HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine (131I) metuximab injection (Licartin), a novel 131I-labeled HAb18G/CD147-specific monoclonal antibody Fab'2 ...fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials.
In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints.
No life-threatening toxic effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p = 0.0019).
Iodine (131I) metuximab injection is safe and active for HCC patients.
The optical and radiative properties of aerosols during a severe haze episode from 15 to 22 December 2016 over Beijing, Shijiazhuang, and Jiaozuo in the North China Plain were analyzed based on the ...ground-based and satellite data, meteorological observations, and atmospheric environmental monitoring data. The aerosol optical depth at 500 nm was 〈 0.30 and increased to 〉 1.4 as the haze pollution developed. The Angstr6m exponent was 〉 0.80 for most of the study period. The daily single-scattering albedo was 〉 0.85 over all of the North China Plain on the most polluted days and was 〉 0.97 on some particular days. The volumes of fine and coarse mode particles during the haze event were approximately 0.05-0.21 and 0.01-0.43 μm^3, respectively-that is, larger than those in the time without haze. The daily absorption aerosol optical depth was about 0.01-0.11 in Beijing, 0.01-0.13 in Shijiazhuang, and 0.01-0.04 in Jiaozuo, and the average absorption Angstrom exponent varied between 0.6 and 2.0. The aerosol radiative forcing at the bottom of the atmosphere varied from -23 to -227, -34 to -199, and -29 to -191 W m^-2 for the whole haze period, while the aerosol radiative forcing at the top of the atmosphere varied from -4 to -98, -10 to -51, and -21 to -143 W m^-2 in Beijing, Shijiazhuang, and Jiaozuo, respectively. Satellite observations showed that smoke, polluted dust, and polluted continental components of aerosols may aggravate air pollution during haze episodes. The analysis of the potential source contribution function and concentration-weighted trajectory showed that the contribu- tion from local emissions and pollutants transport from upstream areas were 190-450 and 100-410 btg m-3, respectively.
Recently, attention has focused on the impact of global climate change on infectious diseases. Storm flooding is an extreme weather phenomenon that not only impacts the health of the environment but ...also worsens the spread of pathogens. This poses a significant challenge to public health security. However, there is still a lack of research on how different levels of storm flooding affect susceptible enteric infectious diseases over time.
Data on enteric infectious diseases, storm flooding events, and meteorology were collected for Changsha, Hunan Province, between 2016 and 2020. The Wilcoxon Rank Sum Test was used to identify the enteric infectious diseases that are susceptible to storm flooding. Then, the lagged effects of different levels of storm flooding on susceptible enteric infectious diseases were analyzed using a distributed lag nonlinear model.
There were eleven storm flooding events in Changsha from 2016 to 2020, concentrated in June and July. 37,882 cases of enteric infectious diseases were reported. During non-flooding days, the daily incidence rates of typhoid/paratyphoid and bacillary dysentery were 0.3/100,000 and 0.1/100,000, respectively. During flooding days, the corresponding rates increased to 2.0/100,000 and 0.8/100,000, respectively. The incidence rates of both diseases showed statistically significant differences between non-flooding and flooding days. Correlation analysis shows that the best lags for typhoid/paratyphoid and bacillary dysentery relative to storm flooding events may be 1 and 3 days. The results of the distributed lag nonlinear model showed that typhoid/paratyphoid had the highest cumulative RR values of 2.86 (95% CI: 1.71-4.76) and 8.16 (95% CI: 2.93-22.67) after 4 days of general flooding and heavy flooding, respectively; and bacillary dysentery had the highest cumulative RR values of 1.82 (95% CI: 1.40-2.35) and 3.31 (95% CI: 1.97-5.55) after 5 days of general flooding and heavy flooding, respectively.
Typhoid/paratyphoid and bacillary dysentery are sensitive enteric infectious diseases related to storm flooding in Changsha. There is a lagging effect of storm flooding on the onset of typhoid/paratyphoid and bacillary dysentery, with the best lagging periods being days 1 and 3, respectively. The cumulative risk of typhoid/paratyphoid and bacillary dysentery was highest at 4/5 days lag, respectively. The higher of storm flooding, the higher the risk of disease, which suggests that the authorities should take appropriate preventive and control measures before and after storm flooding.
