Canady Helios Cold Plasma Induces Breast Cancer Cell Death by Oxidation of Histone mRNA

Breast cancer is the most common cancer among women worldwide. Its molecular receptor marker status and mutational subtypes complicate clinical therapies. Cold atmospheric plasma is a promising adjuvant therapy to selectively combat many cancers, including breast cancer, but not normal tissue; however, the underlying mechanisms remain unexplored. Here, four breast cancer cell lines with different marker status were treated with Canady Helios Cold Plasma™ (CHCP) at various dosages and their differential progress of apoptosis was monitored. Inhibition of cell proliferation, induction of apoptosis, and disruption of the cell cycle were observed. At least 16 histone mRNA types were oxidized and degraded immediately after CHCP treatment by 8-oxoguanine (8-oxoG) modification. The expression of DNA damage response genes was up-regulated 12 h post-treatment, indicating that 8-oxoG modification and degradation of histone mRNA during the early S phase of the cell cycle, rather than DNA damage, is the primary cause of cancer cell death induced by CHCP. Our report demonstrates for the first time that CHCP effectively induces cell death in breast cancer regardless of subtyping, through histone mRNA oxidation and degradation during the early S phase of the cell cycle.

Usefulness of oxidative stress marker evaluation at admission to the intensive care unit in patients with COVID-19

Objective Two critical processes in the coronavirus disease 2019 (COVID-19) pandemic involve assessing patients’ intensive care needs and predicting disease progression during patients’ intensive care unit (ICU) stay. We aimed to evaluate oxidative stress marker status at ICU admission and ICU discharge status in patients with COVID-19. Methods We included patients in a tertiary referral center ICU during June–December 2020. Scores of Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and clinical severity, radiologic scores, and healthy discharge status were noted. We collected peripheral blood samples at ICU admission to evaluate total antioxidants, total oxidants, catalase, and myeloperoxidase levels. Results Thirty-one (24 male, 7 female) patients were included. At ICU admission, patients’ mean APACHE II score at ICU admission was 17.61 ± 8.9; the mean SOFA score was 6.29 ± 3.16. There was no significant relationship between clinical severity and oxidative stress (OS) markers nor between radiological imaging and COVID-19 data classification and OS levels. Differences in OS levels between patients with healthy and exitus discharge status were not significant. Conclusions We found no significant relationship between oxidative stress marker status in patients with COVID-19 at ICU admission and patients’ ICU discharge status.

PD-L1 Expression on Circulating Tumor Cells and Platelets in Patients with Metastatic Breast Cancer

Background: Immune checkpoint inhibition (ICPi) is effective in several cancers. Expression of programmed death-ligand 1 (PD-L1) on circulating tumor or immune effector cells could provide insights into selection of patients for ICPi. Methods: Whole blood (WB) was collected at serial timepoints from metastatic breast cancer (MBC) patients and healthy donors for circulating tumor cell (CTC) and platelet PD-L1 analysis using the CellSearch® assay. CTC PD-L1 was considered positive if detected on at least 1% of the cells; platelet PD-L1 was considered positive if ≥100 platelets per CellSearch frame expressed PD-L1. Results: A total of 207 specimens from 124 MBC patients were collected. 52/124 (42%) samples at timepoint-1 (at or close to time of progressive disease) had ≥5 CTC/7.5ml WB. Of those, 21 (40%) had positive CTC PD-L1. In addition, platelet PD-L1 expression was observed in 35/124 (28%) at timepoint-1. Platelet PD-L1 was not detected in more than 70 specimens from 12 healthy donors. Platelet PD-L1 was associated with ≥5 CTC/7.5ml WB (p=0.0002), less likely in patients with higher red blood cell counts (OR=0.72, p<0.001) and a history of smoking tobacco (OR=0.76, p<0.001). Platelet PD-L1 staining was not associated with tumor marker status, recent procedures or treatments, platelet-affecting drugs, or CTC PD-L1 expression. Conclusion: PD-L1 expression was found in MBC patients on both CTC and platelets in an independent fashion. Inter-patient platelet PD-L1 expression was highly heterogeneous suggesting that it is a biological event associated with cancer in some but not all patients. Taken together, our data suggest that CTC and platelet PD-L1 expression could play a role in predicting which patients should receive ICPi and as a pharmacodynamics biomarker during treatment.

