Are immune checkpoint inhibitors ineffective in treating patients with head and neck squamous cell carcinoma aged 75 years or Older? A Meta-Analysis.

OBJECTIVES: The efficacy of immune checkpoint inhibitors (ICIs) is unclear in patients aged ≥ 75 years with head and neck squamous cell carcinoma (HNSCC). We conducted a systematic review and meta-analysis of randomized trials that compared ICIs with standard-of-care (SOC) therapy for recurrent/metastatic HNSCC. MATERIALS AND METHODS: PubMed, EMBASE, Web of Science, and ClinicalTrials.gov were searched for eligible trials. We evaluated the overall survival (OS) benefit of ICIs versus SOC according to patient age (<75 versus ≥ 75 years). The OS benefit was evaluated and compared between the age subgroups using hazard ratios (HRs). Data were pooled using a random-effects model. RESULTS: Five phase 3 trials involving 3437 patients were included. In patients aged ≥ 75 years (n = 207), ICIs did not improve OS compared to SOC (HR = 1.30, 95 % confidence interval [CI]: 0.93-1.81, P = 0.127). However, an improvement in OS was observed in patients aged < 75 years (n = 3230, HR = 0.90, 95 % CI: 0.83-0.99, P = 0.025). There is a significant difference in OS benefit between patients aged < 75 and ≥ 75 years (ratio of HR = 0.69, 95 % CI: 0.49-0.98, P = 0.036). Subgroup, meta-regression, and sensitivity analyses supported the reliability of the results. CONCLUSIONS: Given the small sample size, our findings showing no improvement in OS suggest a lack of evidence to support the use of ICIs in patients with recurrent/metastatic HNSCC aged ≥ 75 years. Therefore, prospective studies are needed to clarify their efficacy among this age group.

Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity.

Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

Promotion of Lung Cancer Metastasis by SIRT2-Mediated Extracellular Protein Deacetylation.

Acetylation of extracellular proteins has been observed in many independent studies where particular attention has been given to the dynamic change of the microenvironmental protein post-translational modifications. While extracellular proteins can be acetylated within the cells prior to their micro-environmental distribution, their deacetylation in a tumor microenvironment remains elusive. Here it is described that multiple acetyl-vWA domain-carrying proteins including integrin ß3 (ITGB3) and collagen 6A (COL6A) are deacetylated by Sirtuin family member SIRT2 in extracellular space. SIRT2 is secreted by macrophages following toll-like receptor (TLR) family member TLR4 or TLR2 activation. TLR-activated SIRT2 undergoes autophagosome translocation. TNF receptor associated factor 6 (TRAF6)-mediated autophagy flux in response to TLR2/4 activation can then pump SIRT2 into the microenvironment to function as extracellular SIRT2 (eSIRT2). In the extracellular space, eSIRT2 deacetylates ITGB3 on aK416 involved in cell attachment and migration, leading to a promotion of cancer cell metastasis. In lung cancer patients, significantly increased serum eSIRT2 level correlates with dramatically decreased ITGB3-K416 acetylation in cancer cells. Thus, the extracellular space is a subcellular organelle-like arena where eSIRT2 promotes cancer cell metastasis via catalyzing extracellular protein deacetylation.

