Stem-like CD8 T cells in stage I lung adenocarcinoma as a prognostic biomarker: A preliminary study.

OBJECTIVES: This study aimed to investigate the presence of stem-like CD8 T (CD8 TSL) cells in lung adenocarcinoma (LUAD) and explore their relationships with the clinical outcomes. METHODS: Multiplex immunofluorescence (mIF) was performed to identify CD8 TSL and antigen-presenting cells (APC) in 76 LUAD patients. Differences in the number of CD8 TSL cells based on tumor stage and the spatial relationships between CD8 TSL cells and APC niches were determined. The optimal cutoff value of CD8 TSL cells for predicting survival in patients with stage I LUAD was calculated. RESULTS: CD8 TSL cells were present in all tumors, and their numbers were significantly higher in stage I patients than in stage III patients (P = 0.010); CD8 TSL cells located in the APC niches accounted for 69.7% (53/76) of the hotspot fields. The optimal cutoff value for the number of CD8 TSL cells required to predict the overall survival (OS) in patients with stage I LUAD was 2.5 per 10000 µm2. The median OS and progression-free survival (PFS) in the high-level group (>2.5) were significantly (P < 0.001) longer than those in the low-level group (≤2.5). The number of CD8 TSL cells was an independent prognostic factor for stage I LUAD. Patients with more CD8 TSL cells had a lower risk of death and disease progression than those with less CD8 TSL cells. CONCLUSION: CD8 TSL cells were observed in patients with stages I-III LUAD and might serve as prognostic biomarkers for stage I LUAD.

Prediction of heavy metal lead contamination accident in Three Gorges Reservoir Area.

Water contamination incidents have become a significant ecological and environmental threat, particularly concerning the security of drinking water source areas (DWSAs). This research aimed to address this issue by integrating Geographic Information System (GIS) into bidimensional hydrodynamic water quality mathematical model developed using C + + and FORTRAN programming languages. The focus was on the Heshangshan drinking water source area (HDWSA), and the TECPLOT360 software was utilized for visualizing pollutant migration and dispersion processes. The study specifically considered a hypothetical lead (Pb) contamination accident, which is situated in the Three Gorges Reservoir Area (TGRA). The spatio-temporal variations in Pb concentration throughout the entire DWSA were analyzed, along with a comparison of Pb concentration changes during different water seasons. The results indicate that, during the accident, the Pb concentration at the water intake in the drought season, decline season, flood season, and impounding season reached the standard limits at 76, 58, 44, and 48 min, respectively. Moreover, the entire DWSA achieved standard levels of Pb concentration at 124, 89, 71, and 74 min during the respective seasons. The study also observed an expansion and subsequent contraction of the Pb contamination area in the DWSA, with the transfer rate of Pb concentration ranked as flood season > impounding season > decline season > drought season.

A new assessment method for water environment safety and its application.

The Three Gorges Reservoir area is recognized by its vast size, dense population, bustling economic and social activities along its banks, and by the significant volume of waterway traffic. These factors make it with a high risk of water pollution accidents, posing a serious threat to water environmental safety. Therefore, it is imperative to conduct a water environmental safety assessment in this region to ensure the safety of the water environment. In the present work, the Driving-Pressure-State-Impact-Response-Risk Water Environmental Safety model was proposed, and a comprehensive water environmental safety assessment system was established. The Water Environment Safety Index was introduced to measure the degree of water environment safety. This model synthesized multiple factors and their interrelationships, enabling a more accurate assessment of water environment safety. By adopting scientifically rigorous evaluation criteria, this assessment method enhanced the reliability and credibility of the results obtained. The water environment safety in the 22 counties and districts of the Three Gorges Reservoir area of Chongqing region from 2017 to 2021 was assessed in terms of temporal changes and spatial differentiation. In general, the overall water environment safety situation in the Three Gorges Reservoir area of Chongqing region is relatively safe, but a few counties/districts (such as Wanzhou District, Jiangjin District, etc.) are still in Warning. Spatially, the water environmental safety condition was relatively better in the northeast compared to the southwest. The main factors threatening water environment safety include: 1) the consequence of the Three Gorges Project, 2) severe soil erosion, 3) industrial, agricultural, and domestic pollution, and 4) frequent water pollution accidents. The present work provided a new method for conducting water environment safety assessments, which is expected to positively contribute to further research in this field.