The Sociolectal and Stylistic Variability of Rhythm in Stockholm

The question of “staccato” rhythm in Stockholm’s multiethnolect is investigated by comparing nPVIV measurements of the speech of 36 adult male speakers. The men, ages 24–43, come from a stratified sample of social classes and racial groups. Three contextual styles were recorded and analyzed: informal, formal, and very formal. The distribution of nPVIV values in informal speech across class and racial group indicates that speech rhythm splits three ways: low-alternation “staccato” rhythm among the racialized lower-class men, high-alternation rhythm among the white lower-class men, and an intermediate level of rhythm among higher-class men, regardless of racialized category. The “staccato” low-alternation feature is also less stylistically sensitive than the high-alternation feature, implying that the latter is a more established feature than the former. Further, the “staccato” feature is more stylistically sensitive among younger speakers than older speakers, implying an ongoing change from indicator to marker status. For all speakers, age has a stable main effect, which means that younger speakers, independent of racial group and class, have lower alternation than older speakers. Implied here is that low-alternation is a change from below that originates within the racialized working class. While it may be incrementally transmitting into the wider speech community, the white working class is the most resistant to its incursion.

Intratumoral Susceptibility Signals Reflect Biomarker Status in Gliomas

Susceptibility-weighted imaging (SWI) can be a useful tool to depict vascular structures in brain tumors as well as micro-bleedings, which represent tumor invasion to blood vessels and could also be representative of tumoral angiogenesis. In this study, we investigated the relationship between SWI features and glioma grades, and the expression of key molecular markers isocitrate dehydrogenase 1 (IDH1), O-6-methylguanine-DNA methyltransferase (MGMT), and 1p19q. The gliomas were graded according to the intratumoral susceptibility signals (ITSS). We used the Mann-Whitney test to analyze the relationship between ITSS grades and the pathological level and status of these markers. Additionally, the area under the curve (AUC) was used to determine the predictive value of glioma SWI characteristics for the molecular marker status. In these cases, the ITSS grades of low-grade gliomas (LGG) were significantly lower than those of high-grade gliomas (HGG). Similarly, the ITSS grades of gliomas with IDH1 mutations and MGMT methylation were significantly lower than those of gliomas with Wild-type IDH1 and unmethylated MGMT. However, ITSS grades showed no relationship with 1p19q deletion status, while they did show significant predictive ability for glioma grade, IDH1 mutation, and MGMT methylation. These findings indicate an association between some molecular markers and cerebral microbleeds in gliomas, providing a new avenue for non-invasive prediction of molecular genetics in gliomas and an important basis for preoperative personalized surgical treatment based on molecular pathology.

PEG10 is associated with treatment-induced neuroendocrine prostate cancer

Neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy is becoming increasingly recognized. Several models of this transdifferentiation provide insight into its molecular pathogenesis and have highlighted the placental gene PEG10 for further study. Using our unique model of enzalutamide resistance (ENZR) and NE differentiation, we studied PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42DENZR and 42FENZR compared to LNCaP and castration-resistant 16DCRPC cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16DCRPC. Antagonism of AR activity increased PEG10 expression followed by an increase in terminal NE markers. Conversely, stimulating AR activity via androgen supplementation reversed PEG10 and NE marker expression in a time and dose-dependent manner. These results were supported by human data showing that PEG10 expression is highest in NEPC and that AR-dependent gene, PSA, is negatively correlated with PEG10 in adenocarcinoma. Further, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression. While PEG10 did not drive NEPC, its knockdown reduced NE markers in our cell lines. Moreover, PEG10 knockdown in vitro- and in vivo-attenuated tumor growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates NE markers in ENZR cells and targeting PEG10 in advanced prostate cancer with NE features is a rational and viable option.