Effects of human umbilical cord mesenchymal stem cell-derived exosomes in the rat osteoarthritis models.

Mesenchymal stem cells (MSCs) offer great potential for treatment of osteoarthritis (OA) by promoting articular cartilage regeneration via paracrine secretion of exosomes; however, the underlying mechanisms are not fully understood. This study aimed to explore the therapeutic effects of exosomes secreted by human umbilical cord-derived MSCs (hUC-MSCs) in rat models of OA and reveal the underlying mechanisms. UC-MSCs and UC-MSC-exosomes were prepared and identified by transmission electron microscopy and flow cytometry. IL-1ß-induced OA chondrocytes and the operation and collagenase-induced OA rat models were established. The results of micro-computed tomography, histology, and immunohistochemistry showed that UC-MSC-exosomes promoted cartilage regeneration in OA rats. ELISA results showed that the levels of synovial fluid cytokines, TNF-α, IL-1ß, and IL-6, were lower in exosome therapy group than control group in both OA rat models. Exosome treatment significantly downregulated the expression of MMP-13 and ADAMTS-5 in chondrocytes stimulated by IL-1ß, and upregulated collagen II expression. These findings suggest that hUC-MSC-exosomes offer a promising option for the therapy for OA.

Deuteration-Driven Photopharmacology: Deuterium-Labeled AzoCholine for Controlling Alpha 7 Nicotinic Acetylcholine Receptors.

Photopharmacology is a powerful approach to investigate biological processes and overcomes the common therapeutic challenges in drug development. Enhancing the photopharmacology properties of photoswitches contributes to extend their applications. Deuteration, a tiny structural modification, makes it possible to improve the photopharmacology and photophysical properties of prototype compounds, avoiding extra complex chemical changes or constructing multicomponent systems. In this work, we developed a series of D-labeled azobenzenes to expand the azobenzene photoswitchable library and introduced the D-labeled azobenzene unit into the photoagonist of α7 nicotinic acetylcholine receptors (α7 nAChRs) to investigate the effects of deuteration in photopharmacology. Spectral data indicated that deuteration maintained most of the photophysical properties of azobenzenes. The D-labeled photoagonist exhibited good control of the activity of α7 nAChRs than the prototype photoagonist. These results confirmed that deuteration is a promising strategy to improve the photopharmacological properties.

Pb isotopic fingerprinting of uranium pollution: New insight on uranium transport in stream-river sediments.

Uranium mill tailings (UMT) present a significant environmental concern due to high levels of radioactive and toxic elements, including uranium (U), thorium (Th), and lead (Pb), which can pose serious health risks to aquatic ecosystems. While Pb isotopic tracers have been widely utilized in environmental studies to identify elemental sources and geological processes, their application in U geochemistry remains relatively limited. In this study, we investigate the distribution and migration of U in stream-river sediments surrounding a decommissioned U hydrometallurgical area, employing Pb isotopes as tracers. Our findings reveal significant enrichment and ecological risk of U, Pb, and Th in the sediments. Uranium predominantly associates with quartz and silicate minerals, and its dispersion process is influenced by continuous leaching and precipitation cycles of typical U-bearing minerals. Furthermore, we establish a compelling positive relationship (r2 = 0.97) between 208Pb/207Pb and 206Pb/207Pb in the stream-river sediments and sediment derived from UMT. Application of a binary Pb mixing model indicates that anthropogenic hydrometallurgical activities contribute to 2.5-62.7% of the stream-river sediments. Notably, these values are lower than the 6.6-89.6% recorded about 10 years ago, prior to the decommissioning of the U hydrometallurgical activity. Our results underscore the continued risk of U pollution dispersion even after decommission, highlighting the long-term environmental impact of UMT.

A randomized controlled trial to compare short-term outcomes following infragastric and infracolic omentectomy at the time of primary debulking surgery for epithelial ovarian cancer with normal-appearing omentum.

