Dynamic Cortical Connectivity During Propofol Sedation in Glioma Patients.

BACKGROUND: The behavioral manifestations and neurophysiological responses to sedation can assist in understanding brain function after neurological damage, and can be described by cortical functional connectivity. Glioma patients may experience neurological deficits that are not clinically detectable before sedation. We hypothesized that patients with gliomas exhibit distinct cortical connectivity patterns compared to non-neurosurgical patients during sedation. METHODS: This is a secondary analysis of a previously published prospective observational study. Patients scheduled for resection of supratentorial glioma (n=21) or a non-neurosurgical procedure (n=21) under general anesthesia were included in this study. Frontal electroencephalography (EEG) signals were recorded at different sedation levels as assessed by the Observer Assessment of Alertness/Sedation (OAA/S) score. Kernel principal component analysis and k-means clustering were used to determine possible temporal dynamics from the weighted phase lag index characteristics. RESULTS: Ten EEG connectivity states were identified by clustering (76% consistency), each with unique properties. At OAA/S 3, the median (Q1, Q3) occurrence rates of state 6 (glioma group, 0.110 [0.083, 0.155] vs. control group, 0.070 [0.030, 0.110]; P=0.008) and state 7 (glioma group, 0.105 [0.083, 0.148] vs. control group: 0.065 [0.038, 0.090]; P=0.001), which are dominated by beta connectivity, were significantly different between the 2 groups, reflecting differential conversion of the beta band between the left and right brain regions. In addition, the temporal dynamics of the brain's functional connectivity was also reflected in the transition relationships between metastable states. CONCLUSIONS: There were differences in EEG functional connectivity, which is dynamic, between the glioma and nonglioma groups during sedation.

Electroencephalography characteristics of patients with supratentorial glioma in different consciousness states induced by propofol.

Gliomas are the most common primary intracranial malignant tumors. Some of these patients exhibit previously clinically undetected neurological deficits after sedation. The absence of neurophysiological evidence for this phenomenon limits the use of time-sensitive monitoring methods. The study aims to compare differences between glioma patients under sedation and those without intracranial lesions by comparing their EEG features. Twenty-one patients without intracranial tumors and 21 with frontal lobe supratentorial gliomas were enrolled. The EEG power spectrum of the glioma group was comparable to that of the control group for both sides of the brain (P > 0.05 for all frequencies). Compared with those without intracranial lesions, the weighted phase lag index (wPLI) in the alpha and beta bands on the non-occupied side decreased. Glioma patients had weaker functional connectivity during sedation than patients without intracranial lesions, manifesting as reduced functional connectivity on the non-occupied side.

Genetic differences between lung metastases and liver metastases from left-sided microsatellite stable colorectal cancer: next generation sequencing and clinical implications.

BACKGROUND: Data regarding the clinical characteristics and outcomes of lung metastases (LuM) from colorectal cancer (CRC) are different from those of liver metastases (LiM) from CRC. However, little is known about the genetic features of LuM. This study aimed to identify the different genetic characteristics of LuM and LiM from left-sided microsatellite stable CRC. METHODS: Tissue samples of the primary tumors and paired metastases from 18 CRC patients with isolated LuM (LuM cohort), 18 patients with isolated LiM (LiM cohort), and 10 locally advanced CRC patients without metastases (control cohort) were selected for next-generation sequencing. Patients in the LiM cohort had matched clinicopathological characteristics with the LuM cohort. The single-nucleotide variations (SNVs), copy number variations (CNVs), pathway alterations, and tumor mutation burdens (TMBs) were also calculated and analyzed. RESULTS: The CNV results showed that ZFHX4, GATA2, and FAM131B amplifications were more common in the metastatic cohorts than in the control cohort, while RECQL4 and FLCN amplifications were common in the controls. The LuM cohort had significantly higher proportions of HNF4A, BRD4, and U2AF1 amplification. The LuM, LiM, and control cohorts were successfully separated using pathway alteration analysis. The LuM cohort had more frequent alterations in the RTK/RAS pathway, HIPPO pathway, KRAS, and MET than the LiM group. The LuM cohort also had relatively higher TMBs than the LiM cohort. CONCLUSIONS: CNVs in primary tumors could identify patients with LuM. Targeting the HIPPO pathway or MET and immune checkpoint inhibitors (ICIs) combined with other agents might be novel therapies for LuM.