Prediction and countermeasures of heavy metal copper pollution accident in the Three Gorges Reservoir Area.

In order to mitigate the hazards of water pollution in drinking water source areas (DWSAs), developing applicable models and proposing effective solutions is of paramount significance. The study developed the Heshangshan Drinking Water Source Area (HDWSA) Hydrodynamic Model, integrating Geographic Information System (GIS) into a two-dimensional hydrodynamic water quality model using FORTRAN. TECPLOT360 software (Software Tools for Numerical Simulation with Visualization) visualized contamination transportation and diffusion. The model's relative error is less than 6%, indicating its strong stability and high reliability. The HDWSA in the Three Gorges Reservoir Area (TGRA) was used as a case study, focusing on copper (Cu) as a pollutant. By regulating the flow downstream from the Xiangjiaba Reservoir, Scheduling Group 1 and Scheduling Group 2 respectively increased the flow by 4000 m3/s and 8000 m3/s. The study analyzed the spatio-temporal variations of Cu concentration following pollution accident and flow scheduling. Under accident conditions, it took 71, 61, 49, and 56 min for the Cu concentration in the study area to decrease to below the standard value (1 mg/L) during dry, falling, flood, and storage periods. Scheduling Groups 1 and 2 reduced the pollutant exceedance duration by 19-26 min and 12-18 min across the four water periods.

Can carbon emission trading improve carbon emission performance? Evidence from a quasi-natural experiment in China.

Carbon emission trading policies play a key role in reducing carbon emissions through market-based mechanisms. In the context of China's carbon neutrality goals and carbon peaking targets, it is important to predict and evaluate the effectiveness of such policies. The combined impact of carbon trading policies on carbon emission reduction and economic output has not been well investigated in previous studies. In this study, the impact of carbon emission trading policies on regional carbon emission performance was assessed through mechanism analysis and empirical tests. The mechanism analysis showed that carbon emission intensity reduction relied on three mediating effects: technological innovation incentives, industrial structure optimization, and energy substitution. For the empirical test, the multi-time difference-in-differences (DID) method was adopted to study the impact using panel data from 30 provinces in China between 2005 and 2019. Moreover, the specific impact mechanism was further tested using mediating effects. The results showed that China's carbon trading policy has significantly affected the carbon emission performance of the pilot regions, and factors such as GDP per capita, urbanization level, and capital-labor ratio have notably contributed to the reduction of carbon emission intensity. The proportions of the three mediating effects in the total effect were estimated to be 60.98%, 23.17%, and 10.14%, respectively. This study provides an empirical approach to the study of the impact of carbon trading policy on carbon emission reduction and economic output and can serve as a reference for addressing climate change and alleviating conflicts between the environment and economic growth in similar regions.

Potential biomarkers for predicting immune response and outcomes in lung cancer patients undergoing thermal ablation.

Thermal ablation is a promising alternative treatment for lung cancer. It disintegrates cancer cells and releases antigens, followed by the remodeling of local tumor immune microenvironment and the activation of anti-tumor immune responses, enhancing the overall effectiveness of the treatment. Biomarkers can offer insights into the patient's immune response and outcomes, such as local tumor control, recurrence, overall survival, and progression-free survival. Identifying and validating such biomarkers can significantly impact clinical decision-making, leading to personalized treatment strategies and improved patient outcomes. This review provides a comprehensive overview of the current state of research on potential biomarkers for predicting immune response and outcomes in lung cancer patients undergoing thermal ablation, including their potential role in lung cancer management, and the challenges and future directions.

Diagnostic value of CT and MRI combined with serum LDH, NSE, CEA, and MYCN in pediatric neuroblastoma.

