Study on the effects and mechanisms of Wenzhong Bushen Formula in improving ovarian reserve decline in mice based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: The Wenzhong Bushen Formula (WZBSF) is a traditional Chinese medicine empirical formula known for its effects in tonifying qi, strengthening the spleen, warming the kidneys, promoting yang, regulating blood circulation, and balancing menstruation. Clinical evidence has demonstrated its significant efficacy in treating Diminished Ovarian Reserve (DOR) by improving ovarian reserves. However, the specific pharmacological mechanisms of WZBSF remain unclear. AIM OF THE STUDY: This study aims to investigate the mechanisms by which WZBSF improves ovarian reserve decline through network pharmacology and animal experiments. METHODS AND MATERIALS: WZBSF was analyzed using a dual UPLC-MS/MS and GC-MS platform. Effective components and targets of WZBSF were obtained from the TCMSP database and standardized using UniProt. Disease targets were collected from GeneCard, OMIM, PHARMGKB, and DisGeNET databases, with cross-referencing between the two sets of targets. A PPI protein interaction network was constructed using Cytoscape3.9.1 and STRING database, followed by KEGG and GO enrichment analysis using the Metascape database. Finally, an ovarian reserve decline model was established in mice, different doses of WZBSF were administered, and experimental validation was conducted through serum hormone detection, H&E staining, immunofluorescence (IF), immunohistochemistry (IHC), and Western blot analysis (WB). RESULTS: WZBSF shares 145 common targets with ovarian reserve decline. GO enrichment analysis revealed involvement in biological processes such as response to hormone stimulation and phosphatase binding, while KEGG analysis implicated pathways including the PI3K-AKT signaling pathway and FoxO signaling pathway. In mice with ovarian reserve decline, WZBSF restored weight gain rate, increased ovarian index, normalized estrous cycles, reversed serum hormone imbalances, restored various follicle counts, and improved ovarian morphology. Additionally, WZBSF reduced p-AKT and p-FOXO3a levels, preventing excessive activation of primordial follicles and maintaining ovarian reserve. CONCLUSION: WZBSF can ameliorate cyclophosphamide and busulfan-induced ovarian reserve decline, and its mechanism may be associated with the inhibition of the PI3K/AKT/FOXO3a signaling pathway.

Ultrasound Treatment Improves Fruit Quality of Postharvest Blood Oranges (Citrus sinensis L. Osbeck): Anthocyanin Enrichment and Its Biosynthesis.

This study was to investigate the effects of different nonthermal treatments on quality attributes, anthocyanin profiles, and gene expressions related to anthocyanin biosynthesis during low-temperature storage, including pulsed light (PL), magnetic energy (ME), and ultrasound (US). Among these treatments, 1 min US treatment was the most effective method for improving fruit quality and increasing total anthocyanin contents (by 29.89 ± 3.32%) as well as individual anthocyanins during low-temperature storage of 28 days. This treatment resulted in high color intensity, intact cellular architectures, and positive sensory evaluation. In contrast, PL and ME treatments displayed negative effects on quality improvement, leading to the destruction of cell architectures and inhibiting anthocyanin levels. Furthermore, qPCR analysis revealed that the structural genes (C4H, CHS1, CHS2, CHI, F3H, ANS, and GST) related to anthocyanin biosynthesis and transport were the target genes and upregulated in response to the cavitation effect of US treatment.

Associations of fine particulate matter and its metal constituents with blood pressure: A panel study during the seventh World Military Games.

Evidence is needed to elucidate the association of blood pressure (BP) changes with metal constituents in fine particulate matter (PM2.5). Therefore, we designed a longitudinal panel study enrolling 70 healthy students from Wuhan University in the context of the seventh World Military Games (the 7th WMG) from September 2019 to January 2020. A total of eight visits were conducted before, during, and after the 7th WMG. During every visit, each participant was asked to carry a personal PM2.5 monitor to measure hourly PM2.5 levels for three consecutive days. Questionnaire investigation and physical examination were completed on the fourth day. We analyzed ten metal constituents of ambient PM2.5 collected from the fixed station, and blood pressure was recorded during each visit. The linear mixed-effects models were performed to evaluate associations of metal constituents and blood pressure measurements. We observed a dramatic variation of PM2.5 concentration ranging from 7.38 to 132.04 µg/m3. A 10 µg/m3 increment of PM2.5 was associated with an increase of 0.64 mmHg (95% CI: 0.44, 0.84) in systolic BP (SBP), 0.40 mmHg (0.26, 0.54) in diastolic BP (DBP), 0.31 mmHg (0.15, 0.47) in pulse pressure (PP) and 0.44 mmHg (0.26, 0.62) in mean artery pressure (MAP), respectively. For metal constituents in PM2.5, robust positive associations were observed between BP and selenium, manganese, arsenic, cadmium, and thallium. For example, for an IQR (0.93 ng/m3) increment of selenium, SBP and MAP elevated by 0.98 mmHg (0.09, 1.87) and 0.71 mmHg (0.03, 1.39), respectively. Aluminum was found to be robustly associated with decreased SBP, DBP, and MAP. The study indicated that exposure to PM2.5 total mass and metal constituents including selenium, manganese, arsenic, cadmium, and thallium were associated with the elevated BP.