Efficacy of cetuximab plus PD-1 inhibitor differs by HPV status in head and neck squamous cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: The addition of cetuximab significantly increased the antitumor effect of programmed cell death protein 1 (PD-1) inhibitors in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, preliminary analyses suggested that human papillomavirus (HPV)-positive disease benefited less than HPV-negative disease. Therefore, we conducted a meta-analysis to assess whether the efficacy of the combination therapy varied according to HPV status in HNSCC. METHODS: We identified clinical trials of patients with recurrent or metastatic HNSCC who received PD-1 inhibitor monotherapy or the combination therapy of cetuximab plus a PD-1 inhibitor. The participants were divided into four groups based on the type of therapy (combination vs monotherapy) and HPV status (positive vs negative). We focused on three comparisons (monotherapy vs combination therapy by HPV status and HPV-positive vs HPV-negative disease in combination therapy). The primary and secondary endpoints were objective response rate (ORR) and 1-year overall survival (OS) rate, respectively. The ORR and 1-year OS rate were pooled using random-effects models for each group and were compared for the different comparisons. RESULTS: Overall, 802 patients from seven trials were eligible for the ORR assessment; of which, 684 patients received PD-1 inhibitor monotherapy and 118 patients underwent the combination therapy. Compared with PD-1 inhibitor monotherapy, the addition of cetuximab improved the ORR in HPV-negative disease (pooled ORR in monotherapy vs combination therapy: 15% vs 46%, p<0.001) but not in HPV-positive disease (17% vs 18%, p=0.686). The efficacy of adding cetuximab was consistent for the 1-year OS rate in HPV-negative disease (pooled 1-year OS rate in monotherapy vs combination therapy: 36% vs 59%, p<0.001) and in HPV-positive disease (40% vs 55%, p=0.252). After the combination therapy, HPV-positive disease had a significantly lower ORR than HPV-negative disease (odds ratio: 0.29, p=0.004), but no differences were shown in the 1-year OS rate. CONCLUSIONS: Our meta-analysis suggests that the addition of cetuximab to a PD-1 inhibitor is more effective compared with PD-1 inhibitor monotherapy only in patients with HPV-negative HNSCC. Despite the retrospective nature of this meta-analysis, these findings should help in designing relevant clinical trials rationally.

Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS.

Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases.

CDK inhibitor Palbociclib targets STING to alleviate autoinflammation.

Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.

Emerging role of SIRT2 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most devastating cancer types, accounting for >80% of lung cancer cases. The median relative survival time of patients with NSCLC is <1 year. Lysine acetylation is a major post-translational modification that is required for various biological processes, and abnormal protein acetylation is associated with various diseases, including NSCLC. Protein deacetylases are currently considered cancer permissive partly due to malignant cells being sensitive to deacetylase inhibition. Sirtuin 2 (SIRT2), a primarily cytosolic nicotinamide adenine dinucleotide-dependent class III protein deacetylase, has been shown to catalyze the removal of acetyl groups from a wide range of proteins, including tubulin, ribonucleotide reductase regulatory subunit M2 and glucose-6-phosphate dehydrogenase. In addition, SIRT2 is also known to possess lysine fatty deacylation activity. Physiologically, SIRT2 serves as a regulator of the cell cycle and of cellular metabolism. It has been shown to play important roles in proliferation, migration and invasion during carcinogenesis. It is notable that both oncogenic and tumor suppressive functions of SIRT2 have been described in NSCLC and other cancer types, suggesting a context-specific role of SIRT2 in cancer progression. In addition, inhibition of SIRT2 exhibits a broad anticancer effect, indicating its potential as a therapeutic for NSCLC tumors with high expression of SIRT2. However, due to the diverse molecular and genetic characteristics of NSCLC, the context-specific function of SIRT2 remains to be determined. The current review investigated the functions of SIRT2 during NSCLC progression with regard to its regulation of metabolism, stem cell-like features and autophagy.

Design of a simulation platform for fast neutron multiplicity counting measurements.

Fast neutron multiplicity counting analysis is a new nondestructive analysis method for nuclear materials. On the basis of the basic theory of fast neutron multiplicity counting technology, an integrated neutron multiplicity simulation platform is designed and set up with the optimized combination of multiple computational tools. The platform consists of four modules: geometric modeling, particle transport, data processing and analysis, and cloud data management modules. It can implement multiple functions, such as automatic modeling, neutron transport, data visual analysis and simulation, and management of cloud platform data. Finally, simulation calculations and an experimental study of fast neutron multiplicity based on a liquid scintillator are performed with this platform. The results show that the deviation between the simulation results and the experimental results is less than 10%, and thus the simulation platform can be used for mutual inspection of mass.

Transcriptomic analysis provides insights into candidate genes and molecular pathways involved in growth of Manila clam Ruditapes philippinarum.