A photoinduced vicinal difluoroalkylation and aminosulfonylation of alkynes under photocatalysis was realized. The combination of ethyl 2‐bromo‐2,2‐difluoroacetate, alkynes, and DABCO⋅(SO2)2 with ...hydrazines, catalyzed by 9‐mes‐10‐methyl acridinium perchlorate in the presence of visible light, afforded (E)‐ethyl 2,2‐difluoro‐4‐aryl‐4‐sulfamoylbut‐3‐enoates in good yields with high stereoselectivity. This four‐component reaction proceeds through radical addition with the insertion of sulfur dioxide.
Photocatalyzed tandem reaction: Photoinduced vicinal difluoroalkylation and aminosulfonylation of alkynes was realized. Combination of ethyl 2‐bromo‐2,2‐difluoroacetate, alkynes, and DABCO⋅ (SO2)2 with hydrazines, catalyzed by 9‐mes‐10‐methyl acridinium perchlorate in the presence of visible light, afforded (E)‐ethyl 2,2‐difluoro‐4‐aryl‐4‐sulfamoylbut‐3‐enoates in good yields with high stereoselectivity. This four‐component reaction proceeds through radical addition with the insertion of sulfur dioxide.
Alzheimer's disease is the most common neurodegenerative disease.
Acanthopanax senticosus
, also known as Ciwujia or Siberian ginseng in Chinese, has a wide range of antioxidant and anti-inflammatory ...activities. The study aims to explore the action mechanism of
A. senticosus
against Alzheimer's disease using network pharmacology and molecular docking. The active ingredients and targets of
A. senticosus
were searched through the ETCM database, and Alzheimer's disease-related targets were obtained through the OMIM and GeneCards databases. The Cytoscape 3.7.2 software was used to construct a “drug-component-target” relationship network, and the target genes of
A. senticosus
against Alzheimer's disease were imported into the String database to establish a protein interaction (PPI) network. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene enrichment analyses were performed through the Metascape database to obtain potential pathways of action of
A. senticosus
for the treatment of Alzheimer's disease, and the ability of these active ingredients to bind to core targets was then verified by molecular docking. 51 active ingredients were screened from
A. senticosus
, and 88 effective targets for Alzheimer's disease were screened. Topological and pathway-enrichment analyses revealed that
A. senticosus
could play a beneficial role in the treatment of Alzheimer's disease by regulating apoptosis and inflammation. Molecular docking results showed that Ciwujianoside B, Chiisanoside, and Ciwujianoside D1 had strong binding abilities to key target proteins (TNFα, IL1β, and CASP3). Collectively,
A. senticosus
is feasible in the treatment of Alzheimer's disease.
Graphical abstract
PD-L1 is a promising therapeutic target in aggressive cancers. However, immune landscapes and cancer hallmarks of human PD-L1+ tumors, as well as their roles in determining therapeutic efficacies are ...unknown. Here we identified, in detailed studies of gene data regarding 9769 patients of 32 types of human cancers, that PD-L1 could not exclusively represent IFN-γ signature and potentially signified pro-inflammatory myeloid responses in a tumor. PD-L1 heterogeneity endowed by local immune landscapes controlled cancer hallmarks and clinical outcomes of patients. Mechanically, NF-κB signal elicited by macrophage inflammatory responses generated PD-L1+ cancer cells exhibiting capabilities to aggressively survive, support angiogenesis, and metastasize, whereas STAT1 signal triggered by activated T cells induced PD-L1+ cancer cells susceptive to apoptosis. Importantly, PD-L1+ cancer cells generated by macrophages established great resistance to conventional chemotherapy, cytotoxicity of tumor-specific effector T cells, and therapy of immune checkpoint blockade. Therapeutic strategy combining immune checkpoint blockade with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited caner regression. Our results provide insight into the functional features of PD-L1+ tumors and suggest that strategies to influence functional activities of inflammatory cells may benefit immune checkpoint blockade therapy.
