Genomic Amplification of TBC1D31 Promotes Hepatocellular Carcinoma Through Reducing the Rab22A-Mediated Endolysosomal Trafficking and Degradation of EGFR.

Hepatocellular carcinomas (HCCs) are characterized by a vast spectrum of somatic copy number alterations (CNAs); however, their functional relevance is largely unknown. By performing a genome-wide survey on prognosis-associated focal CNAs in 814 HCC patients by an integrative computational framework based on transcriptomic data, genomic amplification is identified at 8q24.13 as a promising candidate. Further evidence is provided that the 8q24.13 amplification-driven overexpression of Rab GTPase activating protein TBC1D31 exacerbates HCC growth and metastasis both in vitro and in vivo through activating Epidermal growth factor receptor (EGFR) signaling. Mechanistically, TBC1D31 acts as a Rab GTPase activating protein to catalyze GTP hydrolysis for Rab22A and then reduces the Rab22A-mediated endolysosomal trafficking and degradation of EGFR. Notably, overexpression of TBC1D31 markedly increases the resistance of HCC cells to lenvatinib, whereas inhibition of the TBC1D31-EGFR axis can reverse this resistance phenotype. This study highlights that TBC1D31 at 8q24.13 is a new critical oncogene, uncovers a novel mechanism of EGFR activation in HCC, and proposes the potential strategies for treating HCC patients with TBC1D31 amplification or overexpression.

Insights into the Mechanism of Efficient Cr(VI) Removal from Aqueous Solution by Iron-Rich Wheat Straw Hydrochar: Coupling DFT Calculation with Experiments.

Agricultural solid waste has become one of the raw materials for hydrothermal carbon production, promoting resource utilization. This study synthesized two types of ball-milling carbons (Fe-MHBC vs MHBC) with and without FeCl3 modification using wheat straw hydrochars. Cr(VI) adsorption on these two types of ball-milling carbons was investigated. According to Langmuir's maximum adsorption capacity analysis, Fe-MHBC had a capacity of 116.29 mg g-1. The thermodynamic analysis based on isothermal adsorption reveals the spontaneous process of the reaction between the two materials. The adsorption of Cr(VI) on Fe-MHBC exhibited excellent agreement with the pseudo-second-order kinetics model. Furthermore, X-ray photoelectron spectroscopy analysis showed that Fe(II) in the material reduced Cr(VI) when it participated in the reaction. The acidic conditions facilitate the elimination of Cr(VI). The Fe-MHBC has a higher zeta potential, which enhances the electrostatic attraction of Cr(VI) particles. Even with a starting pH of 10, the removal rate can be consistently maintained at over 64%. The adsorption of Cr(VI) was inhibited by various anions and higher ion concentrations. Density functional theory demonstrates that the presence of Fe enhances the adsorption capacity and electron transfer flux of Cr(VI). Fe-MHBC effectively eliminates Cr(VI) by the process of electrostatic adsorption, redox, and complexation reactions. This study demonstrated that hydrochar materials modified by FeCl3 through a ball-milling process show considerable potential as effective adsorbents in the treatment of Cr(VI) pollution, offering a viable and environmentally friendly solution for mitigating this prevalent environmental issue.

Totally Caged Type I Pro-Photosensitizer for Oxygen-Independent Synergistic Phototherapy of Hypoxic Tumors.

Activatable type I photosensitizers are an effective way to overcome the insufficiency and imprecision of photodynamic therapy in the treatment of hypoxic tumors, however, the incompletely inhibited photoactivity of pro-photosensitizer and the limited oxidative phototoxicity of post-photosensitizer are major limitations. It is still a great challenge to address these issues using a single and facile design. Herein, a series of totally caged type I pro-photosensitizers (Pro-I-PSs) are rationally developed that are only activated in tumor hypoxic environment and combine two oxygen-independent therapeutic mechanisms under single-pulse laser irradiation to enhance the phototherapeutic efficacy. Specifically, five benzophenothiazine-based dyes modified with different nitroaromatic groups, BPN 1-5, are designed and explored as latent hypoxia-activatable Pro-I-PSs. By comparing their optical responses to nitroreductase (NTR), it is identified that the 2-methoxy-4-nitrophenyl decorated dye (BPN 2) is the optimal Pro-I-PSs, which can achieve NTR-activated background-free fluorescence/photoacoustic dual-modality tumor imaging. Furthermore, upon activation, BPN 2 can simultaneously produce an oxygen-independent photoacoustic cavitation effect and a photodynamic type I process at single-pulse laser irradiation. Detailed studies in vitro and in vivo indicated that BPN 2 can effectively induce cancer cell apoptosis through synergistic effects. This study provides promising potential for overcoming the pitfalls of hypoxic-tumor photodynamic therapy.

