Backgroundkalirin RhoGEF kinase (KALRN) is mutated in a wide range of cancers. Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. Identification of biomarkers for cancer immunotherapy response is crucial because immunotherapies only show beneficial effects in a subset of patients with cancer.MethodsWe explored the correlation between KALRN mutations and antitumor immunity in 10 cancer cohorts from The Cancer Genome Atlas program by the bioinformatics approach. Moreover, we verified the findings from the bioinformatics analysis with in vitro and in vivo experiments. We explored the correlation between KALRN mutations and immunotherapy response in five cancer cohorts receiving immune checkpoint blockade therapy.ResultsAntitumor immune signatures were more enriched in KALRN-mutated than KALRN-wildtype cancers. Moreover, KALRN mutations displayed significant correlations with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties, which may explain the high antitumor immunity in KALRN-mutated cancers. Also, programmed cell death 1 ligand (PD-L1) expression was markedly upregulated in KALRN-mutated versus KALRN-wildtype cancers. The increased antitumor immune signatures and PD-L1 expression in KALRN-mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in five cancer cohorts receiving antiprogrammed cell death protein 1 (PD-1)/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy. Furthermore, the significant association between KALRN mutations and increased antitumor immunity was associated with the fact that KALRN mutations compromised the function of KALRN in targeting Rho GTPases for the regulation of DNA damage repair pathways. In vitro and in vivo experiments validated the association of KALRN deficiency with antitumor immunity and the response to immune checkpoint inhibitors.ConclusionsThe KALRN mutation is a useful biomarker for predicting the response to immunotherapy in patients with cancer.
A series of N-phenyl-7H-pyrrolo [2,3-d]pyrimidin-4-amine derivatives with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chemistry. Among them,3d]pyrimidin-4-yl)amino)-4-morpholinophenyl)-2-(thiazol-2-yl)but-3-yn-2-ol (12f) was identified as a highly potent NIK inhibitor, along with satisfactory selectivity. The pharmacokinetics of 12f and its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compound 1 developed by Amgen. Oral administration of different doses of 12f in an imiquimod-induced psoriasis mouse model showed effective alleviation of psoriasis, including invasive erythema, swelling, skin thickening, and scales. The underlying pathological mechanism involved attenuation of proinflammatory cytokine and chemokine gene expression, and the infiltration of macrophages after the treatment of 12f. This work provides a foundation for the development of NIK inhibitors, highlighting the potential of developing NIK inhibitors as a new strategy for the treatment of psoriasis.
<b><i>Introduction:</i></b> The Apgar score is a standardized method of assessing the primary adaptation and clinical status of a neonate after birth. Our objective was to systematically review and meta-analyze the survival and the survival without moderate-to-severe neurodevelopmental impairment (NDI) of neonates with a 10-min Apgar score of zero. <b><i>Methods:</i></b> Six electronic databases were searched for reports published until November 2021 of neonates with a 10-min Apgar score of zero. Risk of bias was assessed using the Newcastle-Ottawa scale for cohort studies and the Joanna Briggs Institute Critical Appraisal Checklist for case series/reports. Meta-analyses of the proportion of outcomes were conducted using a random-effects model for studies published after year 2000 and reporting >5 neonates. Meta-regression using the median year of the study period and subgroup analyses by treatment with therapeutic hypothermia and by gestational age were conducted. <b><i>Results:</i></b> Twenty-eight studies of 820 neonates with moderate risk of bias were included. Survival was 40% (95% confidence interval 30–50%, 16 studies, 646 neonates, <i>I</i><sup>2</sup> = 83%), and it increased by 2.3% per year (95% CI 1.3–3.2%, <i>p</i> < 0.001). Survival without moderate-to-severe NDI was 19% (95% confidence interval 11–27%, 13 studies, 211 neonates, <i>I</i><sup>2</sup> = 62%). Survival was higher for neonates who received therapeutic hypothermia and for those with a gestational age ≥32 weeks compared to <32 weeks. <b><i>Conclusion:</i></b> Approximately 2 in 5 neonates with a 10-min Apgar score of zero survived, and 1 in 5 survive without moderate-to-severe NDI survived. Survival has improved over the years, especially since the era of therapeutic hypothermia.
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