BACKGROUND: To analyze the diagnostic value of computed tomography (CT), magnetic resonance imaging (MRI) combined with serum lactate dehydrogenase (LDH), neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), and N-myc (MYCN) in the diagnosis of pediatric neuroblastoma. METHODS: Fifty-two children diagnosed with neuroblastoma were selected as the neuroblastoma group. During the same period, 52 children who visited our hospital with abdominal distension, diarrhea, constipation, and vomiting but were finally excluded from neuroblastoma were selected as the control group. CT and MRI were performed on all children. RESULTS: Fifty-two cases of neuroblastoma of the central nervous system were confirmed by pathological examination. The levels of LDH, NSE, CEA, and MYCN in the neuroblastoma group were clearly higher than those in the control group (P < 0.05). The results of CT and MRI combined with serum LDH, NSE, CEA, and MYCN were false positive in 10 cases and false negative in 6 cases, which were consistent with the pathological results. The sensitivity of CT and MRI combined with serum LDH, NSE, CEA, and MYCN in the diagnosis of neuroblastoma was notably higher than that of the three alone (P < 0.05). CONCLUSION: The imaging findings of CT and MRI in children with central nervous system neuroblastoma were definitely characteristic. MRI had higher diagnostic value than CT. The diagnostic value of CT and MRI combined with serum LDH, NSE, CEA, and MYCN was improved to some extent.

The controversial expression of SOX2 in gastric cancer and its correlation with Helicobacter pylori infection: A meta-analysis.

BACKGROUND: The expression of sex-determining region Y (SRY)-like high-mobility group (HMG) box 2 (SOX2) in gastric cancer and the prognosis of patients are controversial. This study analyzed the relationship between SOX2 expression and baseline data, clinicopathological parameters, prognosis, and Helicobacter pylori infection in patients with gastric cancer, and provided new supplements for the diagnosis and treatment of gastric cancer. METHODS: The articles which reported SOX2 expression in gastric cancer from medical database was collected. The literature search was conducted in PubMed, Google Scholar, Cochrane library, SpringerLink, China National Knowledge Infrastructure, Web of Science, and Wanfang databases, which were written in English and Chinese. RESULTS: A total of 32 articles, including 4641 gastric cancer patients. The results showed that SOX2 expression in gastric cancer group was lower than that in the para-cancerous control group (P < .001). Statistical difference was found between the SOX2 expression and differentiation (Well/Moderate vs Poor), TNM stage (I/II vs III/IV), lymphatic invasion (N0 vs N+), edge infiltration (R0 vs R1), and H pylori infection in the pathological parameters. The prognosis analysis showed that the level of SOX2 expression was unrelated to the overall survival of patients (P = .329). No statistical difference was observed between the SOX2 expression and the baseline data of the patients (all P > .05). CONCLUSIONS: Although downregulation expression of SOX2 are related to clinicopathological parameters in gastric cancer, which is not correlated with prognosis. This controversy over the expression of SOX2 will provide a new idea for the study of gastric cancer.

Transferability and reproducibility of the EpiSkin™ Micronucleus Assay.

A novel in vitro 3D micronucleus assay was developed in China using the EpiSkin™ 3D human skin model. This EpiSkin™ Micronucleus Assay showed good predictivity and reproducibility during internal validation and is expected to contribute to in vitro genotoxicity testing as a follow-up for positive results from 2D micronucleus assay. Having developed the assay in one laboratory, further work focused on the transferability and inter-laboratory reproducibility in two additional Chinese authority laboratories (Guangdong Provincial Center for Disease Control and Prevention and Zhejiang Institute for Food and Drug Control). Formal training was provided for both laboratories, which resulted in good transferability based on the results of two positive compounds, such as mitomycin C and vinblastine. Independent experiments were then performed, and inter-laboratory reproducibility was checked using 2-acetylaminofluorene, 5-fluorouracil, 2,4-dichlorophenol, and d-limonene. The dose-responses of the positive control chemical, mitomycin C, were similar to those of the developing laboratory, and all test chemicals were correctly classified by all laboratories. Overall, there was a good transferability as well as intra- and inter-laboratory reproducibility of the EpiSkin™ Micronucleus Assay. This study further confirmed the assay's robustness and provided confidence to enter following validation stages for scientific acceptance.

