Mouse anti-Human PKCλ monoclonal antibody, clone 52/QLDλ

We have previously shown a novel antimetastatic role for neutrophils in the premetastatic lung of mice in models of breast cancer. Here we expand on those findings in the context of human breast cancer. We assessed the cytotoxicity of neutrophils from 90 newly diagnosed breast cancer patients, 24 ductal carcinoma in situ patients, 56 metastatic breast cancer patients, and 64 women with no history of cancer. We report that neutrophils from metastatic and newly diagnosed breast cancer patients are significantly more cytotoxic than neutrophils from cancer-free individuals. We hypothesized that tumor-secreted factors 'prime' neutrophils to become cytotoxic. To identify these factors we assayed for cytokines in serum from 54 breast cancer patients and 35 cancer-free controls. Tumor necrosis factor (TNF alpha), MCP-1 (CCL2), and IL1RA significantly correlated with cytotoxicity and directly stimulated neutrophil cytotoxicity ex vivo. RNA-seq analyses found protein kinase C iota (PRKCI) to be over expressed in patient neutrophils relative to neutrophils from cancer-free individuals. PRKCI has been implicated in NADPH oxidase assembly, required for neutrophil-mediated cell cytotoxicity. Treatment of human neutrophils with TNF-induced PRKCI expression and cytotoxicity in samples that had low basal levels of PRKCI expression. To date, this work is the first to demonstrate the cytotoxic role of neutrophils in the peripheral blood of a large cohort of breast cancer patients, and that select cytokines appear to mediate the stimulation of neutrophil cytotoxicity. Further functional studies are necessary to identify clinically relevant means of stimulating neutrophil cytotoxicity as an effective barrier against disease progression and metastasis.

Glutamatergic neurotransmission has been shown to be dysregulated in bipolar disorder (BD), alcohol use disorder (AUD) and substance use disorder (SUD). Similarly, disruption in the hypothalamic-pituitary-adrenal (HPA)-axis has also been observed in these conditions. BD is often comorbid with AUD and SUD. The effects of the glutamatergic and HPA systems have not been extensively examined in individuals with BD-AUD and BD-SUD comorbidity. The aim of this investigation was to determine whether variants in the glutamatergic pathway and HPA-axis are associated with BD-AUD and BD-SUD comorbidity. The research cohort consisted of 498 individuals with BD type I from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). A subset of the cohort had comorbid current AUD and current SUD. A total of 1935 SNPs from both the glutamatergic and HPA pathways were selected from the STEP-BD genome-wide dataset. To identify population stratification, IBS clustering was performed using the program Plink 1.07. Single SNP association and gene-based association testing were conducted using logistic regression. A pathway analysis of glutamatergic and HPA genes was performed, after imputation using IMPUTE2. No single SNP was associated with BD-AUD or BD-SUD comorbidity after correction for multiple testing. However, from the gene-based analysis, the gene PRKCI was significantly associated with BD-AUD. The pathway analysis provided overall negative findings, although several genes including GRIN2B showed high percentage of associated SNPs for BD-AUD. Even though the glutamatergic and HPA pathways may not be involved in BD-AUD and BD-SUD comorbidity, PRKCI deserves further investigation in BD-AUD.