Targeting PD-L1 and PD-1 interactions is a relatively new therapeutic strategy used to treat cancer. Inhibitors of PD-1/PD-L1 include peptides, small molecule chemical compounds, and antibodies. ...Several approved antibodies targeting PD-1 or PD-L1 have been patented with good curative effect in various cancer types in clinical practices. While the current antibody therapy is facing development bottleneck, some companies have tried to develop PD-L1 companion tests to select patients with better diagnosis potential. Meanwhile, many companies have recently synthesized small molecule inhibitors of PD-1/PD-L1 interactions and focused on searching for novel biomarker to predict the efficacy of anti-PD-1/PD-L1 drugs. This review summarized clinical studies and patent applications related to PD-1/PD-L1 targeted therapy and also discussed progress in inhibitors of PD-1/PD-L1.
Diet is an important factor in shaping and influencing both an insect's phenotype and gut bacterial community, which commonly establishes diversely symbiotic interactions with the host. Efforts to ...leverage the connection between diet, insects, and gut microbiome primarily focus on how diet alters insect's phenotype or gut microbial composition and relatively few studies have illuminated the link between the diet-induced insect phenotypic difference and variation of gut microbiota. Mirids bugs, Adelphocoris suturalis, are plant sap-feeding omnivores that sometimes complementarily prey on other insects, like aphids (the dietary regime is referred to hereafter as balanced diet). In this study, we found that an imbalanced diet (exclusive ingestion of aphids) induced significantly higher mortality in A. suturalis (86.66%). Further gut microbial community analysis showed that the dietary difference significantly changed both the abundance and composition of the bug's gut microbiome. Most notably, an abundance of entomopathogenic Serratia bacteria in the A. suturalis gut was positively correlated with the proportion of aphids in A. suturalis diet, and Serratia marcescens was found to transfer into the hemocoels of carnivorous bugs. Injection of S. marcescens to the hemocoels further confirmed its detrimental effect to the bugs. Collectively, our study suggests that the diet-altered variation of gut microbiota may be detrimental to host insect, advancing the knowledge of omnivorous insects' strategy in forage allocation of different foods.
Display omitted
•Different diets can sufficiently change both the size and composition of the insect's gut microbiota.•Diet altered variation of gut microbiota is detrimental to host insect.•Serratia marcescens is significantly accumulated in carnivorous bugs and further lead to the insect's death.
Engagement of programmed death-ligand 1 (PD-L1) with its receptor programmed death 1 (PD-1) on T cells has been speculated to play a major role in suppressing the immune system, which helps tumor ...cells evade anti-tumor immunity. With the development of whole genome sequencing technologies, microRNAs have gained more attention as an important new layer of molecular regulation. Recent studies have revealed that altered expression of microRNAs play a pivotal role in immune checkpoint and various cellular processes in cancer. In this review, we focused on the latest progress about microRNAs research which involves the regulation of PD-1/PD-L1 immune checkpoint.
Epiretinal membrane (ERM) is a common ophthalmological disorder of high prevalence. Its symptoms include metamorphopsia, blurred vision, and decreased visual acuity. Early diagnosis and timely ...treatment of ERM is crucial to preventing vision loss. Although optical coherence tomography (OCT) is regarded as a de facto standard for ERM diagnosis due to its intuitiveness and high sensitivity, ophthalmoscopic examination or fundus photographs still have the advantages of price and accessibility. Artificial intelligence (AI) has been widely applied in the health care industry for its robust and significant performance in detecting various diseases. In this study, we validated the use of a previously trained deep neural network based-AI model in ERM detection based on color fundus photographs. An independent test set of fundus photographs was labeled by a group of ophthalmologists according to their corresponding OCT images as the gold standard. Then the test set was interpreted by other ophthalmologists and AI model without knowing their OCT results. Compared with manual diagnosis based on fundus photographs alone, the AI model had comparable accuracy (AI model 77.08% vs. integrated manual diagnosis 75.69%, χ
= 0.038, P = 0.845, McNemar's test), higher sensitivity (75.90% vs. 63.86%, χ
= 4.500, P = 0.034, McNemar's test), under the cost of lower but reasonable specificity (78.69% vs. 91.80%, χ
= 6.125, P = 0.013, McNemar's test). Thus our AI model can serve as a possible alternative for manual diagnosis in ERM screening.