Growth is one of the most important traits of aquaculture breeding programs. Understanding the mechanisms underlying growth differences between individuals can contribute to improving growth rates through more efficient breeding schemes. Ruditapes philippinarum is an economically important marine bivalve. In order to gain insights into the molecular mechanisms to growth variability in marine shellfish, we conducted the transcriptome sequencing and examined the expression differences in growth-related gene and molecular pathways involved in growth trait of R. philippinarum. In this study, we investigated the molecular and gene expression differences in fast-growing and slow-growing Manila clam and focused on the analysis of the differential expression patterns of specific genes associated with growth by RNA-seq and qPCR analysis. A total of 61 differentially expressed genes (DEGs) were captured significantly differentially expressed, and were categorized into Ras signaling pathway, hedgehog signaling pathway, AMPK signaling pathway, p53 signaling pathway, regulation of actin cytoskeleton, focal adhesion, mTOR signaling pathway, VEGF signaling pathway, and TGF-beta signaling pathway. A total of 34 growth-related genes were validated significantly and up/downregulated at fast growing and slow growing of R. philippinarum. Functional enrichment analysis revealed the insulin signaling pathway, PI3K-Akt signaling pathway, and mTOR signaling pathway play pivotal roles in molecular function and regulation of growth trait in R. philippinarum. The growth-related genes and pathways obtained here provide important insights into the molecular basis of physiological acclimation, metabolic activity, and growth variability in marine bivalves.

RNA-Seq analysis of differentially expressed genes in the grand jackknife clam Solen grandis under aerial exposure.

Aerial exposure tolerance has been long considered as an important trait for the life survival under acute environmental stress. In this study, we utilized RNA-seq-based transcriptomic profiling to characterize the molecular responses of grand jackknife clam in response to aerial exposure. This assembly yielded 190,856 unigenes with an average length of 1147 bp, a minimum length of 201 bp, and a maximum length of 51,869 bp, with an N50 length of 1875 bp. After differential expression analysis, a total of 1344 genes were captured significantly differentially expressed, and were categorized into antioxidant/oxidative stress response, immune alteration, and apoptosis. GO and KEGG analyses revealed that signal transduction, immune response, cellular component organization or biogenesis, and energy production processes were the most highly enriched pathways among the genes that were differentially expressed under aerial exposure stress. All these pathways could be assigned to the following biological functions in the aerial exposure tolerant Solen grandis: signaling, transporter activity, macromolecular complex, cellular component organization or biogenesis, and molecular transducer activity. This study highlighted candidate genes linked to stress response during aerial exposure and provide a useful resource for further work on gills tissue or for selection of aerial exposure tolerant phenotypes.

Effects of Chain Length and Degree of Unsaturation of Fatty Acids on Structure and in Vitro Digestibility of Starch-Protein-Fatty Acid Complexes.

The effects of chain length and degree of unsaturation of fatty acids (FAs) on structure and in vitro digestibility of starch-protein-FA complexes were investigated in model systems. Studies with the rapid visco analyzer (RVA) showed that the formation of ternary complex resulted in higher viscosities than those of binary complex during the cooling and holding stages. The results of differential scanning calorimetry (DSC), Raman, and X-ray diffraction (XRD) showed that the structural differences for ternary complexes were much less than those for binary complexes. Starch-protein-FA complexes presented lower in vitro enzymatic digestibility compared with starch-FAs complexes. We conclude that shorter chain and lower unsaturation FAs favor the formation of ternary complexes but decrease the thermal stability of these complexes. FAs had a smaller effect on the ordered structures of ternary complexes than on those of binary complexes and little effect on enzymatic digestibility of both binary and ternary complexes.

Insights into the Formation and Structures of Starch-Protein-Lipid Complexes.

The aim of the present study was to characterize the multiscale structures of ternary complexes of a model system of starch, fatty acid (FA), and ß-lactoglobulin (ßLG) prepared using a Rapid Visco Analyzer (RVA). The addition of ßLG to starch-lauric acid or starch-oleic acid RVA pastes resulted in the increased intensity or occurrence of a new viscosity peak during cooling when the RVA protocol was repeated. The viscosity peak was attributed to the formation of starch-ßLG-FA complexes. Differential scanning calorimetry (DSC) results showed clearly that the starch-ßLG-FAs complex was formed as gelatinized starch was cooled in the presence of ßLG and FAs. The results of Raman, FTIR, and X-ray diffraction analyses showed that starch can interact with ßLG and FAs to form a ternary V-type crystalline complex, which had a greater short-range molecular order and higher relative crystallinity compared with those of the binary starch-FA complex. The present study provided insights into the structure of a model starch-protein-fatty acid complex as an example of what might occur during food processing.