Removal of 6-methylquinoline from shale gas wastewater using electrochemical carbon nanotubes filter.

6-Methylquinoline (6-MQ) is identified as a high-concentration organic compound pervasive in shale gas wastewater (SGW) and poses a significant risk of environmental pollution. In response, this study aimed to address these challenges by introducing an innovative electrochemical membrane constructed with multi-walled carbon nanotubes (CNTs) for the removal of 6-MQ. The investigation systematically explored the impact of voltage, initial pollutant concentration, and salinity on the performance of the electrochemical CNTs filter. It was found a positive correlation between removal efficiency and increasing voltage and salinity levels. Conversely, as the initial concentration of pollutants increased, the efficiency showed a diminishing trend. The electrochemical CNTs filter exhibited remarkable efficacy in both adsorption removal and electrochemical oxidation of 6-MQ. Notably, the CNTs membrane exhibited robust adsorption capabilities, evidenced by the sustained adsorption of 6-MQ for over 33 h. Furthermore, applying an electrochemical oxidation voltage of 3 V consistently maintained a removal rate exceeding 34.0% due to both direct and indirect oxidation, underscoring the sustained efficacy of the electrochemical membranes. Besides, real wastewater experiments, while displaying a reduction in removal efficiency compared to synthetic wastewater experiments, emphasized the substantial potential of the electrochemical CNTs filter for practical applications. This study underscores the significant promise of electrochemical membranes in addressing low molecular weight contaminants in SGW, contributing valuable insights for advancing SGW treatment strategies.

Function of NEK2 in clear cell renal cell carcinoma and its effect on the tumor microenvironment.

BACKGROUND: Previous studies have revealed the critical functions of NEK2 in controlling the cell cycle which is linked to poor prognosis in multiple tumor types, but less research has been devoted to clear cell renal cell carcinoma (ccRCC). METHODS: We downloaded clinical data from the gene expression omnibus (GEO) and TCGA databases together with transcriptional and mutational datasets. Strongly coexpressed genes with NEK2 were extracted from TCGA-KIRC cohort, and were submitted to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional analyses. According to NEK2 levels, the survival status, mutational characteristics, response to immunotherapy and sensitivity to drugs of the patients were studied. The potential correlations between NEK2 levels and immune cell state as well as immune cell infiltration were examined using the GEPIA, TIMER and TISIDB databases. Double immunofluorescence (IF) was performed to identify the NEK2 overexpression and relationship with CD8 in ccRCC. RESULTS: The NEK2 gene was overexpressed and would enhance the nuclear division and cell cycle activities in ccRCC. ccRCC patients with high NEK2 expression had worse clinical outcomes, higher mutation burden and better therapeutic response. Moreover, NEK2 gene overexpression was positively related to various immune cell marker sets, which was also proved by validation cohort, and more infiltration of various immune cells. CONCLUSION: ccRCC patients with NEK2 high expression have a poorer prognosis than those with NEK2 low expression, resulting from its function of promoting proliferation, accompanied by increased infiltration of CD8 + T cells and Tregs and T-cell exhaustion and will respond better to proper treatments.

Efficacy and Perioperative Safety of Robot-Assisted Minimally Invasive Esophagectomy for Esophageal Cancer.

Background: Esophageal cancer (EC) remains a significant global health concern. Minimally invasive surgical techniques, including robot-assisted approaches, have emerged as promising options for improving outcomes and patient recovery in EC management. Objective: This study aims to evaluate the clinical utility of robot-assisted minimally invasive esophagectomy (RAMIE) in the treatment of EC. Methods: A total of 160 EC patients undergoing treatment at our hospital were included in this study. Patients were randomly assigned to either the research group, receiving RAMIE, or the control group, undergoing thoracoscopic minimally invasive esophagectomy (MIE). Surgical outcomes, postoperative recovery, complication rates, and changes in inflammatory factors (IFs) such as malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels were compared between the two groups. Additionally, prognostic survival and EC recurrence rates were assessed at a 1-year follow-up. Results: The research group demonstrated longer operative times, a higher number of dissected lymph nodes, reduced intraoperative bleeding, and quicker postoperative recovery compared to the control group, with significantly fewer complications (P < .05). Furthermore, the research group exhibited lower levels of postoperative IFs and MDA, along with higher levels of SOD and GSH-Px, compared to the control group (P < .05). There was no significant difference between the two groups in terms of prognostic survival and EC recurrence rates (P > .05). Conclusion: RAMIE demonstrates superior efficacy in enhancing therapeutic outcomes and accelerating postoperative recovery in patients with EC, thus establishing its value in EC treatment protocols. RAMIE is suggested as a valuable therapeutic option and warrants clinical adoption for EC management.

Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial.

Background: Anlotinib is a new type of tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1/2/3, platelet-derived growth factor receptors α/ß, and fibroblast growth factor receptors 1-4 and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. It has been proven effective in HER2-negative metastatic breast cancer, but its efficacy in early-stage triple-negative breast cancer (TNBC) is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients with TNBC. Methods: Patients with clinical stage II/III TNBC were treated with 5 cycles of anlotinib (12 mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 ,d1, q3w or nab-paclitaxel 125 mg/m2, d1 and d8, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0) and the secondary endpoints include breast pCR (bpCR), axillary pCR (apCR), residual cancer burden (RCB), objective response rate (ORR), survival, and safety. Exploratory endpoints were efficacy biomarkers based on Fudan University Shanghai Cancer Center Immunohistochemical (FUSCC IHC) classification for TNBC and next-generation sequencing (NGS) of DNA from tumor tissue and blood samples of patients with 425-gene panel. This trial is registered with www.chictr.org.cn (ChiCTR2100043027). Findings: From Jan 2021 to Aug 2022, 48 patients were assessed and 45 were enrolled. All patients received at least one dose of study treatment and underwent surgery. The median age was 48.5 years (SD: 8.7), 71% were nodal involved, and 20% had stage III. In the intention-to-treat population, 26 out of 45 patients achieved pCR (57.8%; 90% CI, 44.5%-70.3%), and 39 achieved residual cancer burden class 0-I (86.7%; 95% CI, 73.2%-94.9%). The bpCR and apCR rate were 64.4% (29/45) and 71.9% (23/32), respectively. No recurrence or metastasis occurred during the short-term follow-up. Based on the FUSCC IHC-based subtypes, the pCR rates were 68.8% (11/16) for immunomodulatory subtype, 58.3% (7/12) for basal-like immune-suppressed subtype and 33.3% (4/12) for luminal androgen receptor subtype, respectively. NGS revealed that the pCR were 77% (10/13) and 50% (14/28) in MYC-amplified and wild-type patients, respectively, and 78% (7/9) and 53% (17/32) in gBRCA1/2-mutated and wild-type patients, respectively. The median follow-up time of the study was 14.9 months (95% CI: 13.5-16.3 months). There was no disease progression or death during neoadjuvant therapy. No deaths occurred during postoperative follow-up. In the safety population (N = 45), Grade 3 or 4 treatment emergent adverse events occurred in 29 patients (64%), and the most common events were neutropenia (38%), leukopenia (27%), thrombocytopenia (25%), anemia (13%), and hypertension (13%), respectively. Interpretation: The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and encouraging antitumor activity for patients with clinical stage II/III TNBC. Funding: Chongqing Talents Project, Chongqing Key Project of Technology Innovation and Application Development and Chongqing Outstanding Youth Natural Science Foundation.

Long-term dietary exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) reduced feeding in common carp (Cyprinus carpio): Via the JAK-STAT signaling pathway.

Polybrominated diphenyl ethers (PBDEs) are widely present in water ecosystems where they pose a significant threat to aquatic life, but our knowledge about how PBDEs affect feeding is limited. Therefore, this study explored the effects of continuous dietary exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) (40 and 4000 ng/g) on the feeding in common carp (Cyprinus carpio) and the underlying mechanism. BDE-47 significantly decreased the food intake of carp. Transcriptome analysis of brain tissue showed that BDE-47 mainly affected the nervous, immune, and endocrine systems. Further examination of the expression levels of appetite factors in the brain revealed that BDE-47 caused dysregulation of appetite factors expressions such as agrp, pomc, cart, etc. In addition, the JAK-STAT signaling pathway was activated under BDE-47 exposure. It can be concluded from these findings that BDE-47 activated the JAK-STAT signaling pathway, causing imbalanced expression of appetite factors, leading to disordered feeding behavior and decreased food intake in carp. These results provide an important reference for a more comprehensive understanding of the hazards posed by BDE-47 on animal feeding and the associated mechanisms.

