Mutations in the PRRT2 gene have recently been identified in patients with familial paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and patients with sporadic PKD/IC from ...several ethnic groups. To extend these recent genetic reports, we investigated the frequency and identities of PRRT2 mutations in a cohort of Taiwanese patients with PKD/IC.
We screened all 3 coding exons of PRRT2 for mutations in 28 Taiwanese patients with PKD/IC. Among them, 13 had familial PKD/IC and 15 were apparently sporadic cases. In total, 7 disparate mutations were identified in 13 patients, including 8 familial cases and 5 apparently sporadic cases. The mutations were not present in 500 healthy controls. Four mutations were novel. One patient had a missense mutation and all other patients carried PRRT2 mutations putatively resulting in a protein truncation. Haplotype analysis revealed that 5 of the 7 patients with the PRRT2 p.R217Pfs*8 mutation shared the same haplotype linked to the mutation.
PRRT2 mutations account for 61.5% (8 out of 13) of familial PKD/IC and 33.3% (5 out of 15) of apparently sporadic PKD/IC in the Taiwanese cohort. Most patients with the PRRT2 p.R217Pfs*8 mutation in Taiwan likely descend from a single common ancestor. This study expands the spectrum of PKD/IC-associated PRRT2 mutations, highlights the pathogenic role of PRRT2 mutations in PKD/IC, and suggests genetic heterogeneity within idiopathic PKD.
EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen presentation during anti-PD-1 ...monotherapy in humans remain unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor, would improve outcomes in patients treated with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) by promoting antigen presentation and immune activation in the tumor microenvironment.
The ALPHA study (NCT03695510) was a single-arm, Phase II study with Simon's 2-stage design. Afatinib and pembrolizumab were administered to patients with platinum-refractory, recurrent, or metastatic HNSCC. The primary endpoint was the objective response rate (ORR). The study applied gene expression analysis using a NanoString PanCancer Immune Profiling Panel and next-generation sequencing using FoundationOne CDx.
From January 2019 to March 2020, the study enrolled 29 eligible patients. Common treatment-related adverse events were skin rash (75.9%), diarrhea (58.6%), and paronychia (44.8%). Twelve patients (41.4%) had an objective partial response to treatment. The median progression-free survival was 4.1 months, and the median overall survival was 8.9 months. In a paired tissue analysis, afatinib-pembrolizumab were found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity. Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict the clinical response to the therapy.
Afatinib may augment pembrolizumab therapy and improve the ORR in patients with HNSCC. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment.
Purpose: Immune checkpoint inhibitors are effective therapies for advanced hepatocellular carcinoma (HCC); however, comparisons of the clinical efficacy and safety profile for these drugs are still ...scarce. Thus, the aims of this study were to investigate the differences in efficacy and safety between nivolumab and pembrolizumab in unresectable HCC patients in a real-world setting. Patients and methods: A total of 115 patients who received treatment with nivolumab (n = 73) or pembrolizumab (n = 42) in combination with or without tyrosine kinase inhibitors was enrolled. Therapeutic response, survival outcomes, and safety profiles were compared among these groups. Multivariate analysis of survival response was performed using Cox proportional hazards regression. Results: Patients treated with pembrolizumab demonstrated a significantly higher objective response rate than those with nivolumab (38.1% vs. 15.1%; odds ratio 4.18, p = 0.005) regardless of the combination strategies. In addition, pembrolizumab performed a better overall survival (OS) than nivolumab, (34.9 vs. 9.5 months; hazard ratio (HR) = 0.39, p = 0.004). In subgroup analysis, pembrolizumab exhibited favorable OS than nivolumab for monotherapy (HR = 0.16, p = 0.001) or combination therapy (HR = 0.33, p = 0.006) as second-line or later-line (HR = 0.19, p = 0.001) therapy and those with (HR = 0.31, p = 0.006) or without (HR = 0.15, p = 0.004) well-compensated liver disease. The incidence of adverse events was comparable for both treatments. Conclusion: Both pembrolizumab and nivolumab had significant effects for HCC therapy, and pembrolizumab had a significant survival benefit as compared with nivolumab.