BACKGROUND: Omentectomy is an important procedure in surgery for epithelial ovarian cancer, but the scope of omentectomy is not recommended in the guidelines. This study was performed to evaluate the benefits and risks of infragastric omentectomy in patients with epithelial ovarian cancer. METHODS: This trial is a single center prospective study. Primary epithelial ovarian cancer patients with normal-appearing omentum were randomly assigned to either the control or experimental group and underwent infracolic or infragastric omentectomy, respectively. The primary endpoint was progression-free survival. This trial is registered on Chinese clinical trial registry site (ChiCTR1800018771). RESULTS: A total of 106 patients meeting the inclusion criteria for ovarian cancer were included during the study period. Of these, 53 patients underwent infracolic omentectomy, whereas 53 patients received infragastric omentectomy. Multivariate analysis revealed that infragastric omentectomy could improve the detection rate of omental metastases (OR: 6.519, P = 0.005). Infragastric omentectomy improved progression-free survival significantly for those cases with higher than stage IIB disease (HR: 0.456, P = 0.041). Based on the short-term results, infragastric omentectomy did not cause more perioperative complications. CONCLUSIONS: Compared with infracolic omentectomy, infragrastric omentectomy may be a more appropriate surgical procedure for stage IIB-IIIC epithelial ovarian cancer patients with normal-appearing omentum.

Salinity and pH related microbial nitrogen removal in the largest coastal lagoon of Chinese mainland (Pinqing Lagoon).

Coastal lagoon is critical habitat for human and provides a wide range of ecosystem services. These vital habitats are now threatened by waste discharge and eutrophication. Previous studies suggest that the pollution mitigation of coastal lagoon relies on the water exchange with open sea, and the role of microbial processes inside the lagoon is overlooked. This study takes the Pinqing Lagoon which is the largest coastal lagoon in Chinese mainland as example. The distribution of nutrients, microbial activity of nitrogen removal and community structure of denitrifying bacteria in sediment are analyzed. The results showed that the nutrient in sediment represented by DIN (1.65-12.78 mg kg-1), TOM (0.59-8.72 %) and TN (0.14-1.93 mg g-1) are at high levels and are enriched at the terrestrial impacted zone (TZ). The microbial nitrogen removal is active at 0.27-19.76 µmol N kg-1 h-1 in sediment and denitrification is the dominate pathway taking 51.44-98.71 % of total N removal. The composition of the denitrifying microbial community in marine impacted zone (MZ) is close to that of ocean and estuary, but differs considerably with those of TZ and transition zone (TM). The denitrification activity is mainly controlled by salinity and pH, and the denitrifying bacterial community composition related to the nutrient parameters of TN, TOM, etc. Our study suggested that the distribution of nutrients, microbial activity of nitrogen removal and community structure in Lagoon are the combined effects of terrestrial input and exchange with open sea. The microbial processes play important role in the nitrogen removal of coastal lagoon.

Immunological role and clinical prognostic significance of P2RY6 in lung adenocarcinoma: a multi-omics studies and single-cell sequencing analysis.