Colon cancer ranks among the most prevalent malignancies worldwide, trailing only lung and breast cancer in incidence. Despite the availability of numerous therapeutic strategies, the burden of new ...cases and fatalities remains high in countries undergoing socioeconomic transitions. Natural products offer promising avenues for developing more effective and less toxic anticancer agents, expanding the clinical arsenal. In this investigation, we isolated a triterpenoid, (21 S,23 R,24 R)-21,23-epoxy-24-hydroxy-21-methoxytirucalla-7,25-dien-3-one (EHMT), from the fruits of Melia azedarach L., which exhibited significant inhibitory activity against colon cancer cells while sparing normal cells. EHMT effectively curtailed colony formation and induced apoptosis and cell cycle arrest in the HCT116 cell line. Furthermore, EHMT prompted the generation of reactive oxygen species (ROS) and the depolarization of mitochondrial membrane potential. Notably, EHMT treatment triggered ROS-mediated cell apoptosis via activation of the JNK signaling pathway in HCT116 cells. Additionally, our findings extended to Caenorhabditis elegans, where EHMT induced ROS accumulation and apoptosis. Collectively, these findings position EHMT as a promising candidate for the development of anticancer agents in the treatment of colon cancer, offering new hope in the battle against this formidable disease.
Display omitted
(21 S,23 R,24 R)-21,23-epoxy-24-hydroxy-21-methoxytirucalla-7,25-dien-3-one (EHMT) was isolated from the fruit of M. azedarach L. EHMT caused ROS generation and induces apoptosis both in vivo and in vitro, triggered ROS-modulated cell apoptosis associated with JNK signaling pathway activation in colon cancer cells.
•Natural products represent the biggest source of small molecules, providing a great potential to develop new anticancer agents.•EHMT, a novel anit-cancer triterpenoid isolated from Melia azedarach L. fruits, triggers ROS-modulated cell apoptosis and activates the JNK signaling pathway in colon cancer cells.•EHMT demonstrates a pronounced ability to inhibit the proliferation of colon cancer cells while exerting minimal impact on normal colon cells.•The findings in this study shed light on the potential of EHMT as a promising candidate for colon cancer therapy.
Jianghan Basin is the largest terrestrial saline lake basin in China, with the largest salinization area in the Paleogene. Research on salt rhythmite formations is crucial for petroleum exploration ...in salt lake basins. With alternating dry and wet climates, the difference in the organic matter (OM) provenance and enrichment remain controversial. In this study, petrology, element geochemistry, and molecular geochemical analyses were performed for the Qianjiang Formation to determine the depositional environment and provenance of its OM. The response of OM enrichment in the saline lake to the alternating dry and wet climates was reassessed. Three lithofacies associations (LAs) were designated: (1) LA1 was rich in argillaceous dolomite and argillaceous limestone with high total organic carbon (TOC); (2) LA3 was interbedded argillaceous glauberite and argillaceous dolomite with low TOC; (3) LA2 was a mixture of the above minerals with moderate TOC values. LA1 was deposited during desalination with a reducing environment and water stratification. The ∑C21-/∑C22+, C29/C30 hopane and maceral indicate the OM of LA1 derive from algae. Compared with LA1, LA2 was deposited with higher salinity and less algae. LA3 was deposited during intense evaporation, high salinity, and a disturbed environment. The OM sources of LA3 include higher plants and low aquatic organisms. Dry and wet climates control changes in organic enrichment. Hypersalinity is unfavorable to algae but beneficial to preservation. The stratified deep water is conducive to the accumulation of OM. The desalination is a crucial period for organic matter enrichment in the saline lake.
•Desalination is a crucial period for organic matter enrichment in saline lake.•Mechanisms of organic matter accumulation are different in dry and wet climates.•Hypersalinity is unfavorable to algae but beneficial to preservation.
In the tumor microenvironment, interferon gamma (IFN-γ) secreted by tumor infiltrating lymphocytes can upregulate programmed cell death 1 ligand 1 (PD-L1) expression in many cancers. The present ...study evaluated the expression of PD-L1 in selected colorectal cancer cell lines with IFN-γ treatment and explored the correlation between programmed cell death 1 ligand 1 expression and KRAS/TP53 mutation status.
The selected colorectal cancer cell lines had known KRAS mutations or TP53 mutations. TCGA data analysis were used to investigate the correlation between overall survival of patient with anti-PD-1/PD-L1 immunotherapy and KRAS/TP53 mutation status. Besides, the correlation between PD-L1 expression and KRAS/TP53 mutation status were also investigated by using TCGA data analysis.
experiments were used to explore the mechanism underlying KRAS- and TP53-related PD-L1 expression.
Firstly, TCGA data analysis for gene expression and overall survival and an
study revealed that the wild-type KRAS/TP53 cell lines exhibited hyperresponsiveness to interferon gamma exposure and correlated with better survival in patients receiving anti-PD-1/PD-L1 treatment. Secondly, experimental data revealed that interferon gamma induced the upregulation of programmed cell death 1 ligand 1 mainly through regulating MYC in wild-type KRAS and TP53 colorectal cancers.