The prognosis of hepatocellular carcinoma (HCC) varies widely due to variable tumor extent and liver reserve. We aimed to develop and validate a new prognostic model based on tumor burden score (TBS) ...and albumin-bilirubin (ALBI) grade for HCC. We prospectively identified 3794 HCC patients who were randomized into derivation and validation groups. Survival predictors were evaluated by a multivariate Cox model. The TBS-ALBI system allocated two points for high TBS and ALBI grade 3, and one point each for the presence of ascites, serum α-fetoprotein ≥ 400 ng/mL, vascular invasion or distant metastasis, performance status 2-4, medium TBS, and ALBI grade 2, with a maximal score of 8 points. Significant survival differences were found across different TBS-ALBI score groups in the validation cohort (all
< 0.001). The TBS-ALBI system had the lowest corrected Akaike information criterion (AICc) and the highest homogeneity compared with other proposed staging models. The discriminative ability of the TBS-ALBI system was consistently stable across different viral etiologies, cancer stages, and treatment strategies. Conclusions: This new TBS-ALBI system is a feasible and robust prognostic system in comparison with other systems; it is a user-friendly tool for long-term outcome assessment independent of treatment modality and cancer stage in HCC.
Humanization of mouse monoclonal antibodies (mAbs) is crucial for reducing their immunogenicity in humans. However, humanized mAbs often lose their binding affinities. Therefore, an in silico ...humanization method that can prevent the loss of the binding affinity of mAbs is needed.
We developed an in silico V(D)J recombination platform in which we used V(D)J human germline gene sequences to design five humanized candidates of anti-tumor necrosis factor (TNF)-α mAbs (C1-C5) by using different human germline templates. The candidates were subjected to molecular dynamics simulation. In addition, the structural similarities of their complementarity-determining regions (CDRs) to those of original mouse mAbs were estimated to derive the weighted interatomic root mean squared deviation (wRMSD
) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (K
) of the humanized anti-TNF-α candidates was examined. To confirm whether our in silico estimation method can be used for other humanized mAbs, we tested our method using the anti-epidermal growth factor receptor (EGFR) a4.6.1, anti-glypican-3 (GPC3) YP9.1 and anti-α4β1 integrin HP1/2L mAbs.
The R
value for the correlation between the wRMSD
and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R
value for the correlation between wRMSD
and log(K
) was 0.9921. The results indicated that our in silico V(D)J recombination platform could predict the binding affinity of humanized candidates and successfully identify the high-affinity humanized anti-TNF-α antibody (Ab) C1 with a binding affinity similar to that of the parental chimeric mAb (5.13 × 10
). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4β1 integrin HP1/2L mAbs, the wRMSD
and log(EC50) exhibited strong correlations (R
= 0.9908, 0.9999, and 0.8907, respectively).
Our in silico V(D)J recombination platform can facilitate the development of humanized mAbs with low immunogenicity and high binding affinities. This platform can directly transform numerous mAbs with therapeutic potential to humanized or even human therapeutic Abs for clinical use.
We have synthesized a new blue‐emitting iridium complex, FIrpytz (iridium(III) bis(4,6‐difluorophenylpyridinato)‐4‐(pyridin‐2‐yl)‐1,2,3‐triazolate), and two new bis(triphenylsilyl) derivatives, BSB ...(4,4'‐bis‐triphenylsilanyl‐biphenyl) and BST (4,4″‐bis(triphenylsilanyl)‐(1,1′,4′,1″)‐terphenyl) as hosts for blue phosphorescence devices. The photoluminescence (PL) and electroluminescence (EL) properties of different host/dopant combinations were studied in details. These two arylsilanes showed glass transition temperatures (Tgs) ≥ 100 °C higher than those of UGH1 (diphenyl‐di(o‐tolyl)silane) and UGH2 (1,4‐bis(triphenylsilyl)benzene), the common arylsilane‐based hosts. The band gaps for BSB and BST are 4.16 and 3.78 eV, respectively, lower than that of UGH2 of 4.40 eV. The FIrpytz‐doped UGH2, BSB and BST films exhibit PL quantum yields of 0.58, 0.83 and 0.48, respectively. The EL devices using FIrpytz or FIrpic (iridium(III) bis(4,6‐difluorophenylpyridinato)‐picolinate) as the blue phosphorescence dopants and UGH2, BSB and BST as the hosts also showed that BSB‐based devices gave the best device efficiencies. Both PL and EL studies show that BSB is better than UGH2 and BST as the host material for FIrpytz and FIrpic. In particular, the use of FIrpytz as dopant, BSB as host and LiF/Al as cathode provides a remarkably efficient combination for blue electrophosphorescence device reaching a very high external quantum efficiency of 19.3% at 8.5 V and a high luminance level of 20500 cd m−2 at 19.3 V after electroluminescence started at 5.1 V.
