Pan-cancer analysis of CDKN2A alterations identifies a subset of gastric cancer with a cold tumor immune microenvironment.

BACKGROUND: Although CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer. METHODS: This study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT). RESULTS: Our research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response. CONCLUSIONS: This study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.

Systematic analysis of the cuprotosis in tumor microenvironment and prognosis of gastric cancer.

Cuprotosis is a new programmed cell death related to cancer. However, the characteristics of cuprotosis in gastric cancer (GC) remain unknown. Ten cuprotosis molecules from 1544 GC patients were used to identify three GC molecular genotypes. Cluster A was characterized by the best clinical outcome and was significantly enriched in metabolic signaling pathways. Cluster B exhibited elevated immune activation, high immune stroma scores and was significantly enriched in tumor immune signaling pathways. Cluster C was characterized by severe immunosuppression and poor response to immunotherapy. Notably, the citrate cycle, cell cycle, and p53 signaling pathways were enriched in the differentially expressed genes among the three subtypes, which were critical signaling pathways for cell death. We also developed a cuprotosis signature risk score that could accurately predict the survival, immunity, and subtype of GC. This study presents a systematic analysis of cuprotosis molecules and provides new immunotherapeutic targets for GC patients.

An antigen processing and presentation signature for prognostic evaluation and immunotherapy selection in advanced gastric cancer.

Objective: The aim of the study was to propose a signature based on genes associated with antigen processing and presentation (APscore) to predict prognosis and response to immune checkpoint inhibitors (ICIs) in advanced gastric cancer (aGC). Background: How antigen presentation-related genes affected the immunotherapy response and whether they could predict the clinical outcomes of the immune checkpoint inhibitor (ICI) in aGC remain largely unknown. Methods: In this study, an aGC cohort (Kim cohort, RNAseq, N=45) treated by ICIs, and 467 aGC patients from seven cohorts were conducted to investigate the value of the APscore predicting the prognosis and response to ICIs. Subsequently, the associations of the APscore with the tumor microenvironment (TME), molecular characteristics, clinical features, and somatic mutation variants in aGC were assessed. The area under the receiver operating characteristic curve (AUROC) of the APscore was analyzed to estimate response to ICIs. Cox regression or Log-rank test was used to estimate the prognosis of aGC patients. Results: The APscore constructed by principal component analysis algorithms was an effective predictive biomarker of the response to ICIs in the Kim cohort and 467 aGC patients (Kim: AUC =0.85, 95% CI: 0.69-1.00; 467 aGC: AUC =0.69, 95% CI: 0.63-0.74). The APscore also was a prognostic biomarker in 467 aGC patients (HR=1.73, 95% CI: 1.21-2.46). Inhibitory immunity, decreased TMB and low stromal scores were observed in the high APscore group, while activation of immunity, increased TMB, and high stromal scores were observed in the low APscore group. Next, we evaluated the value of several central genes in predicting the prognosis and response to ICIs in aGC patients, and verified them using immunogenic, transcriptomic, genomic, and multi-omics methods. Lastly, a predictive model built successfully discriminated patients with vs. without immunotherapy response and predicted the survival of aGC patients. Conclusions: The APscore was a new biomarker for identifying high-risk aGC patients and patients with responses to ICIs. Exploration of the APscore and hub genes in multi-omics GC data may guide treatment decisions.

Extracts of Bauhinia Championii Alleviate Acute Neuronal Injury After Ischemic Reperfusion by Improving Endoplasmic Reticulum Stress-Mediated Neuronal Apoptosis.

OBJECTIVE: Cerebral ischemia/reperfusion (I/R) is a potential factor for lethal injury, and currently lacks effective remedies. Bauhinia championii extracts (BCEs) have been reported to exhibit anti-oxidative and anti-hypoxia properties. The current work aimed to study whether BCE could alleviate neuronal injury caused by I/R. METHODS: To investigate the protective effects of BCE, oxygen-glucose deprivation/reperfusion (OGD/R) was applied to the HT22 cell line in vitro and to a cerebral I/R mouse model in vivo. RESULTS: Under OGD/R, the survival of HT22 cells was significantly prolonged after treatment with BCE. In vivo, BCE significantly reduced the infarct area and decreased neuronal apoptosis caused by I/R. It was further found that OGD/R could trigger endoplasmic reticulum (ER) stress and induce ER stress-mediated neuronal apoptosis in vivo and in vitro, while BCE could effectively alleviate ER stress and neuronal apoptosis. CONCLUSION: These results suggested that BCE exhibits neuroprotective effects by reducing ER stress-mediated apoptosis after cerebral I/R injury. BCE may therefore be an effective therapeutic regimen against cerebral I/R damage.

Experimental Parity-Time Symmetric Quantum Walks for Centrality Ranking on Directed Graphs.

Using quantum walks (QWs) to rank the centrality of nodes in networks, represented by graphs, is advantageous compared to certain widely used classical algorithms. However, it is challenging to implement a directed graph via QW, since it corresponds to a non-Hermitian Hamiltonian and thus cannot be accomplished by conventional QW. Here we report the realizations of centrality rankings of a three-, a four-, and a nine-vertex directed graph with parity-time (PT) symmetric quantum walks by using high-dimensional photonic quantum states, multiple concatenated interferometers, and dimension dependent loss to achieve these. We demonstrate the advantage of the QW approach experimentally by breaking the vertex rank degeneracy in a four-vertex graph. Furthermore, we extend our experiment from single-photon to two-photon Fock states as inputs and realize the centrality ranking of a nine-vertex graph. Our work shows that a PT symmetric multiphoton quantum walk paves the way for realizing advanced algorithms.

Changes in platelet GPIbα and ADAM17 during the acute stage of atherosclerotic ischemic stroke among Chinese.

Glycoprotein (GP) Ibα ectodomain shedding has important implications for thrombosis and hemostasis. A disintegrin and metalloproteinase 17 (ADAM17) was identified to play an essential role in agonist induced GPIbα shedding. The relationship of GPIbα shedding and ADAM17 in the acute stage of atherosclerotic ischemic stroke (AIS) patients has not been thoroughly studied. A total of 306 patients and 230 controls matched for age, sex, race, history of hypertension and diabetes mellitus were enrolled in the study. GPIbα, ADAM17, glycocalicin were detected by flow cytometry, Western blotting, and enzyme-linked immunosorbent assay (ELISA) respectively. Compared with the control group, the expression of GPIbα in patients with acute ischemic stroke was significantly lower (P=0.000, P<0.01). Plasma glycocalicin and ADAM17 in AIS group were higher than those in control group (P=0.699, P=0.000). Pearson's analysis showed glycocalicin bore no correlation with GPIbα in AIS patients (r=0.095, P>0.05). GPIbα and National Institute of Health Stroke Scale (NIHSS) had negative correlation (r=-0.514, P<0.01). Our findings indicate that ADAM17 may be a risk factor for ischemic stroke in Chinese and the expression of GPIbα can serve as a measure for stroke severity.