Self-Assembled Skin-Penetrating Peptides with Controlled Supramolecular Properties for Enhanced Transdermal Delivery.

The use of nanocarriers decorated with penetration-enhancing agents (PEAs) is considered to be a promising approach for efficient transdermal delivery. In this study, we developed short amphiphilic skin-penetrating peptides (17 amino acids) that functioned not only as PEAs but also as building blocks of nanocarriers without the incorporation of additional macromolecules for self-assembly and guest molecule encapsulation. Interestingly, varying only two amino acids in the hydrophobic moiety of the peptides resulted in significantly different self-assembly behavior, thermal stability, protease resistance, and skin-penetration efficiency in a human skin model. The analysis of the peptide secondary structure revealed that such characteristic changes arose due to the sequence variation-mediated conformational change in the hydrophobic block. These findings hold significant promise for the development of simple and effective delivery systems exhibiting controllable supramolecular properties.

Comparative Study on Simulated Outdoor Navigation for Agricultural Robots.

This research presents a comprehensive comparative analysis of SLAM algorithms and Deep Neural Network (DNN)-based Behavior Cloning (BC) navigation in outdoor agricultural environments. The study categorizes SLAM algorithms into laser-based and vision-based approaches, addressing the specific challenges posed by uneven terrain and the similarity between aisles in an orchard farm. The DNN-based BC navigation technique proves efficient, exhibiting reduced human intervention and providing a viable alternative for agricultural navigation. Despite the DNN-based BC navigation approach taking more time to reach its target due to a constant throttle limit for steady speed, the overall performance in terms of driving deviation and human intervention is notable compared to conventional SLAM algorithms. We provide comprehensive evaluation criteria for selecting optimal techniques for outdoor agricultural navigations. The algorithms were tested in three different scenarios: Precision, Speed, and Autonomy. Our proposed performance metric, P, is weighted and normalized. The DNN-based BC algorithm showed the best performance among the others, with a performance of 0.92 in the Precision and Autonomy scenarios. When Speed is more important, the RTAB-Map showed the best score with 0.96. In a case where Autonomy has a higher priority, Gmapping also showed a comparable performance of 0.92 with the DNN-based BC.

Cholesterol sulfate inhibits osteoclast differentiation and survival by regulating the AMPK-Sirt1-NF-κB pathway.

Cholesterol sulfate (CS) is an activator of retinoic acid-related orphan receptor α (RORα). CS treatment or RORα overexpression attenuates osteoclastogenesis in a collagen-induced arthritis mouse model. However, the mechanism by which CS and RORα regulate osteoclast differentiation remains largely unknown. Thus, we aimed to investigate the role of CS and RORα in osteoclastogenesis and their underlying mechanism. CS inhibited osteoclast differentiation, but RORα deficiency did not affect osteoclast differentiation and CS-mediated inhibition of osteoclastogenesis. CS enhanced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and sirtuin1 (Sirt1) activity, leading to nuclear factor-κB (NF-κB) inhibition by decreasing acetylation at Lys310 of p65. The NF-κB inhibition was restored by AMPK inhibitor, but the effects of CS on AMPK and NF-κB were not altered by RORα deficiency. CS also induced osteoclast apoptosis, which may be due to sustained AMPK activation and consequent NF-κB inhibition, and the effects of CS were significantly reversed by interleukin-1ß treatment. Collectively, these results indicate that CS inhibits osteoclast differentiation and survival by suppressing NF-κB via the AMPK-Sirt1 axis in a RORα-independent manner. Furthermore, CS protects against bone destruction in lipopolysaccharide- and ovariectomy-mediated bone loss mouse models, suggesting that CS is a useful therapeutic candidate for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

PSMD1 as a prognostic marker and potential target in oropharyngeal cancer.