Characterizing hazardous substances of shale gas wastewater from the upper Yangtze River: A focus on heavy metals and organic compounds.

In the last decade, rapid shale gas exploration in upper Yangtze River ecological zone in China has led to increasing concerns about the environmental impact of shale gas wastewater (SGW). However, our understanding of the types of potential hazardous substances of SGW remains limited. In this study, eight SGW samples from three shale gas regions in upper Yangtze River: the Sichuan Basin, the Guizhou Plateau, and the Three Gorges Area were collected, and their general water quality, trace metals, and organic compounds were comprehensively analyzed. Our in-depth analysis detected 55 kinds of trace heavy metals, with 24 exceeding detection limits. Most of them were of the concentration below 100 µg/L. Concentrations of primary pollutants, including Cd, Cr, As, Pb, and Ni, remained below Integrated Wastewater Discharge Standard (GB 8978-1996), indicating minimal environmental risk. The organic analysis identified 45 to 104 kinds of volatile and semi-volatile organic compounds in SGW samples from different regions. SGW samples from the Sichuan Basin exhibited a balanced proportion of aliphatic and aromatic compounds, with oxygen and nitrogen-substituted heteroatomic compounds prevailing, while SGW samples from the Guizhou Plateau and the Three Gorges Area were dominated by aromatic compounds, particularly hydrocarbons. Several organic substances exhibited high response strengths across multiple SGW samples, including isoquinoline, dibenzylamine, 2,4-di-tert-butylphenol, 1,2,3,4-tetrahydro-naphthalene, and 1,2,3,4-tetrahydro-6-methyl-naphthalene. The Globally Harmonized System (GHS) of Classification and Labelling of Chemicals classified most high-response organics as high acute and chronic aquatic hazards. Our findings indicate that high salinity and a variety of high-risk organic pollutants, rather than heavy metals, are the primary pollutants in SGW, underscoring the urgency of safety management of SGW.

Genome-wide identification, phylogeny and expression analysis of the R2R3-MYB gene family in quinoa (Chenopodium quinoa) under abiotic stress.

The MYB transcription factor (TF) are among the largest gene families of plants being responsible for several biological processes. The R2R3-MYB gene family are integral player regulating plant primary and secondary metabolism, growth and development, and responses to hormones and stresses. The phylogenetic analysis combined with gene structure analysis and motif determination resulted in division of R2R3-MYB gene family into 27 subgroups. Evidence generated from synteny analyses indicated that CqR2R3-MYBs gene family is featured by tandem and segmental duplication events. On the basis of RNA-Seq data, the expression patterns of different tissues under salt treatment were investigated resulting CqR2R3-MYB genes high expression both in roots and stem of quinoa (Chenopodium quinoa ) plants. More than half of CqR2R3-MYB genes showed expression under salt stress. Based on this result, CqR2R3-MYB s may regulate quinoa plant growth development and resistance to abiotic stresses. These findings provided comprehensive insights on role of CqR2R3-MYBs gene family members in quinoa and candidate MYB gene family members can be further studies on their role for abiotic stress tolerance in crop plants.

The significance of HAUS1 and its relationship with immune microenvironment in hepatocellular carcinoma.