Rare SMARCA4-deficient thoracic tumor: Insights into molecular characterization and optimal therapeutics methods.

INTRODUCTIONS: The 2021 WHO Classification of Thoracic Tumors recognized SMARCA4-deficient undifferentiated thoracic tumors (SMARCA4-dUT) as a distinct entity that shows a striking overlap in demographic and molecular profiles with SMARCA4-deficient non-small lung cancer (SMARCA4-dNSCLC). The implications of SMARCA4 deficiency based on immunohistochemistry remain unclear. We aimed to investigate molecular characteristics of SMARCA4-deficient thoracic tumors (SDTT) and explore optimal therapeutics. METHODS: From June.15, 2018, to Nov.15, 2023, a large cohort including patients diagnosed with SMARCA4-deficient (N = 196) and SMARCA4-intact (N = 438) thoracic tumors confirmed by immunohistochemistry at SYSUCC were screened. Clinicopathologic and molecular characteristics were identified and compared. External SRRSH cohort (N = 34) was combined into a pooled cohort to compare clinical outcome of first-line therapy efficacy. RESULTS: SDTT is male predominance with smoking history, high tumor burden, and adrenal metastases. The relationship between SMARCA4 mutation and protein expression is not completely parallel. The majority of SMARCA4-deficient patients harbor truncating (Class-I) SMARCA4 mutations, whereas class-II alterations and wild-type also exist. Compared with SMARCA4-intact thoracic tumors, patients with SDTT displayed a higher tumor mutation burden (TMB) and associated with a shorter median OS (16.8 months vs. Not reached; P < 0.001). Notably, SMARCA4 protein deficiency, rather than genetic mutations, played a decisive role in these differences. SDTT is generally resistant to chemotherapy, while sensitive to chemoimmunotherapy (median PFS: 7.5 vs. 3.5 months, P < 0.001). In particular, patients with SMARCA4 deficient thoracic tumors treated with paclitaxel-based chemoimmunotherapy achieved a longer median PFS than those with pemetrexed-based chemoimmunotherapy (10.0 vs. 7.3 months, P = 0.028). CONCLUSIONS: SMARCA4 protein deficiency, rather than genetic mutations, played a decisive role in its characteristics of higher TMB and poor prognosis. Chemoimmunotherapy serves as the optimal option in the current treatment regimen. Paclitaxel-based chemoimmunotherapy performed better than those with pemetrexed-based chemoimmunotherapy.

Clinical features and prognostic factors of nasopharyngeal carcinoma with brain metastases.

BACKGROUND: Brain metastasis in nasopharyngeal carcinoma is a rare occurrence, and the characteristics of patients in this subgroup remain poorly defined. This study aims to delineate the clinical features, treatment modalities, prognostic factors, and survival of nasopharyngeal carcinoma patients with brain metastasis. METHODOLOGY: A retrospective analysis was conducted on patients diagnosed with nasopharyngeal carcinoma who developed brain metastasis and were treated at the Sun Yat-sen University Cancer Center between July 2000 and July 2023. Clinical data from patients were collected and used to assess their survival after brain metastases and prognostic factors. RESULTS: Among 82,434 nasopharyngeal carcinoma patients, 40 (0.06 %) developed Brain metastasis with a median follow-up of 5.1 years. The predominant histological subtype was non-keratinizing squamous cell carcinoma (85 %). The median post-BM survival was 25 months. The age, the Eastern Cooperative Oncology Group (ECOG), and the procedural treatment of BM were prognostic factors. Notably, patients receiving local treatments had significantly prolonged post-BM survival compared to those receiving systemic therapy alone (median, 47.00 vs. 11.00 months; p = 0.011). CONCLUSIONS: This is the largest cohort of brain metastasis in nasopharyngeal carcinoma to date. Local therapeutic measures after brain metastasis can significantly enhance the prognosis of these patients, particularly when radiotherapy is applied.