BACKGROUND: Despite the diverse genetic mutations in head and neck cancer, the chemotherapy outcome for this cancer has not improved for decades. It is urgent to select prognostic factors and therapeutic targets for oropharyngeal cancer to establish precision medicine. Recent studies have identified PSMD1 as a potential prognostic marker in several cancers. We aimed to assess the prognostic significance of PSMD1 expression in oropharyngeal squamous cell carcinoma (OPSCC) patients using immunohistochemistry. METHODS: We studied 64 individuals with OPSCC tissue from surgery at Seoul National University Bundang Hospital between April 2008 and August 2017. Immunostaining analysis was conducted on the tissue microarray (TMA) sections (4 µm) for p16 and PSMD1. H-score, which scale from 0 to 300, was calculated from each nucleus, cytoplasm, and cellular expression. Clinicopathological data were compared with Chi-squared test, Fisher's exact test, t-test, and logistic regression. Survival data until 2021 were achieved from national statistical office of Korea. Kaplan-Meier method and cox-regression model were used for disease-specific survival (DSS) analysis. RESULTS: H-score of 90 in nucleus was appropriate cutoff value for 'High PSMD1 expression' in OPSCC. Tonsil was more frequent location in low PSMD1 group (42/52, 80.8%) than in high PSMD1 group (4/12, 33.3%; P = .002). Early-stage tumor was more frequent in in low PSMD1 group (45/52, 86.5%) than in high PSMD1 group (6/12, 50%; P = .005). HPV was more positive in low PSMD1 group (43/52, 82.7%) than in high PSMD1 group (5/12, 41.7%; P = .016). Patients with PSMD1 high expression showed poorer DSS than in patients with PSMD1 low expression (P = .006 in log rank test). In multivariate analysis, PSMD1 expression, pathologic T staging, and specimen age were found to be associated with DSS (P = .011, P = .025, P = .029, respectively). CONCLUSIONS: In our study, we established PSMD1 as a negative prognostic factor in oropharyngeal squamous cell carcinoma, indicating its potential as a target for targeted therapy and paving the way for future in vitro studies on drug repositioning.

Dendrimer-Peptide Conjugates for Effective Blockade of the Interactions between SARS-CoV-2 Spike Protein and Human ACE2 Receptor.

The coronavirus disease 2019 (COVID-19) pandemic has threatened the stability of global healthcare, which is becoming an endemic issue. Despite the development of various treatment strategies to fight COVID-19, the currently available treatment options have shown varied efficacy. Herein, we have developed an avidity-based SARS-CoV-2 antagonist using dendrimer-peptide conjugates (DPCs) for effective COVID-19 treatment. Two different peptide fragments obtained from angiotensin-converting enzyme 2 (ACE2) were integrated into a single sequence, followed by the conjugation to poly(amidoamine) (PAMAM) dendrimers. We hypothesized that the strong multivalent binding avidity endowed by dendrimers would help peptides effectively block the interaction between SARS-CoV-2 and ACE2, and this antagonist effect would be dependent upon the generation (size) of the dendrimers. To assess this, binding kinetics of the DPCs prepared from generation 4 (G4) and G7 PAMAM dendrimers to spike protein of SARS-CoV-2 were quantitatively measured using surface plasmon resonance. The larger dendrimer-based DPCs exhibited significantly enhanced binding strength by 3 orders of magnitude compared to the free peptides, whereas the smaller one showed a 12.8-fold increase only. An in vitro assay using SARS-CoV-2-mimicking microbeads also showed the improved SARS-CoV-2 blockade efficiency of the G7-peptide conjugates compared to G4. In addition, the interaction between the DPCs and SARS-CoV-2 was analyzed using molecular dynamics (MD) simulation, providing an insight into how the dendrimer-mediated multivalent binding effect can enhance the SARS-CoV-2 blockade. Our findings demonstrate that the DPCs having strong binding to SARS-CoV-2 effectively block the interaction between ACE2 and SARS-CoV-2, providing a potential as a high-affinity drug delivery system to direct anti-COVID payloads to the virus.

BRAFV600E and TERT promoter C228T mutations on ThyroSeq v3 analysis of delayed skin metastasis from papillary thyroid cancer: a case report and literature review.

BACKGROUND: Skin metastasis from papillary thyroid cancer (PTC) is a rare entity that can occur up to decades after treatment of the primary tumor. Here, we present a patient who developed skin metastasis 10 years after treatment of her primary tumor and describe the molecular findings of the metastatic lesion. CASE PRESENTATION: A 44-year-old female with a history of PTC who underwent a total thyroidectomy and radioactive iodine (RAI) treatment 10 years ago presented with a 1.3-cm skin lesion along the prior thyroidectomy scar. A biopsy revealed metastatic PTC, and the patient underwent surgical excision of the lesion. ThyroSeq molecular testing showed the copresence of BRAFV600E mutation and TERT promoter C228T mutation. The patient subsequently received one round of adjuvant RAI therapy. CONCLUSIONS: A high index of suspicion is warranted in patients with a history of PTC who develop a skin lesion, even several years after remission of the primary disease. In patients with high-risk mutations, such as BRAFV600E and TERT promoter C228T mutations, long-term surveillance of disease recurrence is particularly important.