Characterization of the immune microenvironment in brain metastases from different solid tumors.

BACKGROUND: Brain metastases are one of the most common intracranial neoplasms. Increasing evidence have indicated that systemic immunotherapy may provide long-term benefits for brain metastases. Herein, we presented the results of an immune oncology panel RNA sequencing platform for patients with brain metastases from different primary sites. METHODS: We investigated 25 samples of human brain metastases from lung cancer (n = 12), breast cancer (n = 6), and colorectal cancer (n = 7). Besides, 13 paired samples of adjacent noncancerous brain tissue (10 from patients with lung cancer and 3 from patients with breast cancer) were collected as controls. By comparing the brain metastases and paired samples of adjacent noncancerous brain tissue from 13 patients, we detected three upregulated and six downregulated genes, representing the malignant properties of cancer cells and increased immune infiltration in the microenvironment. Next, we profiled the immune-related genes in brain metastases from three primary cancer types. RESULTS: A group of genes were significantly overexpressed in the microenvironment of brain metastases from lung cancer, covering the checkpoint pathways, lymphocyte infiltration, and TCR-coexpression. Especially, immune checkpoint molecules, PD-L1, PD-L2, and IDO1 were expressed at higher levels in brain metastases from lung cancer than those from the other two cancer types. CONCLUSIONS: This study presents an immune landscape of brain metastases from different cancer types. With high RNA expression levels of PD-1/PD-L1 axis and immune infiltration in brain metastases, it would be worthwhile to explore the efficacy of immune checkpoint blockade for lung cancer patients with intracranial metastases.

PD-L1 expression and tumor mutational burden status for prediction of response to chemotherapy and targeted therapy in non-small cell lung cancer.

BACKGROUND: Several targeted immunotherapies have recently showed significant advances in treatment of non-small cell lung cancer (NSCLC), including antibodies and inhibitors targeting programmed death-1 (PD-1) and its ligand (PD-L1). METHODS: Tumor tissue samples were prospectively collected from 183 patients with NSCLC including lung adenocarcinoma (ADC) and squamous cell carcinoma (SQCC). PD-L1 expression level was measured by immunohistochemistry assay and tumor mutational burden (TMB) status was assessed by next generation sequencing. Correlations between PD-L1 expressions, TMB status with clinicopathological characteristics were analyzed. RESULTS: PD-L1 expression was detected in 37% of ADC group and 55% in SQCC group while all clinicopathological characteristics were found comparable between these two groups. PD-L1 expression was negatively associated with overall survival in ADC group (P < 0.0001) but not in SQCC group (P = 0.418). In consistent with PD-L1 expression level, TMB status was significantly lower in ADC subjects as compared to SQCC subjects (P = 0.024) while PD-L1 positive subgroup and TMB high subgroup shared less subjects within ADC group than SQCC group. More importantly, the combination of TMB status and PD-L1 expression successfully identified responders, who showed significant longer median overall survival than non-responders (32 months vs. 8.5 months) in ADC subjects (P < 0.0001) but not in SQCC subjects. CONCLUSIONS: Here we tested the hypothesis that monitoring TMB, in addition to the existing PD-L1 expression level, could represent valuable non-invasive biomarkers for the chemotherapy and targeted therapy. Further analyses are in need to further assess the prognostic value of TMB for ADC and SQCC patients receiving immunotherapy.

Carbon Dots/Prussian Blue Satellite/Core Nanocomposites for Optical Imaging and Photothermal Therapy.