Trends in pain undertreatment among lung cancer patients at the EOL: Analysis of urban city medical insurance data in China.

BACKGROUND: Cancer-related pain is one of the common priority symptoms in advanced lung cancer patients at the end-of-life (EOL). Alleviating pain is undoubtedly a critical component of palliative care in lung cancer. Our study was initiated to examined trends in opioid prescription-level outcomes as potential indicators of undertreated pain in China. METHODS: This study used data on 1330 patients diagnosed with lung cancer of urban city medical insurance in China who died between 2014 and 2017. Opioid prescription-level outcomes were determined by annual trends of the proportion of patients filling an opioid prescription, the total dose of opioids filled by decedents, and morphine milligram equivalents per day (MMED) at the EOL (defined as the 60 days before death). We further analyzed monthly changes in the number of opioid prescriptions filled, MMED, and mean daily dose of opioids per prescription (MDDP) of the last 60 days of life by year at death and age, respectively. RESULTS: A total of 959 patients with exact dates of death were included, with 432 cases (45.06%; 95% CI: 44.36%-45.77%) receiving at least one opioid prescription at the EOL. The declining trends were shown in the proportion of patients filling any opioid prescription, the total dose of opioids filled by decedents and MMED, with an annual decrease of 0.341% (p = 0.01), 104.23 mg (p = 0.011) and 2.84 mg (p = 0.014), respectively. Within the 31-60 days to the 0-30 days of life, the MMED declined 6.08 mg (95% CI: -7.14 to -5.03; p = 0.000351), while the number of opioid prescriptions rose 0.66 (95% CI: 0.160-1.16; p = 0.025). Like the MMED, the MDDP fell 4.11 mg (95% CI: -5.86 to -2.37; p = 0.005) within the last month before death compared to the previous month. CONCLUSION: Terminal lung cancer populations in urban China have experienced reduced access to opioids at the EOL. The clinicians did not prescribe a satisfactory dose of opioids per prescription, while the patients suffered increasing pain in the last 30 days of life. Sufficient opioid analgesic administration should be advocated for lung cancer patients during the EOL period.

Case report: Leptomeningeal metastasis of advanced nasopharyngeal carcinoma treated with chemoimmunotherapy.

Leptomeningeal metastasis (LM) of nasopharyngeal carcinoma (NPC) is rare and associated with a poor prognosis. Immune checkpoint inhibitors (ICIs) have been the standard first-line treatment for metastatic NPC, but their effect on meningeal metastasis of NPC needs further investigation. A 38-year-old man complained of bilateral neck masses and sought medical care. He was diagnosed with nasopharyngeal undifferentiated non-keratinizing carcinoma with bilateral cervical lymph node metastasis and multiple bone metastasis, stage cT4N2M1 IVb. Then, the patient received first-line anti-PD-1 antibody tislelizumab combined with gemcitabine and cisplatin and achieved partial response. After seven cycles of first-line chemoimmunotherapy, the patient subsequently developed neurological symptoms, including unsteady walking, slurred speech, coughing on drinking, and unconsciousness. MRI showed leptomeningeal linear enhancement, and cerebrospinal fluid (CSF) analysis indicated Epstein-Barr virus (EBV) infection and squamous cell carcinoma cytology, suggesting the diagnosis of leptomeningeal metastasis. After the definite diagnosis of LM, the patient's condition deteriorated rapidly, leading to his death from brain herniation. We reported the first case of advanced NPC with pathologically confirmed leptomeningeal metastasis after receiving first-line chemoimmunotherapy. Considering the poor prognosis of LM, it is suggested to perform MRI and CSF examination when patients have neurological symptoms. Although immunotherapy significantly improved survival outcomes of advanced NPC patients, it seemed not effective in the setting of LM. The effect of other treatment options, such as radiation therapy and intrathecal therapy, requires further verification.

STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC.