Dynein light chain LC8 alleviates nonalcoholic steatohepatitis by inhibiting NF-κB signaling and reducing oxidative stress.

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by fat accumulation and chronic inflammation in the liver. Dynein light chain of 8 kDa (LC8) was identified previously as an inhibitor of nuclear factor kappa B (NF-κB), a key regulator of inflammation, however, its role in NASH remains unknown. In this study, we investigated whether LC8 can alleviate NASH using a mouse model of methionine and choline-deficient (MCD) diet-induced NASH and examined the underlying mechanism. LC8 transgenic (Tg) mice showed lower hepatic steatosis and less progression of NASH, including hepatic inflammation and fibrosis, compared to wild-type (WT) mice after consuming an MCD diet. The hepatic expression of lipogenic genes was lower, while that of lipolytic genes was greater in LC8 Tg mice than WT mice, which might be associated with resistance of LC8 Tg mice to hepatic steatosis. Consumption of an MCD diet caused oxidative stress, IκBα phosphorylation, and subsequent p65 liberation from IκBα and nuclear translocation, resulting in induction of proinflammatory cytokines and chemokines. However, these effects of MCD diet were reduced by LC8 overexpression. Collectively, these results suggest that LC8 alleviates MCD diet-induced NASH by inhibiting NF-κB through binding to IκBα to interfere with IκBα phosphorylation and by reducing oxidative stress via scavenging reactive oxygen species. Thus, boosting intracellular LC8 could be a potential therapeutic strategy for patients with NASH.

Assessment of the feasibility of developing a clinical pathway using a clinical order log.

A clinical pathway (CP) is a tool for effectively managing a care process. There are several research efforts on developing clinical pathways (CPs) in the process mining domain. However, the nature of the data affects data analysis results, and patient clinical variability makes it challenging to develop CPs. Thus, it is crucial to determine candidate care processes that can be standardized as CPs before applying process mining techniques. This paper proposed a method for assessing CP feasibility regarding clinical complexity using clinical order logs from electronic health records. The proposed method consists of data preparation, activity & trace homogeneity evaluations, and process inspection using process mining. Each step consists of metrics to measure the homogeneity of processes and a visualization method to demonstrate the diversity of processes based on the log. The case study was conducted with five surgical groups of patients from a tertiary hospital in South Korea to validate the proposed method. The five groups of patients were successfully assessed. In addition, the visualization methods helped clinical experts grasp the diversity of care processes.

NuA3 HAT antagonizes the Rpd3S and Rpd3L HDACs to optimize mRNA and lncRNA expression dynamics.

In yeast, NuA3 histone acetyltransferase (NuA3 HAT) promotes acetylation of histone H3 lysine 14 (H3K14) and transcription of a subset of genes through interaction between the Yng1 plant homeodomain (PHD) finger and H3K4me3. Although NuA3 HAT has multiple chromatin binding modules with distinct specificities, their interdependence and combinatorial actions in chromatin binding and transcription remain unknown. Modified peptide pulldown assays reveal that the Yng1 N-terminal region is important for the integrity of NuA3 HAT by mediating the interaction between core subunits and two methyl-binding proteins, Yng1 and Pdp3. We further uncover that NuA3 HAT contributes to the regulation of mRNA and lncRNA expression dynamics by antagonizing the histone deacetylases (HDACs) Rpd3S and Rpd3L. The Yng1 N-terminal region, the Nto1 PHD finger and Pdp3 are important for optimal induction of mRNA and lncRNA transcription repressed by the Set2-Rpd3S HDAC pathway, whereas the Yng1 PHD finger-H3K4me3 interaction affects transcriptional repression memory regulated by Rpd3L HDAC. These findings suggest that NuA3 HAT uses distinct chromatin readers to compete with two Rpd3-containing HDACs to optimize mRNA and lncRNA expression dynamics.