Integration of optical imaging modality with photothermal therapy (PTT) for simultaneously providing oncotherapy and bioimaging enables an optimized therapeutic efficacy and higher treatment accuracy and therefore has emerged as a prospective cancer treatment. However, it remains challenging to develop biocompatible PTT nanoagents capable of imaging, monitoring, and diagnosis. Carbon dots (CDs) possess unique photoluminescent (PL) properties and intrinsic biocompatibility; while Prussian blue nanoparticles (PBNPs) are nontoxic with efficient photothermal conversion capacity for PTT. Herein, a simple, cost-effective, and environmentally benign method was developed to strategically fabricate CD-decorated PBNP (CDs/PBNP) nanocomposites with satellite/core structure. The CDs/PBNPs possess distinct green PL emission and near-infrared photoabsorption with high efficiency and photothermal stability. In vitro and in vivo toxicity tests prove the biocompatibility of the CDs/PBNPs. Moreover, the applicability of CDs/PBNPs as nanotheranostic agents was tested, which suggests that CDs/PBNPs possess promising imaging and effective tumor ablation properties.

Transcription Factors PvERF15 and PvMTF-1 Form a Cadmium Stress Transcriptional Pathway.

In plants, cadmium (Cd)-responsive transcription factors are key downstream effectors of Cd stress transcriptional pathways, which are capable of converging Cd stress signals through triggering the expression of Cd detoxification genes. However, the upstream transcriptional regulatory pathways that modulate their responses to Cd are less clear. Previously, we identified the bean (Phaseolus vulgaris) METAL RESPONSE ELEMENT-BINDING TRANSCRIPTION FACTOR1 (PvMTF-1) that responds to Cd and confers Cd tolerance in planta. Here, we demonstrate an upstream transcriptional regulation of the PvMTF-1 response to Cd Using a yeast one-hybrid system, we cloned the bean ETHYLENE RESPONSE FACTOR15 (PvERF15) that binds to the PvMTF-1 promoter. PvERF15 was strongly induced by Cd stress, and its overexpression resulted in the up-regulation of PvMTF-1 DNA-protein interaction assays further revealed that PvERF15 binds directly to a 19-bp AC-rich element in the PvMTF-1 promoter. The AC-rich element serves as a positive element bound by PvERF15 to activate gene expression. More importantly, knockdown of PvERF15 by RNA interference resulted in reduced Cd-induced expression of PvMTF-1PvERF15 seems to be involved in Cd tolerance, since knockdown of PvERF15 by RNA interference in bean leaf discs decreased Cd tolerance in a transient assay. Since PvERF15 is a component of the Cd stress transcriptional pathway in beans and PvMTF-1 is one of its downstream targets, our findings provide a PvERF15/PvMTF-1 transcriptional pathway and thereby contribute to the understanding of Cd stress transcriptional regulatory pathways in plants.

Bean metal-responsive element-binding transcription factor confers cadmium resistance in tobacco.

Cadmium (Cd) is highly toxic to plants. Modulation of Cd-responsive transcription is an important way for Cd detoxification in plants. Metal-responsive element (MRE) is originally described in animal metallothionein genes. Although functional MREs also exist in Cd-regulated plant genes, specific transcription factors that bind MRE to regulate Cd tolerance have not been identified. Previously, we showed that Cd-inducible bean (Phaseolus vulgaris) stress-related gene2 (PvSR2) produces a short (S) PvSR2 transcript (S-PvSR2) driven by an intronic promoter. Here, we demonstrate that S-PvSR2 encodes a bean MRE-binding transcription factor1 (PvMTF-1) that confers Cd tolerance in tobacco (Nicotiana tabacum). PvMTF-1 expression was up-regulated by Cd at the levels of RNA and protein. Importantly, expression of PvMTF-1 in tobacco enhanced Cd tolerance, indicating its role in regulating Cd resistance in planta. This was achieved through direct regulation of a feedback-insensitive Anthranilate Synthase α-2 chain gene (ASA2), which catalyzes the first step for tryptophan biosynthesis. In vitro and in vivo DNA-protein interaction studies further revealed that PvMTF-1 directly binds to the MRE in the ASA2 promoter, and this binding depends on the zinc finger-like motif of PvMTF-1. Through modulating ASA2 up-regulation by Cd, PvMTF-1 increased free tryptophan level and subsequently reduced Cd accumulation, thereby enhancing Cd tolerance of transgenic tobacco plants. Consistent with this observation, tobacco transiently overexpressing ASA2 also exhibited increased tolerance to Cd. We conclude that PvMTF-1 is a zinc finger-like transcription factor that links MRE to Cd resistance in transgenic tobacco through activation of tryptophan biosynthesis.