INTRODUCTION: Conflicting findings have been reported regarding the association between STK11/LKB1 mutations and immune checkpoint inhibitor (ICB) efficacy in NSCLC. It has been reported that tumors could exhibit impaired STK11/LKB1 function even without STK11 mutations. We hypothesized that STK11 phenotype rather than mutation may better stratify ICB outcomes. METHODS: Selected functional STK11 events and LKB1 protein data were leveraged to establish a transcriptomics-based classifier of STK11 phenotype (STK11-deficient [-def] or -proficient [-prof]). We analyzed in-house and Genentech/Roche's data of three randomized trials of programmed cell death protein-1 or programmed death-ligand 1 (PD-L1) inhibition in NSCLC (ORIENT-11, n = 171; OAK, n = 699; POPLAR, n = 192) and The Cancer Genome Atlas-NSCLC cohort. RESULTS: Tissue STK11 mutation did not affect ICB outcomes. However, the survival benefit of ICB versus chemotherapy were lost or reversed in STK11-def tumors (hazard ratios for death, 95% confidence interval: OAK [0.97, 0.69-1.35]; POPLAR [1.61, 0.88-2.97]; ORIENT-11 [1.07, 0.50-2.29]), while remaining in STK11-prof tumors (hazard ratios for death, 95% confidence interval: OAK [0.81, 0.66-0.99]; POPLAR [0.66, 0.46-0.95]; ORIENT-11 [0.59, 0.37-0.92]). In tumors differentially classified by phenotype and mutation status, STK11-wild-type/def tumors had significantly worse ICB outcomes than STK11-mutated (STK11-MUT)/prof tumors (p < 0.05). The deleterious impact of STK11 deficiency was independent of STK11/KRAS/KEAP1 status or PD-L1 expression. The STING/interferon-I signaling, which was previously shown to be suppressed in STK11-MUT models, was perturbed in patients with STK11-def tumors rather than those with STK11-MUT tumors. Surprisingly, whereas high CD8+ T-cell infiltration was significantly associated with prolonged survival with ICB in STK11-prof tumors (p < 0.05 for 3 trials), it predicted an opposite trend toward worse ICB outcomes in STK11-def tumors across three trials. This suggested an association between STK11 deficiency and CD8+ T-cell dysfunction, which might not be reversed by programmed cell death protein 1 or PD-L1 blockade. CONCLUSIONS: STK11 phenotype rather than mutation status can accurately identify patients with ICB-refractory NSCLC and reflect immune suppression. It can help refine stratification algorithms for future clinical research and also provide a reliable resource aiding basic and translational studies in identifying therapeutic targets.

Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC.

INTRODUCTION: According to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)-negative and tumor-infiltrating lymphocyte (TIL)-negative (type I); (2) PD-L1-positive and TIL-positive (type II); (3) PD-L1-negative and TIL-positive (type III); and (4) PD-L1-positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced NSCLC. METHODS: On the basis of RNA-sequencing and immunohistochemistry data from the ORIENT-11 study, we optimized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy. RESULTS: PD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06-0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13-0.55, p < 0.001). In the combination group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were susceptible to having similar PFS. In the chemotherapy group, there was no marked association between survival outcomes and TIME subtypes. CONCLUSIONS: Only patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.

Prognostic analysis of pT1-T2aN0M0 cervical adenocarcinoma based on random survival forest analysis and the generation of a predictive nomogram.

Background: The efficacy of adjuvant radiotherapy for postoperative patients with early-stage cervical adenocarcinoma who are lymph node-negative is still inconclusive. Establishing a nomogram to predict the prognosis of such patients could facilitate clinical decision-making. Methods: We recruited 4636 eligible patients with pT1-T2aN0M0 cervical adenocarcinoma between 2004 and 2016 from the Surveillance, Epidemiology and End Results (SEER) database. Random survival forest (RSF) and conditional survival forest (CSF) model was used to assess the prognostic importance of each clinical characteristic variable. We identified independent prognostic factors associated with overall survival (OS) by univariate and multivariate Cox regression risk methods and then constructed a nomogram. We stratified patients based on nomogram risk scores and evaluated the survival benefit of different adjuvant therapies. To reduce confounding bias, we also used propensity score matching (PSM) to match the cohorts before performing survival analyses. Results: The RSF and CSF model identified several important variables that are associated with prognosis, including grade, age, radiotherapy and tumor size. Patients were randomly divided into training and validation groups at a ratio of 7:3. Multivariate cox analysis revealed that age, grade, tumor size, race, radiotherapy and histology were independent prognostic factors for overall survival. Using these variables, we then constructed a predictive nomogram. The C-index value for evaluating the prognostic nomogram fluctuated between 0.75 and 0.91. Patients were divided into three subgroups based on risk scores, and Kaplan-Meier (K-M) survival analysis revealed that in the low-risk group, postoperative chemotherapy alone was associated with a significantly worse OS than surgery alone. Following PSM, survival analysis showed that compared with surgery alone, radiotherapy was associated with a worse OS in the training group although there was no significant difference in the validation group. Conclusions: For patients with pT1-T2aN0M0 cervical adenocarcinoma, adjuvant treatments such as postoperative radiotherapy or chemotherapy, compared with surgery alone, are of no benefit with regards to patient survival. Our prognostic nomogram exhibits high accuracy for predicting the survival of patients with early-stage postoperative cervical adenocarcinoma.