Antioxidant and anti-inflammatory activity of constituents isolated from Dendrobium nobile (Lindl.).

Dendrobium nobile (Lindl.) have long been used as herbal tea and a traditional herbal medicine to treat Alzheimer's disease (AD). In the current study, nineteen compounds (1-19), including two new vitamin E homologues (1-2), one new sesquiterpene (6), and two new dendrobines (7, 8), were isolated and identified from stems of Dendrobium nobile. Their structures were elucidated on the basis of NMR, 13C NMR calculation, and DP4+ probability analyses. The absolute configurations of new compounds were determined by electronic circular dichroism (ECD) data analysis. Antioxidant, anti-inflammatory, and cytotoxic activities of isolated compounds were evaluated. Among them, compound 2 demonstrated significant antioxidant activity compared with ascorbic acid (VC), while compounds 2 and 4 also exhibited an equal effect to positive control cisplatin. This study on the biological activity of the new vitamin E homologues from Dendrobium nobile may indicate its potential application in the pharmaceutical and food industries.

Overview of therapeutic drug research for COVID-19 in China.

Since the outbreak of novel coronavirus pneumonia (COVID-19) in December 2019, more than 2,500,000 people worldwide have been diagnosed with SARS-CoV-2 as of April 22. In response to this epidemic, China has issued seven trial versions of diagnosis and treatment protocol for COVID-19. According to the information that we have collected so far, this article provides an overview of potential therapeutic drugs and compounds with much attention, including favipiravir and hydroxychloroquine, as well as traditional Chinese medicine, which have been reported with good clinical treatment effects. Moreover, with further understanding of SARS-CoV-2 virus, new drugs targeting specific SARS-CoV-2 viral components arise and investigations on these novel anti-SARS-CoV-2 agents are also reviewed.

Dendrimer-Au Nanoparticle Network Covered Alumina Membrane for Ion Rectification and Enhanced Bioanalysis.

Ion transport in an artificial asymmetric nanoporous membrane, which is similar to biological ion channels, can be used for biosensing. Here, a dendrimer-Au nanoparticle network (DAN) is in situ assembled on a nanoporous anodic aluminum oxide (AAO) surface, forming a DAN/AAO hybrid membrane. Benefiting from the high surface area and anion selectivity of DAN, the prepared DAN/AAO hybrid presents selective ion transport. Under a bias potential, a diode-like current-potential (I-V) response is observed. The obtained ionic current rectification (ICR) property can be tuned by the ion valence and pH value of the electrolyte. The rectified ionic current endows the as-prepared DAN/AAO hybrid with the ability of enhanced bioanalysis. Sensitive capture and detection of circulating tumor cells (CTCs) with a detection limit of 80 cells mL-1 as well as excellent reusability can be achieved.

Diterpenoid Lactones with Anti-Inflammatory Effects from the Aerial Parts of Andrographis paniculata.

Andrographis paniculata (AP) has been widely used in China for centuries to treat various diseases, and especially to treat inflammation. Diterpenoid lactones are the main anti-inflammatory components of AP. However, systematic chemical composition and biological activities, as well as key pharmacophores, of these diterpenoid lactones from AP have not yet been clearly understood. In this study, 17 diterpenoid lactones, including 2 new compounds, were identified by spectroscopic methods, and most of them attenuated the generation of TNF-α and IL-6 in LPS-induced RAW 274.7 cells examined by ELISA. Pharmacophores of diterpenoid lactones responsible for the anti-inflammatory activities were revealed based on the quantitative structure-activity relationship (QSAR) models. Moreover, new compounds (AP-1 and AP-4) exerted anti-inflammatory activity in LPS microinjection-induced zebrafish, which might be correlated with the inhibition of the translocation of NF-κB p65 from cytoplasm to nucleus. Our study provides guidelines for future structure modification and rational drug design of diterpenoid lactones with anti-inflammatory properties in medical chemistry.