Our findings revealed that the response to anti-PD-1/PD-L1 cancer immunotherapy frequently happened in wild-type KRAS and TP53 colorectal cancers, which were also found to show higher programmed cell death 1 ligand 1 expression. Our results indicate that the wild-type KRAS/TP53 colorectal cancer cell lines may respond better to interferon gamma treatment, which causes increased programmed cell death 1 ligand 1 expression and may be a mechanism underlying the better responses to anti-PD-1/PD-L1 therapies in wild-type KRAS and wild-type TP53 colorectal cancer. Furthermore, the experimental results suggest that interferon gamma regulated programmed cell death 1 ligand 1 expression through the regulation of MYC, which may further affect the response to PD-1/PD-L1 cancer immunotherapy. These results suggest a novel potential treatment strategy for enhancing the efficacy of PD-1/PD-L1 blockade immunotherapy in most colorectal cancer patients.
With the rapid development of the electronic packaging industry, traditional gold bonding wires are tended to be replaced gradually and partially by copper bonding wires with low cost and better ...potential performance. However, it is difficult to control and prevent the oxidation of copper bonding wire even in the case of palladium plating. Therefore, it is necessary to explore a method to inhibit the oxidation of copper wire before plating at room temperature. In this paper, different inhibitors, including organic benzotriazole and carboxymethylcellulose sodium (BTA, CMC), inorganic (Ce(NO
3
)
3
·6H
2
O) and compound (CMC + Ce(NO
3
)
3
·6H
2
O), are selected to form a thin film on the surface of copper bonding wires with different diameters, respectively, and the effects on the antioxidation of copper wire at room temperature are discussed by means of electrochemical polarization and impedance measurement combined with SEM observation, EDS and XPS analysis. The kinetic results demonstrate the antioxidation properties of the copper bonding wires have been improved to a certain extent after an inhibitor film forms on the surface of copper wire. In particular, BTA and compound (CMC + Ce(NO
3
)
3
·6H
2
O) play a better role, attributed to the fact that BTA and compound (CMC + Ce(NO
3
)
3
·6H
2
O) are more beneficial to form a dense and evenly distributed smooth surface with higher electrochemical stability and impedance. For the CMC + Ce(NO
3
)
3
·6H
2
O system, the hydroxides or hydrated oxide particles of Ce
3+
would form on the surface of copper wire after immersion in the Ce(NO
3
)
3
·6H
2
O solution for the first 12 h. Subsequently, Ce
3+
would replace Na
+
to form a more compact and continuous complex film after immersed in CMC solution for another 12 h, as a result, the antioxidation property is enhanced under the synthetic effects.
Facing with increasing competition, many ports are taking innovative approaches to improve productivity and profits. Among a variety of methods, introducing external terminal operators (ETOs) while ...the port acts as a landlord to collect “rents” from those operators for conducting terminal activities inside the port is regarded as an effective way and is commonly observed in practices. This paper analyzes the decisions of two competing ports about whether to introduce their respective ETOs using a three-stage non-cooperative game model when there already exists a port’s self-operation terminal operator (STO). At the first stage, the two ports simultaneously decide whether to introduce an ETO. If a port decided to introduce an ETO, at the second stage, it will further decide the unit fee to charge from the ETO. At the third stage, the two ports and the introduced ETO(s) simultaneously decide their respective profit-maximizing output levels. The findings indicate the equilibrium is both ports will introduce their respective ETOs, but when the ports and ETOs are substitutable in the sense of having the same level of productivity, the equilibrium solution is only one port should introduce an ETO. And simulation results show that even if one of ETOs is inefficient this still hold true.
Zircon U-Pb geochronology and heavy minerals are used in combination to provide valuable insights into the provenance of the early Eocene Jianghan Basin, central China. Five samples for zircon U-Pb ...dating and eighty-five samples for heavy mineral analysis were collected from drill cores or cuttings of the Xingouzui Formation. Most analyzed zircons are of magmatic origin, with oscillatory zoning. Detrital zircons from sample M96 located on eastern basin have two dominant age groups of 113–158Ma and 400–500Ma, and the other samples located on southern basin have three prominent age populations at 113–158Ma, 400–500Ma and 700–1000Ma. Samples on different parts of the basin show distinct differences in heavy mineral compositions and they apparently divide into two groups according to the content of rutile (higher or lower than 4%). The spatial variations of zircon-tourmaline-rutile (ZTR) indices are marked by some noticeable increasing trends from basin margins to the inner part of the basin. Compared with the potential source areas, this study clarifies the multiple source characteristics of the Jianghan basin in the composite basin-mountain system. The majority of clastic material was supplied from the north source area through rift-trough sediment-transport pathways, and the eastern, southern and northwestern source areas also contributed detritus to the basin. This clastic material is broadly dispersed in the basin. The early Eocene paleogeography implies that rift architecture and rifting process had an important influence on sediment dispersal. This study shows that integrated zircon U-Pb geochronology and heavy mineral analysis is a useful and powerful method to identify sediment provenance.
•Detrital zircon U-Pb geochronology and heavy mineral analysis are used in combination.•Multiple source characteristics of rift sediments in the composite basin-mountain system are clarified.•Spatial framework of sediment dispersal is identified.•Rift architecture and rifting process have an important influence on sediment dispersal.
PDF
