The clinical utility of comprehensive measurement of autoimmune disease-related antibodies in patients with advanced solid tumors receiving immune checkpoint inhibitors: a retrospective study.

BACKGROUND: The comprehensive measurement of autoimmune disease-related antibodies (Abs) before immune checkpoint inhibitor (ICI) treatment may be useful for predicting the development of immune-related adverse events (irAEs); however, the clinical utility is not well known. MATERIALS AND METHODS: We retrospectively analyzed patients with advanced solid tumors treated with ICI monotherapy or doublet combination therapy between July 2014 and December 2020 at single institute. Anti-nuclear antibody (ANA), anti-thyroglobulin (Tg) Ab, anti-thyroid peroxidase (TPO) Ab, anti-glutamic acid decarboxylase (GAD) Ab, anti-acetylcholine esterase receptor (AchR) Ab, and platelet-associated immunoglobulin G (PA-IgG) Ab were comprehensively measured for the screening before ICI therapy. RESULTS: Of 275 registered patients (median age, 70 years; male, 64.4%; Eastern Cooperative Oncology Group performance status of 0 or 1, 88.7%; and prior regimen of 0-1/≥2, 88.7%/11.3%), 128 non-small-cell lung cancer, 35 gastric cancer, 33 head and neck cancer, 24 melanoma, 19 renal cell carcinoma, 13 urothelial carcinoma, 12 esophageal cancer, 5 malignant mesothelioma of pleura, 2 endometrial cancer, and 4 other cancer were included. The number of patients with positive ANA, Tg, TPO, PA-IgG, GAD, and AchR Abs was 52 (24.9%), 38 (14.5%), 11 (10.1%), 6 (3.5%), 5 (2.0%), and 1 (0.5%), respectively. There was no association between the development of any irAEs and Abs positivity, while thyroid dysfunction developed more frequently among patients with than without Tg Ab or TPO Ab (39.5% versus 12.5%, P < 0.01; 45.5% versus 14.3%, P = 0.02). CONCLUSIONS: The clinical utility of comprehensive measurement of autoimmune disease-related Abs before introduction of ICI therapy was limited for predicting irAE. However, Tg and TPO Abs were risk factors as regards the development of ICI-induced thyroid dysfunction.

Point-contact spectroscopy of the heavy-fermion superconductor CePt(3)Si.

Differential resistance spectra (dV/dI-V characteristics) have been measured for point contacts between the heavy-fermion superconductor (HFS) CePt(3)Si and a normal metal. Some contacts show a peak at V = 0 that is characteristic of HFS coexisting with a magnetic order such as UPd(2)Al(3), UNi(2)Al(3) and URu(2)Si(2). The evolution of the peak occurs well above the antiferromagnetic transition temperature T(N)∼2.2 K, so that the direct relationship with the magnetic transition is questionable. The half-width of the peak seems to reflect the crystal field splitting or the spin-wave gap as observed for the above-mentioned HFSs, possibly suggesting that some common scattering process induces the zero-bias peaks in these materials.

Use of Bid-ribozymes to characterize and Bid-affiliated apoptotic pathway.

Multiple cell and stimulus specific apoptosis pathways have been identified (1) revealing a complexity of molecular events involved. Tumor necrosis factor (TNF alpha) is known to activate mitochondria dependent or independent pathways for cell death. These pathways converge to activate effector caspases, caspases 3, 6 and 7 (2). The intermediate events including the substrates and effectors however are not clearly understood. In this report, we have employed ribozyme technology to elucidate some of these intermediate events. We show here that Bid, a pro-apoptotic facilitator that plays an important role in the mitochondrial pathway, can be targeted by Bid-specific ribozymes. MCF7 breast carcinoma cells stably transfected with expression plasmids encoding active (but not inactive or mock) Bid ribozymes showed delayed response to TNF alpha. This was accompanied by decreased activation of caspases 7 and 9, but not of caspase 8. The data assign caspase 9 as an upstream activator of caspase 7 in TNF alpha-induced Bid-mediated apoptosis.

Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25.

Cyclin-dependent kinase 5 (CDK5) is a unique CDK, the activity of which can be detected in postmitotic neurons. To date, CDK5 purified from mammalian brains has always been associated with a truncated form of the 35-kDa major brain specific activator (p35, also known as nck5a) of CDK5, known as p25. In this study, we report that p35 can be cleaved to p25 both in vitro and in vivo by calpain. In a rat brain extract, p35 was cleaved to p25 by incubation with Ca(2+). This cleavage was inhibited by a calpain inhibitor peptide derived from calpastatin and was ablated by separating the p35.CDK5 from calpain by centrifugation. The p35 recovered in the pellet after centrifugation could then be cleaved to p25 by purified calpain. Cleavage of p35 was also induced in primary cultured neurons by treatment with a Ca(2+) ionophore and Ca(2+) and inhibited by calpain inhibitor I. The cleavage changed the solubility of the CDK5 active complex from the particulate fraction to the soluble fraction but did not affect the histone H1 kinase activity. Increased cleavage was detected in cultured neurons undergoing cell death, suggesting a role of the cleavage in neuronal cell death.

Okadaic acid-stimulated degradation of p35, an activator of CDK5, by proteasome in cultured neurons.

Degradation of p35, a neuron-specific activator of CDK5, was studied in rat cortical neurons in primary culture. Treatment of cultured neurons with cyclohexamide induced the rapid disappearance of p35 accompanied by parallel inactivation of the kinase activity of CDK5. The disappearance of p35 was blocked with proteasome inhibitors benzyloxycarbonyl-leucyl-leucyl-leucinal and lactacystin, indicating the involvement of proteasome. The degradation of p35 was induced with okadaic acid in the presence of ATP in neuron extracts. The degradation of p35 by proteasome in cultured neurons was stimulated by okadaic acid in the absence of cyclohexamide. These results indicate that p35 is degraded by proteasome in a phosphorylation-dependent manner in neurons.