BACKGROUND: There is increasing evidence that recombinant human P2Y purinoceptor 6 (P2RY6) may be involved in inflammatory responses. However, the role of P2RY6 in lung adenocarcinoma (LUAD) remains unknown. METHODS: We used transcriptomic, genomic, single-cell transcriptomic, and methylation sequencing data from The Cancer Genome Atlas database to analyze the aberrant status and prognostic value of P2RY6 in a variety of tumors. The LUAD single-cell sequencing dataset was used to explore the effect of P2RY6 on the tumor microenvironment. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to quantify immune cells in the tumor microenvironment. We also analyzed the correlation of P2RY6 with immune checkpoints and immune regulation-related genes. The correlation of between tumor mutation burden (TMB), microsatellite instability (MSI), and P2RY6 expression was also analyzed simultaneously. Tissue microarray and immunohistochemistry were employed to assess the expression of P2RY6 in internal tumor samples. RESULTS: Our findings indicate that P2RY6 exhibits significantly higher expression levels in various cancer tissues, particularly in LUAD. High expression of P2RY6 was closely associated with a poor prognosis for patients, and it plays a role in regulating immune-related pathways, such as cytokine-cytokine receptor interaction. Notably, P2RY6 expression is closely linked to the abundance of CD8 + T cells. Furthermore, we have developed a P2RY6-related inflammation prediction model that demonstrates promising results in predicting the prognosis of LUAD patients, with an AUC (area under the curve) value of 0.83. This performance is significantly better than the traditional TNM staging system. Through single-cell transcriptome sequencing analysis, we observed that high P2RY6 expression is associated with increased intercellular communication. Additionally, pathway enrichment analysis revealed that P2RY6 influences antigen presentation and processing pathways within the LUAD microenvironment. CONCLUSIONS: This study suggests that P2RY6 would be a new target for immunotherapy in LUAD.

Reservoirs as high-efficacy sentinels of regional atmospheric pollution and precipitation: magnetic and chemical evidence from a typical subtropical reservoir in South China.

While there is a general sense that reservoirs can act as sentinels of climate change, their efficacy has not been thoroughly analyzed. Here multiple-proxy analyses including 210Pb, grain size, heavy metals, magnetic parameters, and spheroidal carbonaceous particles (SCPs) were conducted for a sediment core from a typical subtropical reservoir in South China (Huangkeng Reservoir). 210Pb dating revealed that the core spans from ~ 1964 to 2019, with the sedimentary rate increasing during recent years. The sedimentary environment was mainly influenced by natural process (especially precipitation), along with the accumulation of Cr, Ni, Cu, V, As, Sb, and Co and most magnetic particles. However, four heave metals (Cd, Pb, Tl, and Zn) were found mainly from atmospheric deposition from industrial/agricultural activities in Huizhou City, which was also indicated by SCPs, S-ratio, and χARM/SIRM. According to temporal variation of SCPs, the atmospheric pollution history of nearby city (Huizhou City as the most close one) from 1964 was reconstructed. The study shows that reservoir sediments, especially in areas with few or no natural lakes, are high-efficacy and high-resolution achieves for research on environmental evolution in the Anthropocene related to global change and intensifying human activities.

Efficacy evaluation of chimeric antigen receptor-modified human peritoneal macrophages in the treatment of gastric cancer.

BACKGROUND: Gastric cancer is one of the most common cancers. Peritoneal carcinomatosis (PC) appears to be the most common pattern of recurrence, and more than half of the GC patients eventually die from PC. Novel strategies for the management of patients with PC are urgently needed. Recently, rapid progress has been made in adoptive transfer therapy by using macrophages as the effector cells due to their capabilities of phagocytosis, antigen presentation, and high penetration. Here, we generated a novel macrophage-based therapy and investigated anti-tumoral effects on GC and potential toxicity. METHODS: We developed a novel Chimeric Antigen Receptor-Macrophage (CAR-M) based on genetically modifying human peritoneal macrophages (PMs), expressing a HER2-FcεR1γ-CAR (HF-CAR). We tested HF-CAR macrophages in a variety of GC models in vitro and in vivo. RESULTS: HF-CAR-PMs specifically targeted HER2-expressed GC, and harboured the FcεR1γ moieties to trigger engulfment. Intraperitoneal administration of HF-CAR-PMs significantly facilitated the HER2-positive tumour regression in PC mouse model and prolonged the overall survival rate. In addition, the combined use of oxaliplatin and HF-CAR-PMs exhibited significantly augment anti-tumour activity and survival benefit. CONCLUSIONS: HF-CAR-PMs could represent an exciting therapeutic option for patients with HER2-positive GC cancer, which should be tested in carefully designed clinical trials.

