PD-1/PD-L1 inhibitors are a group of immune checkpoint inhibitors as front-line treatment of multiple types of cancer. However, the serious immune-related adverse reactions limited the clinical application of PD-1/PD-L1 monoclonal antibodies, despite the promising curative effects. Therefore, it is urgent to develop novel inhibitors, such as small molecules, peptides or macrocycles, targeting the PD-1/PD-L1 axis to meet the increasing clinical demands. Our review discussed the mechanism of action of PD-1/PD-L1 inhibitors and presented clinical trials of currently approved PD-1/PD-L1 targeted drugs and the incidence of related adverse reactions, helping clinicians pay more attention to them, better formulate their intervention and resolution strategies. At last, some new inhibitors whose patent have been published are listed, which provide development ideas and judgment basis for the efficacy and safety of novel PD-1/PD-L1 inhibitors.
Negative bias temperature instability (NBTt) as one of CMOS device degradations has been extensively researched. Based on the theories of NBTI degradations, we optimize a reliability model for the frequency degradation of the ring oscillator (RO), and propose a new ring oscillator structure corresponding to the model. In this paper, the new ring oscillator is working under two different static stress modes. We found that the frequency degradation of the same RO is much different in different static stress modes, and the degree of the frequency degradation of different-stage ROs shows the same trend in different stress modes. The model is demonstrated by using the SMIC 65nm, I.2V technology.
Background and Purpose Lapatinib, a widely-used dual inhibitor of
EGFR/ERBB1 and HER2/ERBB2 effectively targeting HER2 positive breast
cancer, has been seriously limited due to cutaneous toxicity. However,
the specific mechanism of lapatinib-induced cutaneous toxicity has not
been clarified, leading to a lack of effective strategy targets to
improve clinical safety. Here, we aimed to identify molecular mechanism
occurs in this process and strive for effective intervention strategies
against lapatinib-induced cutaneous side effects. Experimental and
Approach C57BL/6 mice were subjected to lapatinib via intragastric
administration, serum was used for ELISA assay, skin tissue was
collected and performed with histopathological analysis. Apoptotic assay
was analyzed in HaCaT and NHEK cell lines, comet assay was conducted to
measure the damage of DNA, real-time PCR was used to assess the level of
HMGB and inflammatory factors. Key Results We found that lapatinib could
induce mitochondrial dysfunction, lead to DNA damage and finally cause
apoptosis of keratinocytes. In addition, we found that lapatinib could
induce aberrant immune response and promote the release of inflammatory
factors in vitro and in vivo. Mechanistically, downregulated expression
of HMGB1 played a critical role in these toxic reaction processes.
Delightfully, we found that saikosaponin A could significantly rescue
the reduced HMGB1 transcription, which could alleviate lapatinib-induced
DNA damage, inhibit keratinocyte apoptosis and further prevent toxicity
of lapatinib in mice. Conclusion and Implications Our study provided
molecular mechanism of lapatinib-induced cutaneous toxicity, and shed
new light on the prevention of cutaneous adverse drug reactions induced
by EGFR inhibitors.
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