Small cell neuroendocrine carcinoma expressing alpha fetoprotein in the endometrium.

Rare small cell neuroendocrine carcinoma (SCNEC) cases showed alpha fetoprotein (AFP) expression in the endometrium. In this study, we reported a case of uterine SCNEC expressing AFP. In addition, a literature review was performed to investigate the potential mechanism and the clinicopathological features of SCNEC to provide clinical guidance. A 65-year-old female was referred to our hospital due to vaginal bleeding for 1 month in November 2020. The clinical features were summarized. After total hysterectomy and removal of bilateral appendages, the histological examination and immunohistochemistry examination were performed. Histological findings showed that the cancer cells were arranged in a nest-like pattern distributed in a lamellar manner. The smooth muscles of the uterus were invaded by cancer cells. Cancer cells were relatively consistent in size. Small glandular duct-like and rosettes-like structures were distinguished, together with necrotic tissues. The deep staining showed that the amount of cytoplasm was lower in the nucleus. Partial cancer cells had small nucleolus with an irregular profile. There were some mitotic figures. Immunohistochemistry examination indicated that there was a diffuse expression of CK, Syn, CgA, CD56, CK8/18, P16, AFP, HepPar-1, Glypican-3, and Ki67 (90%). In this case, we reported a SCNEC patient expressing AFP, Glypican-3, and HepPar-1.

Metformin Inhibited Proliferation and Metastasis of Colorectal Cancer and presented a Synergistic Effect on 5-FU.

The purpose of this study was to investigate the effect of metformin or the combination of metformin and 5-FU on the growth and metastasis of colorectal cancer (CRC). For the in vitro experiments, HCT 116 and SW1463 cell lines were treated with metformin or the combination of metformin and 5-FU. Cell proliferation and invasion were analyzed by CCK-8, colony formation, and transwell assay, respectively. For the in vivo experiments, the CRC xenograft nude mice model was used to observe the effects of metformin or combined with 5-FU on tumor growth and metastasis. Metformin significantly inhibited the proliferation and invasion of HCT116 and SW1463 cells in vitro, which showed synergetic effects to 5-FU. In CRC xenograft nude mice, metformin alone and metformin combined with 5-FU treatment significantly inhibited tumor cell proliferation and tumor metastasis. In summary, metformin played an inhibitory role in the proliferation and metastasis of CRC and had a synergistic effect with 5-FU. Metformin may be a potentially effective anti-metastatic drug or an anticancer adjuvant agent for treating CRC.

Characterization of a new component and impurities in josamycin by trap-free two-dimensional liquid chromatography coupled to ion trap time-of-flight mass spectrometry.

RATIONALE: The toxicities of the impurities of a drug will affect the clinical effects and cause potential health risk; therefore, it is essential to study profiles of the impurities. In this study, a new structural type of component and two acid degradation impurities in josamycin were discovered and characterized for the further improvement of official monographs in pharmacopoeias. METHODS: The component and acid degradation impurities in josamycin were separated and preliminary characterized by trap-free two-dimensional liquid chromatography coupled to high-resolution ion trap time-of-flight mass spectrometry (2D LC/IT-TOF MS) in both positive and negative electrospray ionization mode. The eluent of each peak from the first dimensional chromatographic system was trapped by a switching valve and subsequently transferred to the second dimensional chromatographic system, which was connected to the mass spectrometer. Full scan MS was firstly conducted to obtain the exact m/z values of the molecules. Then LC/MS/MS and LC/MS/MS/MS experiments were performed on the compounds of interest. RESULTS: A new structural type of component, which was named as josamycin A, and two acid degradation impuritiess, which were identified as impurity I and impurity II, were discovered in josamycin. Their structures and fragmentation pattern were deduced according to MSn data. Furthermore, josamycin A was synthesized and impurity I was separated by preparative HPLC. The structures of josamycin A and the impurities were confirmed by 1 H NMR and 13 C NMR data. CONCLUSIONS: Josamycin A was produced when the hydroxyl group on the macrolide of josamycin was oxidized into a carbonyl group. Impurity I and impurity II were produced by the loss of one molecule of acetyl mycaminose from josamycin and josamycin A, respectively. Compared with josamycin, the experimental results showed that josamycin A had a higher antibacterial activity with similar cytotoxicity, while impurity I had no antibacterial activity but a higher cytotoxicity. As a result, the control of impurity I is significant.

