Innate immunity in pancreatic cancer: Lineage tracing and function

Increasingly, patients with gastrointestinal tumors can benefit from immunotherapy, but not patients with pancreatic cancer. While this lack of benefit has been attributed to lower T-cell infiltration in pancreatic cancer, other studies have demonstrated the presence of numerous T cells in pancreatic cancer, suggesting another mechanism for the poor efficacy of immunotherapy. Single-cell RNA sequencing studies on the pancreatic cancer immune microenvironment have demonstrated the predominance of innate immune cells (e.g., macrophages, dendritic cells, mast cells, and innate immune lymphoid cells). Therefore, in-depth research on the source and function of innate immune lymphocytes in pancreatic cancer could guide pancreatic cancer immunotherapy

Lidocaine, an anesthetic drug, protects Neuro2A cells against cadmium toxicity

Purpose: To investigate the neuroprotective effect of lidocaine in Neuro2A cells Methods: Differentiated N2a cells were used in this study. Cell viability and neuroprotection were assessed using dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue assays, while Bax/Bcl-2 expression was assayed by western blotting. Mitochondrial membrane potential, reactive oxygen species and calcium levels were measured using flow cytometry. Results: Lidocaine protected differentiated N2a cells against cadmium-induced toxicity, and also attenuated cadmium toxicity-induced changes in mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and calcium (Ca2+) levels. Furthermore, Bax/Bcl-2 ratio, which was disrupted by cadmium, and cadmium-induced apoptosis, were reversed by lidocaine. Conclusion: Lidocaine protects differentiated N2a cells against cadmium-induced toxicity by reversing apoptosis. Thus, lidocaine is a potential neuroprotective agent

Parameter Estimation of Induction Machine at Standstill Using Two-Stage Recursive Least Squares Method

This paper presents a two-stage recursive least squares (TSRLS) algorithm for the electric parameter estimation of the induction machine (IM) at standstill. The basic idea of this novel algorithm is to decouple an identifying system into two subsystems by using decomposition technique and identify the parameters of each subsystem, respectively. The TSRLS is an effective implementation of the recursive least squares (RLS). Compared with the conventional (RLS) algorithm, the TSRLS reduces the number of arithmetic operations. Experimental results verify the effectiveness of the proposed TSRLS algorithm for parameter estimation of IMs

Expression of neuroendocrine markers predicts increased survival in triple-negative breast cancer patients

BackgroundThe significance of neuroendocrine (NE) markers in triple-negative breast cancer (TNBC) patients has not been investigated. This study aims to clarify the incidence and prognostic significance of NE marker expression in TNBC, determine its association with other clinicopathological parameters, and further explore the pathological features and potential treatment options for TNBC patients expressing NE markers.MethodsClinicopathological data were collected from 396 TNBC patients undergoing radical breast cancer surgery at Peking Union Medical College Hospital from January 2002 to December 2014, with a final follow-up in July 2019. Immunohistochemistry (IHC) staining was performed for NE markers including chromogranin A (CgA) and synaptophysin (Syn). For TNBC patients with positive NE marker expression, IHC staining was then performed for alpha-thalassemia/mental retardation X-linked (ATRX), O(6)-methylguanine-methyltransferase (MGMT), somatostatin receptor 2 (SSTR2), and programmed death receptor-ligand 1 (PD-L1). The chi-square or Fisher exact test was used to evaluate the correlations between NE marker expression and other parameters. Survival curves were plotted using the Kaplan-Meier (K-M) method to assess the prognostic significance of NE markers in TNBC.ResultsNE marker-positive staining was observed in 7.6% (30/396) of all TNBC cases. Only 0.5% (2/396) cases had ≥ 90% neoplastic cells expressing NE markers. Positive NE marker expression was associated with negative basal-like marker expression. K-M survival analysis showed that the NE marker-positive TNBC patients had higher disease-free survival (DFS) rates than the NE marker-negative patients at the same stage. Among the 30 NE marker-positive TNBC cases, 13.3% and 26.7% showed negative IHC staining for ATRX and MGMT, respectively, while 13.3% had a 3+ score for SSTR2 IHC staining. For PD-L1 IHC staining, 13.3% of the 30 TNBC cases were higher than 10 scores in Combined Positive Score (CPS), and 10.0% were higher than 10% in Tumor Cell Proportion Score (TPS).ConclusionThere was a small proportion of TNBC patients expressing NE markers. TNBC patients with positive NE marker expression had a better prognosis than the negative group at the same stage. TNBC cases with positive NE marker expression may potentially benefit from immunotherapy or somatostatin analogue treatment