Oncological Outcomes after Pulmonary Metastasectomy for Head and Neck Squamous-Cell Carcinoma and Adenoid Cystic Carcinoma.

INTRODUCTION: Pulmonary metastatic head and neck cancer has a poor prognosis. Pulmonary metastasectomy has been performed but only in carefully selected patients. The aim of this study was to examine the clinical characteristics and oncological follow-up of patients who underwent pulmonary metastasectomy. METHODS: Data of 54 patients with squamous-cell carcinoma (SCC) or adenoid cystic carcinoma (ACC) who underwent metastasectomy between 2003 and 2019 at two tertiary referral centers were retrospectively reviewed. RESULTS: The 3-year and 5-year disease-free survival rates after metastasectomy were 49.9% and 39.9% for SCC and 38.9% and 32.4% for ACC, respectively. Univariate analysis revealed that a disease-free interval (DFI) less than 14 months and R1 resection (hazard ratio [HR] [95% confidence interval]: 2.95 [0.77-5.62], 4.64 [0.99-21.65], respectively) were risk factors for recurrence in SCC and that a high T stage (HR: 5.24 [1.22-22.58]) was a risk factor in ACC. In SCC, a DFI less than 14 months and R1 resection (hazard ratio: 6.35 [1.36-29.54], 12.79 [1.53-106.95], respectively) were risk factors in a multivariate analysis. CONCLUSION: Pulmonary metastasectomy had a fair effect on head and neck SCC and ACC, and the prognosis was better in SCC patients with a DFI greater than 14 months.

Antioxidant Constituents and Activities of the Pulp with Skin of Korean Tomato Cultivars.

Tomato is a widely distributed, cultivated, and commercialized vegetable crop. It contains antioxidant constituents including lycopene, tocopherols, vitamin C, γ-aminobutyric acid, phenols, and flavonoids. This study determined the contents of the antioxidant components and activities of the pulp with skin of ten regular, six medium-sized, and two small cherry tomato cultivars at red ripe (BR + 10) stage cultivated in Korea. The relationships among the Hunter color coordinates, the content of each component, and antioxidant activities were measured by Pearson's correlation coefficients. As the a* value increased, the carotenoid and vitamin C contents increased, while the L* value, hue angle and tocopherol content decreased. As the b* value increased, the lycopene and total carotenoid contents decreased, and the flavonoid content in the hydrophilic extracts increased. The contents of vitamin C and total carotenoids including lycopene showed high positive correlations with the DPPH radical scavenging activities of both the lipophilic and hydrophilic extracts. Tocopherols and total phenolics in the hydrophilic and lipophilic extracts were not major positive contributors to the antioxidant activity. These findings suggest the quality standards for consumer requirements and inputs for on-going research for the development of better breeds.

Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis.

Many bone diseases such as osteoporosis and periodontitis are caused by hyperactivation of osteoclasts. Calcium (Ca2+ ) signals are crucial for osteoclast differentiation and function. Thus, the blockade of Ca2+ signaling may be a strategy for regulating osteoclast activity and has clinical implications. Flunarizine (FN) is a Ca2+ channel antagonist that has been used for reducing migraines. However, the role of FN in osteoclast differentiation and function remains unknown. Here, we investigated whether FN regulates osteoclastogenesis and elucidated the molecular mechanism. FN inhibited osteoclast differentiation along with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and attenuated osteoclast maturation and bone resorption. FN inhibition of osteoclast differentiation was restored by ectopic expression of constitutively active NFATc1. FN reduced calcium oscillations and its inhibition of osteoclast differentiation and resorption function was reversed by ionomycin, an ionophore that binds Ca2+ . FN also inhibited Ca2+ /calmodulin-dependent protein kinase IV (CaMKIV) and calcineurin leading to a decrease in the cAMP-responsive element-binding protein-dependent cFos and peroxisome proliferator-activated receptor-γ coactivator 1ß expression, and NFATc1 nuclear translocation. These results indicate that FN inhibits osteoclastogenesis via regulating CaMKIV and calcineurin as a Ca2+ channel blocker. In addition, FN-induced apoptosis in osteoclasts and promoted osteogenesis. Furthermore, FN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting that it has therapeutic potential for treating inflammatory bone diseases and postmenopausal osteoporosis.

Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis.

Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor ß-activated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1ß (PGC1ß), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1ß resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

Size-Dependent Drug Loading, Gene Complexation, Cell Uptake, and Transfection of a Novel Dendron-Lipid Nanoparticle for Drug/Gene Co-delivery.

Dendron micelles have shown promising results as a multifunctional delivery system, owing to their unique molecular architecture. Herein, we have prepared a novel poly(amidoamine) (PAMAM) dendron-lipid hybrid nanoparticle (DLNP) as a nanocarrier for drug/gene co-delivery and examined how the dendron generation of DLNPs impacts their cargo-carrying capabilities. DLNPs, formed by a thin-layer hydration method, were internally loaded with chemo-drugs and externally complexed with plasmids. Compared to generation 2 dendron DLNP (D2LNPs), D3LNPs demonstrated a higher drug encapsulation efficiency (31% vs 87%) and better gene complexation (minimal N/P ratio of 20:1 vs 5:1 for complexation) due to their smaller micellar aggregation number and higher charge density, respectively. Furthermore, D3LNPs were able to avoid endocytosis and subsequent lysosomal degradation and demonstrated a higher cellular uptake than D2LNPs. As a result, D3LNPs exhibited significantly enhanced antitumor and gene transfection efficacy in comparison to D2LNPs. These findings provide design cues for engineering multifunctional dendron-based nanotherapeutic systems for effective combination cancer treatment.

Glycogen Synthase Kinase 3ß Regulates Antiviral Responses of TLR3 via TRAF2-Src Axis.

The protein tyrosine kinase Src regulates the synthesis of TLR3-mediated IFN-ß via the TBK1-IFN regulatory factor 3 axis. However, the molecular mechanisms regulating Src activity in TLR3 signaling remain unclear. In this study, we report that GSK3ß regulates Src phosphorylation via TNFR-associated factor 2 (TRAF2)-mediated Src ubiquitination. GSK3ß deficiency in mouse embryonic fibroblasts significantly reduces polyinosinic:polycytidylic acid-induced IFN-ß and IFN-stimulated gene expression, which is caused by diminished phosphorylation of Src at tyrosine 416. Src undergoes polyinosinic:polycytidylic acid-dependent lysine 63 chain ubiquitination, and TRAF2 is a direct E3 ligase for Src. Our study reveals novel mechanisms underlying TLR3-mediated antiviral responses mediated via the GSK3ß-TRAF2-Src axis.

Oncological outcomes of preoperatively unexpected malignant tumors of the parotid gland.

PURPOSE: Unexpected parotid cancers are often encountered due to inaccuracies in the preoperative evaluation. This study aimed to examine the clinical characteristics and oncological outcomes of these cancers and to propose the appropriate management strategy. METHODS: This is a multicenter case series study in which a total of 302 patients were diagnosed postoperatively with parotid cancers between 2003 and 2017. Of these, 85 cases without evidence of malignancy prior to surgery but identified as malignant on postoperative pathology were included. RESULTS: Of 85 patients, 76 and 9 underwent superficial and total parotidectomy, respectively. A positive resection margin was present in 24.7% of the cases. Postoperative radiotherapy was administered to 43.6% of patients; 4.2% had a local recurrence, and no patients died of the disease. The 5-year overall and relapse-free survival rates were 100.0% and 95.2%, respectively. Patients who underwent piecemeal resection had significantly poorer oncologic outcomes. Age, sex, histologic grade, T stage, extracapsular extension, resection margin status, and postoperative radiotherapy did not affect recurrence and survival. CONCLUSION: Preoperatively unexpected parotid cancers had excellent local control and overall survival despite positive or close resection margin, with or without postoperative radiotherapy. Therefore, patients with unexpected parotid malignancies may benefit from less aggressive postoperative management option.

A simple strategy for signal enhancement in lateral flow assays using superabsorbent polymers.

To enhance the sensitivity of lateral flow assays (LFAs), a simple strategy is proposed using a nitrocellulose membrane modified with a superabsorbent polymer (SAP). SAP was incorporated into a nitrocellulose membrane for the flow control of detection probes. When absorbing aqueous solutions, SAP promoted the formation of biomolecule complexes to achieve up to a tenfold sensitivity improvement for the detection of human IgG. The assay time was optimized experimentally and numerically to within 20 min using this strategy. Moreover, fluid saturation in LFAs modified with SAP was mathematically simulated to better understand the underlying process, and molecular dynamics simulations were carried out to determine the effect of SAP. The proposed design was also applied to samples spiked with human immunoglobulin-depleted serum to test its applicability. The strategy presented is unique in that it preserves the characteristics of conventional LFAs, as it minimizes user intervention and is simple to manufacture at scale.