A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection.

Aberrant apoptosis can lead to acute or chronic degenerative diseases. Mitochondrial outer membrane permeabilization (MOMP) triggered by the oligomerization of the Bcl-2 family proteins Bax/Bak is an irreversible step leading to execution of apoptosis. Here, we describe the discovery of small-molecule inhibitors of Bax/Bak oligomerization that prevent MOMP. We demonstrate that these molecules disrupt multiple, but not all, interactions between Bax dimer interfaces thereby interfering with the formation of higher-order oligomers in the MOM, but not recruitment of Bax to the MOM. Small-molecule inhibition of Bax/Bak oligomerization allowed cells to evade apoptotic stimuli and rescued neurons from death after excitotoxicity, demonstrating that oligomerization of Bax is essential for MOMP. Our discovery of small-molecule Bax/Bak inhibitors provides novel tools for the investigation of the mechanisms leading to MOMP and will ultimately facilitate development of compounds inhibiting Bax/Bak in acute and chronic degenerative diseases.

SENP3 regulates the global protein turnover and the Sp1 level via antagonizing SUMO2/3-targeted ubiquitination and degradation.

SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the relationship between SUMO proteases, SENPs, and RNF4 remains obscure. There are limited examples of the SENP regulation of SUMO2/3-targeted proteolysis mediated by RNF4. The present study investigated the role of SENP3 in the global protein turnover related to SUMO2/3-targeted ubiquitination and focused in particular on the SENP3 regulation of the stability of Sp1. Our data demonstrated that SENP3 impaired the global ubiquitination profile and promoted the accumulation of many proteins. Sp1, a cancer-associated transcription factor, was among these proteins. SENP3 increased the level of Sp1 protein via antagonizing the SUMO2/3-targeted ubiquitination and the consequent proteasome-dependent degradation that was mediated by RNF4. De-conjugation of SUMO2/3 by SENP3 attenuated the interaction of Sp1 with RNF4. In gastric cancer cell lines and specimens derived from patients and nude mice, the level of Sp1 was generally increased in parallel to the level of SENP3. These results provided a new explanation for the enrichment of the Sp1 protein in various cancers, and revealed a regulation of SUMO2/3 conjugated proteins whose levels may be tightly controlled by SENP3 and RNF4.

[Establishment of Schatzker classification digital models of tibial plateau fractures and its application on virtual surgery].

OBJECTIVE: To explore the establishment of Schatzker classification digital model of tibial plateau fractures and its application in virtual surgery. METHODS: Proximal tibial of one healthy male volunteer was examined with 64-slice spiral computed tomography (CT). The data were processed by software Mimics 10.01 and a model of proximal tibia was reconstructed. According to the Schatzker classification criteria of tibial plateau fractures, each type of fracture model was simulated.Screen-captures of fracture model were saved from different directions.Each type of fracture model was exported as video mode.Fracture model was imported into FreeForm modeling system.With a force feedback device, a surgeon could conduct virtual fracture operation simulation.Utilizing the GHOST of FreeForm modeling system, the software of virtual cutting, fracture reduction and fixation was developed.With a force feedback device PHANTOM, a surgeon could manipulate virtual surgical instruments and fracture classification model and simulate surgical actions such as assembly of surgical instruments, drilling, implantation of screw, reduction of fracture, bone grafting and fracture fixation, etc. RESULTS: The digital fracture model was intuitive, three-dimensional and realistic and it had excellent visual effect.Fracture could be observed and charted from optional direction and angle.Fracture model could rotate 360 ° in the corresponding video mode. The virtual surgical environment had a strong sense of reality, immersion and telepresence as well as good interaction and force feedback function in the FreeForm modeling system. The user could make the corresponding decisions about surgical method and choice of internal fixation according to the specific type of tibial plateau fracture as well as repeated operational practice in virtual surgery system. CONCLUSION: The digital fracture model of Schatzker classification is intuitive, three-dimensional, realistic and dynamic. The virtual surgery systems of Schatzker classifications make the virtual surgery training more normalized, programmed and standardized.In addition, virtual surgery system can serve as a new tool for preoperative planning and surgeon-patient interactions.