Electroacupuncture Inhibits NLRP3 Activation by Regulating CMPK2 After Spinal Cord Injury.

Objectives: This study aimed to evaluate the expression of cytosine monophosphate kinase 2 (CMPK2) and activation of the NLRP3 inflammasome in rats with spinal cord injury (SCI) and to characterize the effects of electroacupuncture on CMPK2-associated regulation of the NLRP3 inflammasome. Methods: An SCI model was established in Sprague-Dawley (SD) rats. The expression levels of NLRP3 and CMPK2 were measured at different time points following induction of SCI. The rats were randomly divided into a sham group (Sham), a model group (Model), an electroacupuncture group (EA), an adeno-associated virus (AAV) CMPK2 group, and an AAV NC group. Electroacupuncture was performed at jiaji points on both sides of T9 and T11 for 20 min each day for 3 consecutive days. In the AAV CMPK2 and AAV NC groups, the viruses were injected into the T9 spinal cord via a microneedle using a microscope and a stereotactic syringe. The Basso-Beattie-Bresnahan (BBB) score was used to evaluate the motor function of rats in each group. Histopathological changes in spinal cord tissue were detected using H&E staining, and the expression levels of NLRP3, CMPK2, ASC, caspase-1, IL-18, and IL-1ß were quantified using Western blotting (WB), immunofluorescence (IF), and RT-PCR. Results: The expression levels of NLRP3 and CMPK2 in the spinal cords of the model group were significantly increased at day 1 compared with those in the sham group (p < 0.05). The expression levels of NLRP3 and CMPK2 decreased gradually over time and remained low at 14 days post-SCI. We successfully constructed AAV CMPK2 and showed that CMPK2 was significantly knocked down following 2 dilutions. Finally, treatment with EA or AAV CMPK2 resulted in significantly increased BBB scores compared to those in the model group and the AAV NC group (p < 0.05). The histomorphology of the spinal cord in the EA and AAV CMPK2 groups was significantly different than that in the model and AAV NC groups. WB, IF, and PCR analyses showed that the expression levels of CMPK2, NLRP3, ASC, caspase-1, IL-18, and IL-1ß were significantly lower in the EA and AAV CMPK2 groups compared with those in the model and AAV NC groups (p < 0.05). Conclusion: Our study showed that CMPK2 regulated NLRP3 expression in rats with SCI. Activation of NLRP3 is a critical mechanism of inflammasome activation and the inflammatory response following SCI. Electroacupuncture downregulated the expression of CMPK2 and inhibited activation of NLRP3, which could improve motor function in rats with SCI.

Telomere shortening impairs alveolar regeneration.

OBJECTIVES: Short telomeres in alveolar type 2 (AT2) cells have been associated with many lung diseases. The study aimed to investigate the regeneration capacity of AT2 cells with short telomeres by knocking out Tert in mice (G4 Tert-/- ) from the whole to the cellular level. MATERIALS AND METHODS: The lung injury model of mice was established by left pneumonectomy (PNX). The proliferation and differentiation of AT2 cells were observed by immunofluorescence staining in vivo and in vitro. The difference of the gene expression between control and G4 Tert-/- group during the regeneration of AT2 cells was compared by RNA sequencing. The expression of tubulin polymerization promoting protein 3 (TPPP3) was reduced by adeno-associated virus delivery. RESULTS: The alveolar regeneration in G4 Tert-/- mice was impaired after PNX-induced lung injury. The regulation of cytoskeleton remodelling was defective in G4 Tert-/- AT2 cells. The expression of TPPP3 was gradually increased during AT2 cell differentiation. The expression level of TPPP3 was reduced in G4 Tert-/- AT2 cells. Reducing TPPP3 expression in AT2 cells limits the microtubule remodelling and differentiation of AT2 cells. CONCLUSION: Short telomeres in AT2 cells result in the reduced expression level of TPPP3, leading to impaired regeneration capacity of AT2 cells.