A Vascular Centered Surgical Approach to Radical Hysterectomy: Laparoscopic Anatomy of Pelvic Vascular System Revisited.

OBJECTIVE: As a standard therapy for locally invasive cervical cancer, radical hysterectomy (RH) has been in routine medical practice for more than a century [1]. However, challenges still exist due to the troublesome bleeding during parametrium dissection and resection, which could increase the risk of surgical complications and may probably affect surgical outcomes ultimately [2]. This video illustrated the three-dimensional anatomy of the pelvic vascular system with particular emphasis on "deep uterine vein" and further introduced a vascular-centered surgical approach to performing RH, which could facilitate parametrium dissection with less blood loss and obtain enough resection margins. DESIGN: A step-by-step, narrated video demonstration SETTING: A university hospital INTERVENTIONS: After systemic pelvic lymphadenectomy, ureter was then identified along the medial leaf of the broad ligament. By continuously exploring the pelvic cavity along the ureter, communicating branches of the uterine artery to the ureter, urinary bladder, corpus uteri, uterine cervix, and upper vagina were clearly identified in a cranial to caudal direction, demonstrating the arterial network surrounding the urinary system. Coagulating and cutting these blood vessels could free the ureter from retroperitoneum and subsequently excavate the ureteral tunnel easily. Next, a precise dissection of the area below the ureter revealed the whole distribution of currently named "deep uterine vein". Originated from an internal iliac vein, it is much more like a venous confluence than an accompanying vein, with branches crossing directly into the bladder, dorsally to the rectum, and traveling caudally to the anterolateral side of the uterus and vagina in a crisscross fashion, which mandates us to describe it as pampiniform-like venous plexus instead of "deep uterine vein" due to its anatomical distribution and function. Finally, after complete exposure of venous network, enough extent of parametrium could be adequately separated and resected by accurate coagulation of blood vessels on an individualized requirement. CONCLUSION: Recognizing the precise anatomy of pelvic vascular system, especially the entire distribution of currently named "deep uterine vein" and isolating the venous branches connecting to all three parts of parametrium, are key to the RH procedure. Careful attention to the complex vascular anatomy is critical to reducing intraoperative bleeding and avoiding complications in RH.

Targeting CD44 Variant 5 with an Antibody-Drug Conjugate Is an Effective Therapeutic Strategy for Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is the second most frequent type of primary liver cancer. ICC is among the deadliest malignancies, highlighting that novel treatments are urgently needed. Studies have shown that CD44 variant isoforms, rather than the CD44 standard isoform, are selectively expressed in ICC cells, providing an opportunity for the development of an antibody-drug conjugate (ADC)-based targeted therapeutic strategy. In this study, we observed the specific expression of CD44 variant 5 (CD44v5) in ICC tumors. CD44v5 protein was expressed on the surface of most ICC tumors (103 of 155). A CD44v5-targeted ADC, H1D8-DC (H1D8-drug conjugate), was developed that comprises a humanized anti-CD44v5 mAb conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE) via a cleavable valine-citrulline-based linker. H1D8-DC exhibited efficient antigen binding and internalization in cells expressing CD44v5 on the cell surface. Because of the high expression of cathepsin B in ICC cells, the drug was preferentially released in cancer cells but not in normal cells, thus inducing potent cytotoxicity at picomolar concentrations. In vivo studies showed that H1D8-DC was effective against CD44v5-positive ICC cells and induced tumor regression in patient-derived xenograft models, whereas no significant adverse toxicities were observed. These data demonstrate that CD44v5 is a bona fide target in ICC and provide a rationale for the clinical investigation of a CD44v5-targeted ADC-based approach. SIGNIFICANCE: Elevated expression of CD44 variant 5 in intrahepatic cholangiocarcinoma confers a targetable vulnerability using the newly developed antibody-drug conjugate H1D8-DC, which induces potent growth suppressive effects without significant toxicity.