Triggering ferroptosis, an iron-dependent form of cell death, has recently emerged as an approach for treating cancer. A better understanding of the role and regulation of ferroptosis is needed to ...realize the potential of this therapeutic strategy. Here, we observed extensive activation of ferroptosis in hepatoma cells and human hepatocellular carcinoma (HCC) cases. Patients with low to moderate activation of ferroptosis in tumors had the highest risk of recurrence compared to patients with no or high ferroptosis. Upon encountering ferroptotic liver cancer cells, aggregated macrophages efficiently secreted proinflammatory IL1β to trigger neutrophil-mediated sinusoidal vascular remodeling, thereby creating favorable conditions for aggressive tumor growth and lung metastasis. Mechanistically, hyaluronan fragments released by cancer cells acted via an NF-κB-dependent pathway to upregulate IL1β precursors and the NLRP3 inflammasome in macrophages, and oxidized phospholipids secreted by ferroptotic cells activated the NLRP3 inflammasome to release functional IL1β. Depleting either macrophages or neutrophils or neutralizing IL1β in vivo effectively abrogated ferroptosis-mediated liver cancer growth and lung metastasis. More importantly, the ferroptosis-elicited inflammatory cellular network served as a negative feedback mechanism that led to therapeutic resistance to sorafenib in HCC. Targeting the ferroptosis-induced inflammatory axis significantly improved the therapeutic efficacy of sorafenib in vivo. Together, this study identified a role for ferroptosis in promoting HCC by triggering a macrophage/IL1β/neutrophil/vasculature axis.
Ferroptosis induces a favorable tumor microenvironment and supports liver cancer progression by stimulating an inflammatory cellular network that can be targeted to suppress metastasis and improve the efficacy of sorafenib.
B cells constitute a major component of tumor-infiltrating leukocytes. However, the influence of these cells on malignancy is currently under debate, reflecting the heterogeneity of B cell subsets in ...tumors. With recent advances, it becomes apparent that this debate includes not only the evaluation of B cells themselves, but also the underlying immune microenvironment network, which scripts the highly heterogeneous B cell populations in tumors and directs the roles of those sub-populations in disease progression and clinical treatment. In this review, we summarize recent findings on the heterogeneous subset composition of B cells in both human and mouse tumor models and their different impacts on disease progression. We further describe the multidimensional interplays between B cells and other immune cells in the tumor microenvironment, which account for the regulation of B cell differentiation and function in situ. We also assess the potential influences of distinct sub-tumor locations on B cell function in primary tumors during development and those under immunotherapy treatment. Illuminating the heterogeneous nature of B cell subset composition, generation, localization, and related immune network in tumor is of immense significance for comprehensively understanding B cell response in tumor and designing more efficacious cancer immunotherapies.
B cells consistently represent abundant cellular components in tumors; however, direct evidence supporting a role for B cells in the immunopathogenesis of human cancers is lacking, as is specific ...knowledge of their trafficking mechanisms. Here, we demonstrate that chemokine (C‐X‐C motif) receptor 3–positive (CXCR3+) B cells constitute approximately 45% of B‐cell infiltrate in human hepatocellular carcinoma (HCC) and that their levels are positively correlated with early recurrence of HCC. These cells selectively accumulate at the invading edge of HCC and undergo further somatic hypermutation and immunoglobulin G–secreting plasma cell differentiation. Proinflammatory interleukin‐17+ cells are important for the induction of epithelial cell–derived CXCR3 ligands CXCL9, CXCL10, and CXCL11, which subsequently promote the sequential recruitment and further maturation of CXCR3+ B cells. More importantly, we provide evidence that CXCR3+ B cells, but not their CXCR3– counterparts, may operate in immunoglobulin G–dependent pathways to induce M2b macrophage polarization in human HCC. Depletion of B cells significantly suppresses M2b polarization and the protumorigenic activity of tumor‐associated macrophages and restores the production of antitumorigenic interleukin‐12 by those cells in vivo. Conclusion: Selective recruitment of CXCR3+ B cells bridges proinflammatory interleukin‐17 response and protumorigenic macrophage polarization in the tumor milieu, and blocking CXCR3+ B‐cell migration or function may help defeat HCC.(Hepatology 2015;62:1779–1790)
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