Transarterial chemoembolization (TACE) combined with apatinib versus TACE combined with sorafenib in advanced hepatocellular carcinoma patients: a multicenter retrospective study.

BACKGROUND: The combination of transarterial chemoembolization (TACE) with sorafenib has demonstrated superior efficacy over sorafenib and TACE monotherapy in hepatocellular carcinoma (HCC). Apatinib, a new targeted agent, has been recently reported to prolong the survival of HCC patients, either alone or in combination with TACE. However, the superior regimen between TACE-apatinib and TACE-sorafenib in HCC patients has not been determined. In this study, we compared the efficacy and safety of TACE-apatinib versus TACE-sorafenib in advanced stage HCC patients. METHODS: The data of 201 HCC patients who had received TACE-sorafenib or TACE-apatinib between January 2016 and June 2018 in three hospitals were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and adverse effects (AEs) between the two treatment groups were compared. A subgroup analysis based on the doses of targeted agents was also performed. RESULTS: No significant differences in baseline clinicopathological features were found between the two groups except for dose reduction. The TACE-apatinib group had higher incidences of hypertension, oral or anal ulcer and proteinuria, while the TACE-sorafenib group had higher incidences of diarrhea and alopecia. Grade 3/4 AEs occurred more frequently in the TACE-apatinib group than in the TACE-sorafenib group (52.3% vs. 22.6%, P<0.001). The TACE-sorafenib group had better PFS than the TACE-apatinib group (median PFS: 5.0 vs. 6.0 months, P=0.002) while the two groups showed no difference in OS (median OS: 13.0 vs. 13.0 months, P=0.448). The TACE-apatinib group had a higher rate of targeted agent dose reduction than the TACE-sorafenib group (53.5% vs. 17.4%, P<0.001). When the patients were stratified into normal and reduced-dose subgroups, those who received TACE-sorafenib exhibited improved PFS but similar OS compared with the patients who received TACE-apatinib in the reduced-dose subgroup (median OS: 12.0 vs. 13.3 months, P=0.614; median PFS: 3.0 vs. 7.0 months, P<0.001). Multivariable analysis validated that treatments and dose reduction were independent prognostic factors for PFS among all patients. CONCLUSIONS: Compared with TACE-sorafenib, the strategy of TACE-apatinib yielded shorter PFS in advanced HCC patients while no difference in OS was observed. A high rate of AE-related dose reduction of apatinib could account for the observed differences.

Surface modification of fly ash by non-thermal air plasma for elemental mercury removal from coal-fired flue gas.

The fly ash from a coal-fired power plants was modified with non-thermal plasma in air to improve the elemental mercury (Hg0) removal performance. The Hg0 adsorption experiments were implemented via a bench-scale fixed-bed reactor system. Brunauer-Emmett-Teller (BET), X-ray photoelectron spectroscopy (XPS), ultimate, X-ray diffraction (XRD) and XRF analysis were employed to characterize the fly ash. The effect of non-thermal plasma voltage and time on Hg0 removal efficiency was investigated. The results showed that fly ash had better Hg0 removal performance when treatment voltage was 3.0 kV and treatment time was 7 min. Furthermore, the results showed that non-thermal plasma treatment had little influence on the specific surface area. However, non-thermal plasma treatment increased the relative content of oxygen. XPS and temperature programmed desorption results indicated that Hg0 removal process included adsorption and oxidation of Hg0. Moreover, ester and carbonyl groups played extremely vital roles in the improvement of Hg0 removal performance, and their temperature programmed desorption peak occurred at around 250°C and 320°C, respectively.

Quantitative proteomics identifies a plasma multi-protein model for detection of hepatocellular carcinoma.