Background: HAUS Augmin-like complex subunit 1(HAUS1), as a controlling gene, which affected the production of spindle was firstly discovered in Drosophila cells. Although HAUS1 has been intensively studied, but its significance and relationship with the immune microenvironment in Hepatocellular carcinoma (HCC) remain unclear. Materials and Methods: All data of HCC in this paper were obtained from The Cancer Genome Atlas(TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO) and the Human Protein Atlas(HPA) database. The role and potential value of HAUS1 in the tumorigenesis and development of HCC were studied by applying plenty of bioinformatics analysis methods. Knocked down the expression of HAUS1 through siRNA and further investigated the function of HAUS1 in HCC Results: HAUS1 was highly expressed in HCC, which led to a poor prognosis. ROC curve analysis showed that HAUS1 had a excellent diagnostic value. It was also associated with clinical stage, pathological grade and AFP of HCC. Univariate and multivariate COX regression analysis showed that HAUS1 was an independent prognostic factor for HCC patients. HAUS1 was associated with immune cells infiltrate and immune checkpoints in HCC, and it could generate significative therapeutic results when combined with anti-CTLA4 and anti-CD274 treatment. In vitro experiments, HAUS1 was found to promote the proliferation, invasion and metastasis, participated in cell cycle regulation and inhibited apoptosis of HCC. Conclusion: These results suggested that HAUS1 might serve as a potential therapeutic target, as well as a diagnostic, prognostic, and survival biomarker for HCC.

A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.

Polyglycerol-Based Hydrogel as Versatile Support Matrix for 3D Multicellular Tumor Spheroid Formation.

Hydrogel-based artificial scaffolds are essential for advancing cell culture models from 2D to 3D, enabling a more realistic representation of physiological conditions. These hydrogels can be customized through crosslinking to mimic the extracellular matrix. While the impact of extracellular matrix scaffolds on cell behavior is widely acknowledged, mechanosensing has become a crucial factor in regulating various cellular functions. cancer cells' malignant properties depend on mechanical cues from their microenvironment, including factors like stiffness, shear stress, and pressure. Developing hydrogels capable of modulating stiffness holds great promise for better understanding cell behavior under distinct mechanical stress stimuli. In this study, we aim to 3D culture various cancer cell lines, including MCF-7, HT-29, HeLa, A549, BT-474, and SK-BR-3. We utilize a non-degradable hydrogel formed from alpha acrylate-functionalized dendritic polyglycerol (dPG) and thiol-functionalized 4-arm polyethylene glycol (PEG) via the thiol-Michael click reaction. Due to its high multivalent hydroxy groups and bioinert ether backbone, dPG polymer was an excellent alternative as a crosslinking hub and is highly compatible with living microorganisms. The rheological viscoelasticity of the hydrogels is tailored to achieve a mechanical stiffness of approximately 1 kPa, suitable for cell growth. Cancer cells are in situ encapsulated within these 3D network hydrogels and cultured with cell media. The grown tumor spheroids were characterized by fluorescence and confocal microscopies. The average grown size of all tumoroid types was ca. 150 µm after 25 days of incubation. Besides, the stability of a swollen gel remains constant after 2 months at physiological conditions, highlighting the nondegradable potential. The successful formation of multicellular tumor spheroids (MCTSs) for all cancer cell types demonstrates the versatility of our hydrogel platform in 3D cell growth.

Depletion of lncRNA MEG3 Ameliorates Imatinib-Induced Injury of Cardiomyocytes via Regulating miR-129-5p/HMGB1 Axis.

Imatinib is a classical targeted drug to treat chronic myeloid leukemia (CML). However, it shows cardiotoxicity, which limits its clinical application. Long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) shows proapoptotic properties in human cells. This study is performed to investigate whether targeting MEG3 can attenuate imatinib-mediated cardiotoxicity to cardiomyocytes. In this work, H9c2 cells were divided into four groups: control group, hypoxia group, hypoxia + imatinib, and hypoxia + imatinib + MEG3 knockdown group. MEG3 and microRNA-129-5p (miR-129-5p) expression levels were detected by the quantitative real-time PCR (qRT-PCR). The viability and apoptosis of H9c2 cells were then evaluated by cell counting kit-8 (CCK-8), flow cytometry, and TUNEL assays. The targeting relationships between MEG3 and miR-129-5p, between miR-129-5p and high-mobility group box 1 (HMBG1), were validated by dual-luciferase reporter assay and RNA Immunoprecipitation (RIP) assay. The protein expression level of HMGB1 was detected by western blot. It was revealed that, Imatinib-inhibited cell viability and aggravated the apoptosis of H9c2 cells cultured in hypoxic condition, and MEG3 knockdown significantly counteracted this effect. MiR-129-5p was a downstream target of MEG3 and it directly targeted HMGB1, and knockdown of MEG3 inhibited HMGB1 expression in H9c2 cells. In conclusion, targeting MEG3 ameliorates imatinib-induced injury of cardiomyocytes via regulating miR-129-5p/HMGB1 axis.

USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1.

Ubiquitin-specific protease 4 (USP4) represents a potential oncogene involved in various human cancers. Nevertheless, the biological roles and precise mechanism of USP4 in esophageal squamous cell carcinoma (ESCC) progression are not understood. Here, USP4 expression was found to be markedly upregulated in ESCC tumor tissues and cells. Loss- and gain-of-function assays suggested that USP4 silencing inhibited ESCC cell proliferation, migration, and invasion, while USP4 overexpression promoted these behaviors. Consistently, USP4 silencing repressed tumor growth and metastasis in an ESCC nude mouse model in vivo. As a target molecule of USP4, transforming growth factor-ß-activated kinase 1 (TAK1) also showed high expression in ESCC. Moreover, we observed that USP4 specifically interacted with TAK1 and stabilized TAK1 protein levels via deubiquitination in ESCC cells. Importantly, USP4 promotes ESCC proliferation, migration, and invasion via the MEK/ERK signaling pathway and can be inhibited by U0126. Neutral red (NR), an inhibitor of USP4 can suppress ESCC progression in vitro and in vivo. Overall, this study revealed that USP4/TAK1 plays crucial roles in ESCC progression by modulating proliferation, migration, and invasion, and USP4 might be a potential therapeutic target in ESCC.

Radiotranscriptomics identified new mRNAs and miRNA markers for distinguishing prostate cancer from benign prostatic hyperplasia.

The present study investigated ultrasound (US) phenotypes reflecting prostate cancer (PCa)-related genetic mutations. Herein, integration of radiotranscriptomic data, US and contrast-enhanced ultrasound (CEUS) radiomic images, and RNA sequencing was performed with the aim of significantly improving the accuracy of PCa prognosis. We performed radiotranscriptomic analysis of clinical, imaging, and two genomic (mRNA and microRNA expression) datasets from 48 and 22 men with PCa and benign prostatic hyperplasia (BPH), respectively. Twenty-three US texture features and four microvascular perfusion features were associated with various patterns of 52 differentially expressed genes related to PCa (p < 0.05); 17 overexpressed genes were associated with two key texture features. Twelve overexpressed genes were identified using microvascular perfusion features. Furthermore, mRNA and miRNA biomarkers could be used to distinguish between PCa and BPH. Compared with RNA sequencing, B-mode and CEUS features reflected genomic alterations associated with hormone receptor status, angiogenesis, and prognosis in patients with PCa. These findings indicate the potential of US to assess biomarker levels in patients with PCa.

Experience with the safe admission of breast and thyroid cancer patients in non-endemic areas during an epidemic outbreak.

Background: The outbreaks of infectious diseases, such as coronavirus disease 2019 (COVID-19), have seriously affected the normal work and life of the public, as well as the normal diagnosis and treatment of other diseases due to their strong infectivity, high population susceptibility, and diverse clinical manifestations. Breast and thyroid specialists in non-hotspot epidemic areas of COVID-19 must consider factors, including epidemic prevention and control, breast and thyroid cancers and diseases diagnosis and treatment, and access to medical resources to make a reasonable treatment choice and optimize the treatment process. Methods: A cohort study was designed under our center's epidemic prevention and control strategy. The study was conducted between February 3 and April 19, 2020, to explore the safety of clinical diagnosis and treatment of breast and thyroid cancer patients during the epidemic. All the outpatients, inpatients, day-time chemotherapy patients, targeted therapy patients, and relevant medical staff in the observation period in the Department of Breast and Thyroid Surgery in Southwest Hospital in Chongqing municipality, China, were included to investigate the detection and infection rate of COVID-19 and suspected patients. Results: During the observation period, 27,117 patients were admitted to the outpatient unit. We performed 394 inpatient surgeries and 411 day-time surgeries. In our center, 1,046 and 663 patients received day-time chemotherapy and targeted therapy, respectively. All the patients were diagnosed and treated promptly and safely. Three suspected COVID-19 patients were identified in the outpatient unit. Healthcare staff achieved a "zero" infection of COVID-19. Conclusion: The spread and cross-infection of COVID-19 can be avoided in non-hotspot epidemic areas based on scientific prevention and control, and cancer patients can be diagnosed and treated on time. The prevention and control measure implemented in the COVID-19 epidemic for diagnosing and treating cancer patients was effective and can be referenced for other infectious disease outbreaks.