Human development at the cost of the environment?-an application of planetary pressures-adjusted human development index in the lens of planetary boundaries.

The human development index (HDI) was an important step toward a more human-oriented assessment of socioeconomic prosperity. Nevertheless, at the onset of the anthropocene, the environmental pillar of sustainable development is indispensable. This work aims to understand this conundrum of human development and its environmental cost or pressure through the use of the planetary pressures-adjusted human development index (PHDI) as well as introduce another modified version, planetary pressures, and inequality-adjusted human development index (PIHDI). PHDI incorporates two biophysical consumption-based indicators (CO2 emissions and material footprint, MF) as a proxy of environmental pressures into traditionally socioeconomic development-focused HDI. This work spans 164 nations and 27 years (1990-2016). Various statistical techniques such as Pearson's correlation, hierarchical clustering (HCA), generalised additive modelling (GAM), data envelopment analysis (DEA), linear regression, and ARIMA forecasting have been used to explore interrelationships, non-linearity, efficiency analysis, and future projections (up to 2030) and delve into two scenarios: high human development and for human development permitted only within the two planetary boundaries (PBs) (viz. climate change and material footprint) and their consequences when exceeded. Though most of the countries with high PHDI and PIHDI scores are from the global north and have a high income, it is also possible to attain human development (i.e. increase PHDI and PIHDI scores) without overexploiting biophysical resources. From 2016, human development scores could increase by 55-63% (climate change) or 30-46% (material consumption) within a safe operating space in 2030. Without the required focus on the environment, aiming for a superior score in PHDI and PIHDI could result in 43-58% (CO2 emissions) or 57-58% (material footprint) of countries that would exceed PB. Based on the outcome of this work, it can be recommended that governments and policymakers that it is well within the limits of feasibility as well as necessary to make human socioeconomic development aspire to sustainability to address the needs of humanity, while respecting the well-being of the surrounding biosphere.

An Equality-Based Approach to Analysing the Global Food System's Fair Share, Overshoot, and Responsibility for Exceeding the Climate Change Planetary Boundary.

The climate catastrophe is being caused by human effects on earth system processes that are surpassing several planetary boundaries. This crisis is driven significantly by the global food system. It has been increasing over recent years, yet food systems are essential in upholding food and nutrition security. This study proposed a novel method for enumerating national contributions to the cessation of the climate crisis by approximating nations' aggregate greenhouse gas (GHG) emissions from food systems, within the equitable and sustainable planetary boundaries of climate change. This study included 221 nations, which were grouped as per their human development index (HDI) categories, income groups, and continental locations. During 1990−2018, the annual fair share, overshoot of emissions, and collective historical responsibility in the world of each country were assessed. There was a 22.52% increase in overshooting of GHG emissions from the global food system, starting in 1990. A group of 15 countries, including Brazil, China, Indonesia, and the U.S.A., were responsible for >67% of global overshoot. The primary liability is borne by countries with upper-, middle-, and high-income economies, and high to very-high HDI groups, as well as Asia and South America. Countries such as India, China, the Democratic Republic of the Congo, and others have steadily increased their share of responsibility over the last 28 years. More than 76% of countries in the world, mostly from Africa, Europe, and Asia, proved to be absolute overshooters. After contextualising the study's findings, the global food system's decarbonization and its limits were discussed; some recommendations for prospective research were also offered. It appears that academics, governments, and policymakers should start concentrating more on reshaping and redesigning the global food system to be climate-friendly (i.e., a carbon-neutral food system), whilst being able to fairly allocate food and nutrition security to achieve long-term Sustainable Development Goal 2 (SDG 2).

Artificial intelligence-based preoperative prediction system for diagnosis and prognosis in epithelial ovarian cancer: A multicenter study.

