had similar long-term outcomes (OS:
p
= 0.402; DFS:
p
= 0.990), VETC
−
/MVI
−
patients showed the best prognosis, and VETC
+
/MVI
+
patients had the worst prognosis. Further analysis revealed that the VETC-MVI model showed a similar stratification ability for early recurrence but not for late recurrence. The area under the curve values for early recurrence was 0.70, 0.63 and 0.64 for the VETC-MVI model, VETC, and MVI, respectively (VETC-MVI model
vs
VETC:
p
< 0.001; VETC-MVI model
vs
MVI:
p
= 0.004; VETC
vs
MVI:
p
= 0.539). Multivariate Cox regression analysis showed that the VETC-MVI model successfully predicted OS, DFS and early recurrence.
Conclusions
VETC status provides additional discriminative information for patients with either MVI
−
or MVI
+
. A combination of VETC and MVI may help classify subtypes and predict the prognosis of HCC patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
This study aimed to develop an artificial intelligence model for predicting the pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) of locally advanced rectal ...cancer (LARC) using digital pathological images.
Background
nCRT followed by total mesorectal excision (TME) is a standard treatment strategy for patients with LARC. Predicting the PCR to nCRT of LARC remine difficulty.
Methods
842 LARC patients treated with standard nCRT from three medical centers were retrospectively recruited and subgrouped into the training, testing and external validation sets. Treatment response was classified as pCR and non-pCR based on the pathological diagnosis after surgery as the ground truth. The hematoxylin & eosin (H&E)-stained biopsy slides were manually annotated and used to develop a deep pathological complete response (DeepPCR) prediction model by deep learning.
Results
The proposed DeepPCR model achieved an AUC-ROC of 0.710 (95% CI: 0.595, 0.808) in the testing cohort. Similarly, in the external validation cohort, the DeepPCR model achieved an AUC-ROC of 0.723 (95% CI: 0.591, 0.844). The sensitivity and specificity of the DeepPCR model were 72.6% and 46.9% in the testing set and 72.5% and 62.7% in the external validation cohort, respectively. Multivariate logistic regression analysis showed that the DeepPCR model was an independent predictive factor of nCRT (
P
=0.008 and
P
=0.004 for the testing set and external validation set, respectively).
Conclusions
The DeepPCR model showed high accuracy in predicting pCR and served as an independent predictive factor for pCR. The model can be used to assist in clinical treatment decision making before surgery.
BackgroundDickkopf 1 (DKK1) is associated with tumor progression. However, whether DKK1 influences the tumor response to programmed cell death protein 1 (PD-1) blockade in colorectal cancers (CRCs) ...with deficient mismatch repair (dMMR) or microsatellite instability (MSI) has never been clarified.MethodsTumor tissues from 80 patients with dMMR CRC were evaluated for DKK1 expression and immune status via immunohistochemistry. Serum DKK1 was measured in another set of 43 patients who received PD-1 blockade therapy. CT26 cells and dMMR CRC organoids were cocultured with T cells, and CT26-grafted BALB/c mice were also constructed. T-cell cytotoxicity was assessed by apoptosis assays and flow cytometry. The pathway through which DKK1 regulates CD8+ T cells was investigated using RNA sequencing, and chromatin immunoprecipitation and luciferase reporter assays were conducted to determine the downstream transcription factors of DKK1.ResultsElevated DKK1 expression was associated with recurrence and decreased CD8+ T-cell infiltration in dMMR CRCs, and patients with high-serum DKK1 had a poor response to PD-1 blockade. RNA interference or neutralization of DKK1 in CRC cells enhanced CD8+ T-cell cytotoxicity, while DKK1 decreased T-bet expression and activated GSK3β in CD8+ T cells. In addition, E2F1, a downstream transcription factor of GSK3β, directly upregulated T-bet expression. In organoid models, the proportion of apoptotic cells was elevated after individual neutralization of PD-1 or DKK1 and was further increased on combined neutralization of PD-1 and DKK1.ConclusionsDKK1 suppressed the antitumor immune reaction through the GSK3β/E2F1/T-bet axis in CD8+ T cells. Elevated serum DKK1 predicted poor tumor response to PD-1 blockade in dMMR/MSI CRCs, and DKK1 neutralization may restore sensitivity to PD-1 blockade.
The relationship between gastric bare area adipose tissues invasion (GBAI) confirmed pathologically and the prognosis of gastric cancer (GC) patients is undefined. Till present, there has not been ...literature investigating this phenomenon. Here, we aimed at analyzing the implication of GBAI in GC.
The data of 1822 patients who underwent radical surgery between January 2000 and December 2013 at the Sun Yat-sen University Cancer Center were retrieved. Pathologically, tumor deposits (TDs) located > 5 mm from the leading edge of the primary tumor and the lymph nodes (LNs) station number 1, 2, 7, and 9 were considered GBAI. Kaplan-Meier method, log-rank test, and Cox's proportional hazards model were employed to analyze.
Two hundred and five (11.3%) patients were pathologically diagnosed with GBAI, which was more commonly found in proximal or linitis lastica than distal GC (P < 0.001). There was significant difference in 5-year survival between patients with and without GBAI for stages IIB, IIIA, IIIB, and IIIC, respectively (P < 0.009 for IIB, IIIA, and IIIB; P = 0.021 for IIIC). Among the 205 GBAI patients, 61 had detailed radiological follow-up data in which 26 (34.7%) were found to have retroperitoneal infiltration, 27 (36.0%) had peritoneal metastasis, 10 (13.3%) had hematogenous metastasis, 16 (21.3%) had lymphatic metastasis, and 16 (21.3%) had others.
GBAI was identified as a predictor of unfavorable prognosis for GC and was more commonly found in the proximal or linitis plastica of the stomach than in distal stomach. Retroperitoneal infiltration was one of the most commonly identified metastatic route for GC associated with GBAI after radical surgery.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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