More efficient biomarkers are needed to facilitate the early detection of hepatocellular carcinoma (HCC). We aimed to identify candidate biomarkers for HCC detection by proteomic analysis. First, we performed a global proteomic analysis of 10 paired HCC and non-tumor tissues. Then, we validated the top-ranked proteins by targeted proteomic analyses in another tissue cohort. At last, we used enzyme-linked immunosorbent assays to validate the candidate biomarkers in multiple serum cohorts including HCC cases (HCCs), cirrhosis cases (LCs), and normal controls (NCs). We identified and validated 33 up-regulated proteins in HCC tissues. Among them, eight secretory or membrane proteins were further evaluated in serum, revealing that aldo-keto reductase family 1 member B10 (AKR1B10) and cathepsin A (CTSA) can distinguish HCCs from LCs and NCs. The area under the curves (AUCs) were 0.891 and 0.894 for AKR1B10 and CTSA, respectively, greater than that of alpha-fetoprotein (AFP; 0.831). Notably, combining the three proteins reached an AUC of 0.969, which outperformed AFP alone (P < 0.05). Furthermore, the serum AKR1B10 levels dramatically decreased after surgery. AKR1B10 and CTSA are potential serum biomarkers for HCC detection. The combination of AKR1B10, CTSA, and AFP may improve the HCC diagnostic efficacy.

Highly efficient electrochemical gas reduction on a three-dimensional foam electrode: mechanism and application for the determination of hazardous mercury in complex matrix.

For the first time a nickel foam electrode (NFE) is applied in the field of electrochemical vapor generation (EVG) to carry out the electrochemical vapor phase conversion of mercury. Systematical electrochemical and morphological research has demonstrated that the specific surface area of the NFE was several times larger than that of the metal/non-metal electrode with the same geometric size. At the same time, the 3D porous channel composed of multi-layer nickel wire ensures the full contact between reactant and interface. The evident enhancement of spectral signals on a Ni electrode (283%), compared with Pt (27%) and graphite (109%), confirmed that the NFE effectively enhances the yield of mercury reduction. The NFE exhibits low limit of detection (0.017 µg L-1) and a wide linear range (0.2-20 µg L-1) with recoveries of actual samples in the range 87.8-117% towards Hg2+. Although the NFE has no advantage in electronic transmission and catalytic performance, its excellent stability, especially anti-interference and other characteristics, is sufficient for the analysis of hazardous mercury in complex matrix including certified reference materials and real samples.

Adipocytes promote tumor progression and induce PD-L1 expression via TNF-α/IL-6 signaling.

BACKGROUND: Obesity confers increased risk for various types of cancer. PD-L1 is a key molecule in tumor immune evasion by inducing T cell exhaustion. The relationship between obesity and PD-L1 is still ambiguous. This study was designed to reveal the development of hepatocellular carcinoma and melanoma in obese mice and to investigate if adipocytes regulate PD-L1 expression and the underlying mechanism. METHODS: Monosodium glutamate-induced obese mice were inoculated with H22 tumor cells and High fat diet (HFD)-induced obese mice were inoculated with B16-F1 mouse melanoma cells. Human hepatoma HepG2 cells and B16-F1 cells were treated with conditional media from 3T3-L1 adipocytes (adi-CM). Neutralized anti-TNF-α and anti-IL-6 antibodies and inhibitor of NF-κB or STAT3 were used to reveal the mechanism of effect of adi-CM. RESULTS: In obese mice, H22 and B16-F1 tumor tissues grew faster and PD-L1 expression in tumor tissue was increased. Adi-CM up-regulated PD-L1 level in HepG2 and B16-F1 cells in vitro. Differentiated 3T3-L1 adipocytes secreted TNF-α and IL-6, and neutralizing TNF-α and/or IL-6 reduced PD-L1 expression in adi-CM-treated cells. p-NF-κB/NF-κB level was downregulated in HepG2 and B16-F1 cells, and p-STAT3/STAT3 level was also decreased in HepG2 cells. In addition, inhibitor of NF-κB or STAT3 reversed the effect of adi-CM on PD-L1 expression. CONCLUSIONS: TNF-α and IL-6 secreted by adipocytes up-regulates PD-L1 in hepatoma and B16-F1 cells, which may be at least partially involved in the role of obesity in promoting tumor progression.