Background: Ovarian cancer (OC) is the most lethal gynecological malignancy, with limited early screening methods and poor prognosis. Artificial intelligence technology has made a great breakthrough in cancer diagnosis. Purpose: We aim to develop a specific interpretable machine learning (ML) prediction model for the diagnosis and prognosis of epithelial ovarian cancer (EOC) based on a variety of biomarkers. Methods: A total of 521 patients with EOC and 144 patients with benign gynecological diseases were enrolled including derivation datasets and an external validation cohort. The predicted information was acquired by 9 supervised ML methods, through 34 parameters. Behind predicted reasons for the best ML were improved by using the SHapley Additive exPlanations (SHAP) algorithm. In addition, the prognosis of EOC was analyzed by unsupervised clustering and Kaplan-Meier (KM) survival analysis. Results: ML technology was superior to conventional logistic regression in predicting EOC diagnosis and XGBoost performed best in the external validation datasets. The AUC values of distinguishing EOC and benign disease patients, determining pathological type, grade and clinical stage were 0.958 (0.926-0.989), 0.792 (0.701-0.8834), 0.819 (0.687-0.950) and 0.68 (0.573-0.788) respectively. For negative CA-125 EOC patients, the AUC performance of XGBoost model was 0.835(0.763-0.907). We used unsupervised cluster analysis to identify EOC subgroups with significantly poor overall survival (p-value <0.0001) and recurrence-free survival (p-value <0.0001). Conclusions: Based on the preoperative characteristics, we proved that ML algorithm can provide an acceptable diagnosis and prognosis prediction model for EOC patients. Meanwhile, SHAP analysis can improve the interpretability of ML models and contribute to precision medicine.

An Integrative Analysis Identifying RAB40C as an Oncogenic Immune Protein and Prognostic Marker of Lung Squamous Cell Carcinoma.

Background: RAB40C, a member of the Ras oncogene family, is a protein with GTPase and GTP-binding activity and is also predicted to be important in immunomodulation. However, the link between RAB40C and lung squamous cell carcinoma (LUSC) has not yet been elucidated. Exploring the relationship between RAB40C and LUSC could help expand the repertoire of immunotherapeutic targets for LUSC and provide more effective therapeutic options for LUSC patients, which behalf of our aim for our study. Methods: We analyzed the RAB40C expression in different tumor types and stages based on the TCGA database. Subsequently, we explored the differences in RAB40C expression in LUSC versus paracancerous tissues through immunohistochemical analysis. The prognostic value of RAB40C was assessed by Cox regression and Kaplan-Meier analysis. Gene set enrichment analysis-based RAB40C impact pathways and the correlation between RAB40C expression and immune infiltration were obtained using the TIMER2.0 and the CIBERSORT analytical tools. Tumor mutational load and microsatellite instability (MSI) were assessed by the Spearman correlation analysis. Finally, the close association of RAB40C with LUSC was explored by correlating immune cell infiltration with immunomodulator expression, assessing risk scores in combination with other factors, and analyzing prognostic nomogram. Results: The expression of RAB40C was significantly elevated in LUSC. RAB40C expression was significantly associated with immune factors, immune-related pathways, and MSI. Moreover, RAB40C significantly negatively correlated with LUSC-associated immune infiltrating cells, CD4 memory-activated cells, γδ T cells, M1-like macrophages, and the immune regulator CD28, while it positively associated with the activation of Tregs and natural killer cells. Further, a risk model constructed from RAB40C and its associated immune genes showed that RAB40C might be an independent prognostic factor for LUSC. Conclusion: RAB40C can be used as an effective prognostic biomarker and a potential immunotherapeutic target for the treatment of LUSC.