Chemical and biosynthetic evolution of the antimycin-type depsipeptides.

Evolution of natural products, and particularly those resulting from microbial assembly line-like enzymes, such as polyketide (PK) and nonribosomal peptides (NRP), has resulted in a variety of pharmaceutically important and chemically diverse families of molecules. The antimycin-type depsipeptides are one such grouping, with a significant level of diversity and members that have noted activities against key targets governing human cellular apoptosis (e.g. Bcl-xL and GRP78). Chemical variance originates from ring size, with 9-, 12-, 15-, and 18-membered classes, and we show that such distinctions influence their molecular targeting. Further, we present here a systematic interrogation of the chemistry and assembly line evolution of antimycin-type analogues by conducting metabolomic profiling and biosynthetic gene cluster comparative analysis of the depsipeptide assembly lines for each member of the antimycin-group. Natural molecular evolution principles of such studies should assist in artificial re-combinatorializing of PK and NRP assembly lines.

SUMO2 and SUMO3 transcription is differentially regulated by oxidative stress in an Sp1-dependent manner.

Protein SUMOylation (SUMO is small ubiquitin-related modifier) is a dynamic process that is strictly regulated under physiological and pathological conditions. However, little is known about how various intra- or extra-cellular stimuli regulate expression levels of components in the SUMO system. SUMO isoforms SUMO2 and SUMO3 can rapidly convert to be conjugated in response to a variety of cellular stresses. Owing to the limitations of sequence homology, SUMO2 and SUMO3 cannot be differentiated between and are thus referred to as SUMO2/3. Whether these two isoforms are regulated in distinct manners has never been addressed. In the present paper we report that the expression of SUMO3, but not SUMO2, can be down-regulated at the transcription level by cellular oxidative stress. In the present study, we checked SUMO2 and SUMO3 mRNA levels in cells exposed to various doses of H2O2 and in cells bearing different levels of ROS (reactive oxygen species). We found an inverse relationship between SUMO3 transcription and ROS levels. We characterized a promoter region specific for the mouse Sumo3 gene that is bound by the redox-sensitive transcription factor Sp1 (specificity protein 1) and demonstrated oxidation of Sp1, as well as suppression of Sp1-DNA binding upon oxidative stress. This revealed for the first time that the expression of SUMO2 and SUMO3 is regulated differently by ROS. These findings may enhance our understanding about the regulation of SUMOylation and also shed light on the functions of Sp1.

[Expression of cyclooxygenase-2 and vascular endothelial growth factor in human prostate cancer and its significance].

OBJECTIVE: To evaluate expressions of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in primary prostate cancer and its clinical significance. METHODS: Expressions of COX-2 and VEGF were detected by immunohistochemical assay in tissues of 40 prostate cancer and 10 benign prostatic hyperplasia samples. RESULTS: COX-2 and VEGF levels in prostate cancer were much higher than those in BPH. The degrees of cancer malignancy and invasion positively correlated with the expressions of COX-2 and VEGF. COX-2 level positively correlated with VEGF level. CONCLUSION: The abnormal expression of COX-2 plays an important role in the development of primary prostate cancer. COX-2 and VEGF are good molecular markers of prostate cancer which are hopeful to be used for the assistant diagnosis and the prediction of prognosis of prostate cancer.