Prognostic value of various immune cells and Immunoscore in triple-negative breast cancer

BackgroundThis study aimed to evaluate the expression status and prognostic role of various immunoregulatory cells and test in triple-negative breast cancer (TNBC).MethodsThe expression of five markers (CD3/CD4/CD8/CD19/CD163) of tumor immune cells was evaluated retrospectively in tumor sections from 68 consecutive cases of TNBC by immunohistochemistry. Computational image analysis was used to quantify the density and distribution of each immune marker within the tumor region, tumor invasive margin, and expression hotspots. Immunoscores were calculated using an automated approach. Other clinical characteristics were also analyzed.ResultsFor all patients, Kaplan–Meier survival analysis showed that high CD3+ signals in the tumor region (disease-free survival (DFS), P=0.0014; overall survival (OS), P=0.0031) and total region (DFS, P=0.0014; OS, P=0.0031) were significantly associated with better survival. High CD4+ levels in the tumor region and total regions were significantly associated with better survival (P<0.05). For Hotspot analysis, CD3+ was associated with significantly better survival for all Top1, Top2, and Top3 densities (DFS and OS, P<0.05). High CD4+ levels were significantly associated with better prognosis for Top1 and Top3 densities (DFS and OS, P<0.05). For stage IIB and IIIC patients, CD3+ in the tumor region and all Top hotspots was found to be significantly correlated with survival (DFS and OS, P<0.05). CD4+ cells were significantly associated with survival in the tumor region, total region, and Top3 density (DFS, P=0.0213; OS, P=0.0728). CD8+ cells were significantly associated with survival in the invasive margin, Top2 density, and Top3 density. Spatial parameter analysis showed that high colocalization of tumor cells and immune cells (CD3+, CD4+, or CD8+) was significantly associated with patient survival.ConclusionComputational image analysis is a reliable tool for evaluating the density and distribution of immune regulatory cells and for calculating the Immunoscore in TNBC. The Immunoscore retains its prognostic significance in TNBC later than IIB stage breast cancer. Future studies are required to confirm its potential to predict tumor responses to chemotherapy and immune therapy

Characteristics and potential biomarkers of flavor compounds in four Chinese indigenous chicken breeds

Chinese indigenous chickens have a long history of natural and artificial selection and are popular for their excellent meat quality and unique flavor. This study investigated six meat quality-related traits in Ningdu yellow, Baier yellow, Kangle, and Shengze 901 chickens. Two-dimensional gas chromatography-time-of-flight mass spectrometry was used to detect unique flavors in 24 breast muscle samples from the same phenotyped chickens. Overall, 685, 618, 502, and 487 volatile organic compounds were identified in Ningdu yellow, Baier yellow, Kangle, and Shengze 901 chickens, respectively. The flavor components were separated into eight categories, including hydrocarbons and aldehydes. Multivariate analyses of the identified flavor components revealed some outstanding features of these breeds. For example, the hydrocarbons (22.09%) and aldehydes (14.76%) were higher in Ningdu yellow chickens and the highest content of N, N-dimethyl-methylamine was in Ningdu yellow, Baier yellow, and Shengze 901 chickens, indicating the maximum attribution to the overall flavor (ROAV = 439.57, 289.21, and 422.80). Furthermore, we found that 27 flavor compounds differed significantly among the four Chinese breeds, including 20 (e.g., 1-octen-3-ol), two (e.g., 2-methyl-naphthalene), four (e.g., 2,6-lutidine), and one (benzophenone) flavor components were showed significant enrichment in Ningdu yellow, Baier yellow, Kangle, and Shengze 901 chickens, respectively. The flavor components enriched in each breed were key biomarkers distinguishing breeds and most were significantly correlated with meat quality trait phenotypes. These results provide novel insights into indigenous Chinese chicken meat flavors

Genetic heterogeneity in primary and relapsed mantle cell lymphomas : impact of recurrent CARD11 mutations

The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL

Genomic heterogeneity of multiple synchronous lung cancer

Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events