Identification of anthelmintic parbendazole as a therapeutic molecule for HNSCC through connectivity map-based drug repositioning.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common human cancers; however, its outcome of pharmacotherapy is always very limited. Herein, we performed a batch query in the connectivity map (cMap) based on bioinformatics, queried out 35 compounds with therapeutic potential, and screened out parbendazole as a most promising compound, which had an excellent inhibitory effect on the proliferation of HNSCC cell lines. In addition, tubulin was identified as a primary target of parbendazole, and the direct binding between them was further verified. Parbendazole was further proved as an effective tubulin polymerization inhibitor, which can block the cell cycle, cause apoptosis and prevent cell migration, and it exhibited reasonable therapeutic effect and low toxicity in the in vivo and in vitro anti-tumor evaluation. Our study repositioned an anthelmintic parbendazole to treat HNSCC, which revealed a therapeutic utility and provided a new treatment option for human cancers.

Plant Macrofossils Reveal Aquatic Macrophyte Successions of a Typical Shallow Lake (Huanggai Lake, China) in the Past Century.

Aquatic macrophytes are one of the important biotic components of shallow lake ecosystems. Understanding the long-term evolution of the macrophyte community is crucial for lake management. Huanggai Lake, a typical shallow lake in the middle reach of the Yangtze River, was selected as the research site for this study. Based on 210Pb/137Cs dating, aquatic plant macrofossils were used to reconstruct the succession of aquatic macrophytes in the past century. Our results show that the lake maintained a consistent natural state before 1940, with a relatively low abundance of aquatic plants dominated by species such as Najas minor. From 1940 to 1974, human activities gradually intensified in the lake leading to the emergence of eutrophic species such as Potamogeton maackianus, along with the increasing abundance of other emergent and floating aquatic macrophytes. Since 1974, more pollution-resistant, emergent species such as Potamogeton maackianus and Potamogeton crispus have become dominant. The abundance of aquatic macrophytes reached its maximum in the early 1990s. Combined with macrofossil succession and other multiple sedimentary proxy analyses, driving mechanisms for aquatic macrophytes are discussed. Both the nearby Liangzi Lake and Huanggai Lake share many common features of aquatic plant evolution. This study is the first of its kind to use plant macrofossils (with identifiable images) as a proxy for aquatic macrophyte succession in a shallow Yangtze lake. In absence of long-term monitoring records, this study highlights the increased application of plant macrofossils for reconstructing the vegetation dynamics and restoration of degraded lakes exposed to severe anthropogenic impacts over the past century.

Design, synthesis and biological evaluation of new parbendazole derivatives for the treatment of HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is a lethal disease with a terrible prognosis, accounting for more than 900,000 new cases and 500,000 deaths each year, nevertheless, its pharmacotherapy is rather limited. Parbendazole was previously identified as a potential HNSCC therapy candidate in our research. Herein, we report the discovery of two series of parbendazole derivatives as tubulin inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of compound 9q with the best pharmacological activities and pharmacokinetic properties. This compound exhibited reasonable inhibition activity on cell proliferation (HN6, CAL-27, Fadu) and tubulin polymerization, induced cell apoptosis, blocked cell cycle and suppressed cell migration and invasion. Compound 9q also displayed low toxicity and a favorable therapeutic effect on a xenograft tumor, indicating that it is a promising starting point for further research.

Geochemical baseline establishment and pollution assessment of heavy metals in the largest coastal lagoon (Pinqing Lagoon) in China mainland.

Establishing geochemical baselines and assessment of heavy metal pollution in lagoon sediments are critical for providing guidance to coastal zone environmental management. We analyzed heavy metals in high-resolution sediment cores from Pinqing Lagoon in South China, and defined the baselines of common pollution elements with a significant anthropogenic contribution. With these baselines, a spatiotemporal pollution assessment revealed Cu and Cd as the predominant pollution metals in both core and surface sediments, although the ecological risk level in the interior lagoon remained low during the past ~170 years. Surface sediment pollution status indicate a significant spatial difference. The findings from this typical coastal lagoon evidence a strong self-clean capacity attributable to the frequent water-mass-energy exchange between the lagoon and the sea. Furthermore, despite the significant impact by the sea, the geochemical baselines are close to the catchment soil backgrounds that can be defined using a paleolimnological approach.