Effect of apatinib on the pharmacokinetics of tramadol and O-desmethyltramadol in rats.

Since the combination of anticancer drugs and opioids is very common, apatinib and tramadol are likely to be used in combination clinically. This study evaluated the effects of apatinib on the pharmacokinetics of tramadol and its main metabolite O-desmethyltramadol in Sprague-Dawley (SD) rats and the inhibitory effects of apatinib on tramadol in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP2D6.1. The samples were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The in vivo results showed that compared with the control group, apatinib increased the AUC(0-t), AUC(0-∞) and Cmax values of tramadol and O-desmethyltramadol, and decreased the values of VZ/F and CLz/F. In addition, the MRT(0-t), MRT(0-∞) values of O-desmethyltramadol were increased. In vitro, apatinib inhibited the metabolism of tramadol by a mixed way with IC50 of 1.927 µM in RLMs, 2.039 µM in HLMs and 15.32 µM in CYP2D6.1. In summary, according to our findings, apatinib has a strong in vitro inhibitory effect on tramadol, and apatinib can increase the analgesic effect of tramadol and O-desmethyltramadol in rats.

PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma.

For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency-induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription factor 1 (TEAD1) in a histone demethylation-dependent manner. Subsequently, TEAD1 up-regulates GLUL transcriptionally. Pharmacological inhibition of GLUL by l-methionine sulfoximine not only repressed ccRCC lipid deposition and tumor growth but also enhanced the anticancer effects of everolimus. Thus, the PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment.

Polyglycerol-Based Biomedical Matrix for Immunomagnetic Circulating Tumor Cell Isolation and Their Expansion into Tumor Spheroids for Drug Screening.

Circulating tumor cells (CTCs) are established as distinct cancer biomarkers for diagnosis, as preclinical models, and therapeutic targets. Their use as preclinical models is limited owing to low purity after isolation and the lack of effective techniques to create 3D cultures that accurately mimic in vivo conditions. Herein, a two-component system for detecting, isolating, and expanding CTCs to generate multicellular tumor spheroids that mimic the physiology and microenvironment of the diseased organ is proposed. First, an antifouling biointerface on magnetic beads is fabricated by adding a bioinert polymer layer and conjugation of biospecific ligands to isolate cancer cells, dramatically enhancing the selectivity and purity of the isolated cancer cells. Next, the isolated cells are encapsulated into self-degradable hydrogels synthesized using a thiol-click approach. The hydrogels are mechanochemically tuned to enable tumor spheroid growth to a size greater than 300 µm and to further release the grown spheroids while retaining their tumor-like characteristics. In addition, drug treatment highlights the need for 3D culture environments rather than conventional 2D culture. The designed biomedical matrix shows potential as a universal method to ensure mimicry of in vivo tumor characteristics in individual patients and to improve the predictability of preclinical screening of personalized therapeutics.

Spatial distribution of tumor-infiltrating T cells indicated immune response status under chemoradiotherapy plus PD-1 blockade in esophageal cancer.