Microwave ablation versus sorafenib for intermediate-Stage Hepatocellular carcinoma with transcatheter arterial chemoembolization refractoriness: a propensity score matching analysis.

Purpose: To compared the benefits of sorafenib with microwave ablation (MWA) in intermediate-stage hepatocellular carcinoma (HCC) patients with tumor size ≤7 cm and tumor number ≤5 after Transcatheter Arterial Chemoembolization (TACE) failure.Methods: A retrospective, single-center study was conducted using a one-to-one propensity score matching (PSM) analysis and involved 52 intermediate-stage HCC patients with absence of evidence of intrahepatic vascular invasion and extrahepatic metastasis after TACE failure and underwent treatment with MWA or sorafenib between 2007 and 2019. The overall survival (OS) and progression-free survival (PFS) were evaluated by the Kaplan-Meier method. The factors with OS and PFS were determined by Cox regression.Results: Of the 52 patients included in our study, 30 (57.7%) underwent MWA and 22 (42.3%) received sorafenib. After PSM, 22 pairs were enrolled into different groups for further analysis. Patients in the MWA-group had a significantly longer median PFS than patients in the sorafenib-group on both before (median, 9.3 vs. 2.8 months, p = .001) and after PSM (median, 9.0 vs. 2.8 months, p = .006). They also had a significantly longer median OS than patients in the sorafenib-group on before (median, 48.8 vs. 16.6 months, p = .001) and after PSM (median, Not reached vs. 16.6 months, p = .001). Besides, Cox regression analysis showed that the treatment and age were the independent prognostic factors of OS and PFS (p＜0.05).Conclusions: MWA was superior to sorafenib in improving survival for intermediate-stage hepatocellular carcinoma (HCC) patients with tumor size ≤7 cm and tumor number ≤5 after TACE failure.Key PointsCompared with sorafenib, microwave ablation may be a more reasonable alternative treatment for intermediate-stage hepatocellular carcinoma (HCC) patients with tumor size ≤7 cm and tumor number ≤5 after TACE refractoriness.The treatment (MWA vs sorafenib) and the age of patients were the independent prognostic factors of OS and PFS.

The 58th Cysteine of TcpP Is Essential for Vibrio cholerae Virulence Factor Production and Pathogenesis.

Vibrio cholerae, the causative agent of the severe diarrheal disease cholera, has evolved signal transduction systems to control the expression of virulence determinants. It was previously shown that two cysteine residues in the periplasmic domain of TcpP are important for TcpP dimerization and activation of virulence gene expression by responding to environmental signals in the small intestine such as bile salts. In the cytoplasmic domain of TcpP, there are another four cysteine residues, C19, C51, C58, and C124. In this study, the functions of these four cysteine residues were investigated and we found that only C58 is essential for TcpP dimerization and for activating virulence gene expression. To better characterize this cysteine residue, site-directed mutagenesis was performed to assess the effects on TcpP homodimerization and virulence gene activation. A TcpPC 58 S mutant was unable to form homodimers and activate virulence gene expression, and did not colonize infant mice. However, a TcpPC 19 / 51 / 124 S mutant was not attenuated for virulence. These results suggest that C58 of TcpP is indispensable for TcpP function and is essential for V. cholerae virulence factor production and pathogenesis.

Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells.

Fibrosis can develop in most organs and causes organ failure. The most common type of lung fibrosis is known as idiopathic pulmonary fibrosis, in which fibrosis starts at the lung periphery and then progresses toward the lung center, eventually causing respiratory failure. Little is known about the mechanisms underlying the pathogenesis and periphery-to-center progression of the disease. Here we discovered that loss of Cdc42 function in alveolar stem cells (AT2 cells) causes periphery-to-center progressive lung fibrosis. We further show that Cdc42-null AT2 cells in both post-pneumonectomy and untreated aged mice cannot regenerate new alveoli, resulting in sustained exposure of AT2 cells to elevated mechanical tension. We demonstrate that elevated mechanical tension activates a TGF-ß signaling loop in AT2 cells, which drives the periphery-to-center progression of lung fibrosis. Our study establishes a direct mechanistic link between impaired alveolar regeneration, mechanical tension, and progressive lung fibrosis.