An Avidity-Based PD-L1 Antagonist Using Nanoparticle-Antibody Conjugates for Enhanced Immunotherapy.

Upregulation of programmed death ligand 1 (PD-L1) allows cancer cells to evade antitumor immunity. Despite tremendous efforts in developing PD-1/PD-L1 immune checkpoint inhibitors (ICIs), clinical trials using such ICIs have shown inconsistent benefits. Here, we hypothesized that the ICI efficacy would be dictated by the binding strength of the inhibitor to the target proteins. To assess this, hyperbranched, multivalent poly(amidoamine) dendrimers were employed to prepare dendrimer-ICI conjugates (G7-aPD-L1). Binding kinetics measurements using SPR, BLI, and AFM revealed that G7-aPD-L1 exhibits significantly enhanced binding strength to PD-L1 proteins, compared to free aPD-L1. The binding avidity of G7-aPD-L1 was translated into in vitro efficiency and in vivo selectivity, as the conjugates improved the PD-L1 blockade effect and enhanced accumulation in tumor sites. Our results demonstrate that the dendrimer-mediated multivalent interaction substantially increases the binding avidity of the ICIs and thereby improves the antagonist effect, providing a novel platform for cancer immunotherapy.

Nanoparticle Conjugation Stabilizes and Multimerizes ß-Hairpin Peptides To Effectively Target PD-1/PD-L1 ß-Sheet-Rich Interfaces.

ß-Hairpin peptides present great potential as antagonists against ß-sheet-rich protein surfaces, of which wide and flat geometries are typically "undruggable" with small molecules. Herein, we introduce a peptide-dendrimer conjugate (PDC) approach that stabilizes the ß-hairpin structure of the peptide via intermolecular forces and the excluded volume effect as well as exploits the multivalent binding effect. Because of the synergistic advantages, the PDCs based on a ß-hairpin peptide isolated from an engineered programmed death-1 (PD-1) protein showed significantly higher affinity (avidity) to their binding counterpart, programmed death-ligand 1 (PD-L1), as compared to free peptides (by up to 5 orders of magnitude). The enhanced binding kinetics with high selectivity was translated into an improved immune checkpoint inhibitory effect in vitro, at a level comparable to (if not better than) that of a full-size monoclonal antibody. The results demonstrate the potential of the PDC system as a novel class of inhibitors targeting ß-strand-rich protein surfaces, such as PD-1 and PD-L1, displaying its potential as a new cancer immunotherapy platform.

Estrogen receptor α as a predictive biomarker for survival in human papillomavirus-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Although oropharyngeal squamous cell carcinoma (OPSCC) with human papillomavirus (HPV) infection has a good prognosis, the accurate prediction of survival and risk of treatment failure is essential to design deintensification regimens. Here, we investigated estrogen receptor α (ERα) as a prognostic biomarker with therapeutic implications in OPSCC alongside factors associated with HPV infection. METHODS: We performed immunohistochemistry for ERα and p53 using formalin-fixed, paraffin-embedded tissues and assessed the HPV status using p16 immunohistochemistry and HPV DNA testing in 113 consecutive patients with OPSCC treated with surgical resection or radiotherapy/chemoradiotherapy. RESULTS: ERα expression and p53 alteration was observed in 35.4% and 21.2% OPSCCs; 45.6% and 1.3% p16+/HPV+ OPSCCs; and 11.5% and 76.9% p16- OPSCCs, respectively. These data suggest that OPSCC pathogenesis varies with HPV status. Furthermore, ERα expression was associated with improved overall survival (OS) in both HPV+ (p16+/HPV+ OPSCC) and p16+ (p16+ OPSCC irrespective of HPV status) models (p = 0.005 and p = 0.006, respectively) and with improved OS adjusted for stage (p = 0.037, hazard ratio: 0.109, 95% confidence interval 0.013-0.871) in the p16+ model. CONCLUSIONS: ERα is a potential predictive biomarker for improved survival in both HPV+ and p16+ OPSCC models.