Background: The spatial distribution of tumor-infiltrating T cells and its dynamics during chemoradiotherapy combined with PD-1 blockade is little known in esophageal squamous cell carcinoma (ESCC). Methods: We applied the multiplex immunofluorescence method to identify T cells (CD4+, CD8+ T cells, and their PD-1- or PD-1+ subsets) and myeloid-derived cells (CD11c+ dendritic cells, CD68+ macrophages, and their PD-L1+ subpopulations) in paired tumor biopsies (n = 36) collected at baseline and during combination (40 Gy of radiation) from a phase Ib trial (NCT03671265) of ESCC patients treated with first-line chemoradiotherapy plus anti-PD-1 antibody camrelizumab. We used the FoundationOne CDx assay to evaluate tumor mutational burden (TMB) in baseline tumor biopsies (n = 14). We dynamically assessed the nearest distance and proximity of T-cell subsets to tumor cells under combination and estimated the association between T-cell spatial distribution and combination outcome, myeloid-derived subsets, TMB, and patient baseline characteristics. Findings: We found that the tumor compartment had lower T-cell subsets than the stromal compartment but maintained a comparable level under combination. Both before and under combination, PD-1- T cells were located closer than PD-1+ T cells to tumor cells; T cells, dendritic cells, and macrophages showed the highest accumulation in the 5-10-µm distance. Higher CD4+ T cells in the tumor compartment and a shorter nearest distance of T-cell subsets at baseline predicted poor OS. Higher baseline CD4+ T cells, dendritic cells, and macrophages were associated with worse OS in less than 10-µm distance to tumor cells, but related with better OS in the farther distance. Higher on-treatment PD-1-positive-expressed CD4+ and CD8+ T cells within the 100-µm distance to tumor cells predicted longer OS. T cells, dendritic cells, and macrophages showed a positive spatial correlation. Both high TMB and smoking history were associated with a closer location of T cells to tumor cells at baseline. Conclusions: We firstly illustrated the T-cell spatial distribution in ESCC. Combining chemoradiotherapy with PD-1 blockade could improve the antitumor immune microenvironment, which benefits the treatment outcome. Further understanding the precision spatiality of tumor-infiltrating T cells would provide new evidence for the tumor immune microenvironment and for the combination treatment with immunotherapy.

High expression of PPFIA1 in human esophageal squamous cell carcinoma correlates with tumor metastasis and poor prognosis.

BACKGROUND: PTPRF interacting protein alpha 1 (PPFIA1) is reportedly related to the occurrence and progression of several kinds of malignancies. However, its role in esophageal squamous cell carcinoma (ESCC) is unclear. This current study investigated the prognostic significance and biological functions of PPFIA1 in ESCC. METHODS: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and Gene Expression Omnibus (GEO) were used to investigate PPFIA1 expression in esophageal cancer. The relationship between PPFIA1 expression and clinicopathological characteristics and patient survival was evaluated in GSE53625 dataset, and verified in the cDNA array based on qRT-PCR and tissue microarray (TMA) dataset based on immunohistochemistry. The impact of PPFIA1 on the migration and invasion of cancer cells were investigated by wound-healing and transwell assays, respectively. RESULTS: The expression of PPFIA1 was obviously increased in ESCC tissues versus adjacent esophageal tissues according to online database analyses (all P < 0.05). High PPFIA1 expression was closely related to several clinicopathological characteristics, including tumor location, histological grade, tumor invasion depth, lymph node metastasis, and tumor-node-metastasis (TNM) stage. High PPFIA1 expression was related to worse outcomes and was identified as an independent prognostic factor of overall survival in ESCC patients (GSE53625 dataset, P = 0.019; cDNA array dataset, P < 0.001; TMA dataset, P = 0.039). Downregulation of PPFIA1 expression can significantly reduce the migration and invasion ability of ESCC cells. CONCLUSION: PPFIA1 is related to the migration and invasion of ESCC cells, and can be used as a potential biomarker to evaluate the prognosis of ESCC patients.

Shallow-marine testate amoebae with internal structures from the Lower Devonian of China.

Testate amoebae, a polyphyletic protist group inhabiting a wide variety of extant ecosystems, have evolved as far back as early Neoproterozoic. However, their fossil record is discontinuous and biased toward empty shells. Here, we report an arcellinid testate amoeba species, Cangwuella ampulliformis gen. nov., sp. nov., from a shallow-marine community in the Early Devonian of Guangxi, southwestern China. With the aid of scanning electron microscopy and X-ray micro-tomography, we find that the shell of our testate amoeba contains some acetabuliform structures. Although such configuration does not match exactly with the known internal structures in extant testate amoebae, our fossils highlight the potential of exploring the ecological relationships between fossil testate amoebae and their associated organisms, and increase our knowledge on the diversity of testate amoebae in Early Devonian environments.