Two new bis(triphenylsilyl)‐based hosts BSB and BST and a new iridium complex FIrpytz for blue phosphorescence devices are synthesized. The devices using FIrpytz as dopant and BSB as host show remarkably high electroluminescence efficiencies.
(1) Background: The severity of liver functional reserve plays an important role in the management of hepatocellular carcinoma (HCC). Noninvasive models such as the model for end-stage liver disease ...(MELD), albumin-bilirubin (ALBI) grade and easy (EZ)-ALBI grade, platelet-albumin-bilirubin (PALBI) and platelet-albumin (PAL) are used to evaluate liver dysfunction. We aimed to compare the prognostic performance of these four albumin-based models against MELD in HCC patients undergoing transarterial chemoembolization (TACE). (2) Methods: A total of 1038 treatment naïve HCC patients who received TACE as the primary treatment were enrolled. A multivariate Cox model was used to determine independent survival predictors. (3) Results: Multivariate analysis revealed that higher serum creatinine and α-fetoprotein level, vascular invasion, large tumor size, ALBI grades 2-3, EZ-ALBI grades 2-3, PALBI grades 2-3, PAL grades 2-3, but not the MELD score, were independent predictors associated with decreased survival in different Cox models. Among these models, the PALBI grade had the highest homogeneity and lowest corrected Akaike information criteria value, followed by EZ-ALBI, PAL, ALBI and, lastly, MELD. (4) Conclusions: All four albumin-based liver reserve models are better prognostic tools than MELD score in HCC patients undergoing TACE. Of these, the PALBI score is the best model to evaluate the liver reserve and should be considered a surrogate marker in these patients.
Targeted therapy based on adjustment of microRNA (miRNA)s activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 ...replacement therapy to hepatocellular carcinoma (HCC) remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05). In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT) and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.
Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm ...phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival PFS, clinical benefit rate, adverse events, duration of response, time to progression, overall survival OS) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC.
Tumor microenvironment influences the efficacy of anti-cancer therapies. The dysfunctional tumor vasculature limits the efficiency of oxygenation and drug delivery to reduce treatment outcome. A ...concept of tumor vascular normalization (VN), which inhibits angiogenesis to improve vessel maturity, blood perfusion, and oxygenation, has been demonstrated under the anti-angiogenic therapy. The efficiency of drug delivery and penetration is increased by enhancing perfusion and reducing interstitial fluid pressure during the time window of VN. However, anti-angiogenic agents only induce transient VN and then prune vessels to aggravate tumor hypoxia. To repair tumor vessels without altering vessel density, we proposed to induce tumor VN by local oxygen release via oxygen microbubbles with ultrasound. With tumor perfusion enhancement under ultrasound contrast imaging tracing, the time window of VN was defined as 2-8 days after a single oxygen microbubble treatment. The enhanced tumor oxygenation after oxygen microbubble treatment inhibited hypoxia inducible factor-1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) pathway to improve the morphology and function of tumor vasculature. The pericyte coverage and Hoechst penetration of tumor vessels increased without any changes to the vessel density. Finally, the intratumoral accumulation of anti-cancer drug doxorubicin could be increased 3-4 folds during tumor VN. These findings demonstrate that regulating tumor oxygenation by oxygen microbubbles could normalize dysfunctional vessels to enhance vascular maturity, blood perfusion, and drug penetration. Furthermore, ultrasound perfusion imaging provides a simple and non-invasive way to detect the VN time window, which increases the feasibility of VN in clinical cancer applications.
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