Anti-metastasis traditional Chinese medicine monomer screening system based on perinucleolar compartment analysis in hepatocellular carcinoma cells.

Hepatocellular Carcinoma (HCC) lacks effective anti-metastasis drugs. Traditional Chinese Medicine (TCM) monomers have shown anti-proliferation activity in HCC, but few of them are specifically anti-metastasis. Therefore, further clarifying the indicators of HCC metastasis and screening TCM monomers based on the indicators, will effectively guide the development of novel anti-HCC drugs. The perinucleolar compartment (PNC), existing in the nuclear of tumor cells, is closely correlated with metastasis of several tumors. In this study, we found positive correlation between higher PNC prevalence and metastasis in HCC tissue of patients. The PNC prevalence was also positively correlated with the malignancy of HCC cell lines. On this premise, we established a PNC-based screening system for anti-metastasis TCM monomers and obtained Camptothecin (CPT), Evodiamine and Isoglycyrrhizin, the three most effective TCM monomers from a TCM monomer library to reduce the PNC prevalence in Huh7 cells. The anti-metastasis effect of these TCM monomers was positively correlated with their PNC inhibitor effect. Our data further revealed that CPT reduced metastasis of Huh7 cells possibly by inhibiting Epithelial-Mesenchymal Transition by upregulating the expression of ZO-1, E-cadherin and Claudin-1. The PNC-based screening system is effective and it may provide an effective technical platform for the development of anti-metastasis drugs.

Purpurogallin is a novel mitogen-activated protein kinase kinase 1/2 inhibitor that suppresses esophageal squamous cell carcinoma growth in vitro and in vivo.

Purpurogallin is a natural compound that is extracted from nutgalls and oak bark and it possesses antioxidant, anticancer, and anti-inflammatory properties. However, the anticancer capacity of purpurogallin and its molecular target have not been investigated in esophageal squamous cell carcinoma (ESCC). Herein, we report that purpurogallin suppresses ESCC cell growth by directly targeting the mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling pathway. We found that purpurogallin inhibits anchorage-dependent and -independent ESCC growth. The results of in vitro kinase assays and cell-based assays indicated that purpurogallin also strongly attenuates the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and also directly binds to and inhibits MEK1 and MEK2 activity. Furthermore, purpurogallin contributed to S and G2 phase cell cycle arrest by reducing cyclin A2 and cyclin B1 expression and also induced apoptosis by activating poly (ADP ribose) polymerase (PARP). Notably, purpurogallin suppressed patient-derived ESCC tumor growth in an in vivo mouse model. These findings indicated that purpurogallin is a novel MEK1/2 inhibitor that could be useful for treating ESCC.

Flueggenoids A - E, new dinorditerpenoids from Flueggea virosa.

A phytochemical investigation on the twigs and leaves of Flueggea virosa (Euphorbiaceae) led to the isolation of flueggenoids A - E (1-5), five new 13-methyl-ent-podocarpanes, together with eleven known compounds (6-16). Their structures and absolute configurations were elucidated on the basis of extensive MS and NMR data analysis, and/or single-crystal X-ray diffraction, time-dependent density functional theory (TDDFT)-based electronic circular dichroism (ECD) calculations, and chemical transformation. All isolates were evaluated for anti-HCV activity, the results showed that terpenoids of F. virosa had nonnegligible contribution for the anti-HCV activity.

Phenolics from Eugenia jambolana seeds with advanced glycation endproduct formation and alpha-glucosidase inhibitory activities.

Published data suggest that dietary-derived phenolics exert beneficial effects against hyperglycemia-mediated diseases, such as diabetes, through inhibiting the formation of advanced glycation endproducts (AGEs) and carbohydrate hydrolyzing enzyme activities. In the course of our investigation on the edible berry, Eugenia jambolana (known as Jamun), 21 phenolics (1-21) were isolated and identified from its seeds. Among these, one compound (1) is new and eleven compounds (3, 6, 9-13, 17, and 19-21) are being reported from E. jambolana for the first time. The anti-AGE activities of thirteen pure isolates (2-7, 9-12, 14, 15, and 20) were either comparable or superior to the synthetic anti-glycation agent, aminoguanidine, at three test concentrations (20, 50, and 100 µM) in the BSA-fructose assay. Most of these phenolics with anti-AGE activity exhibited potent free radical scavenging activity in the DPPH assay, and attenuated intracellular levels of LPS-induced reactive oxygen species in RAW264.7 macrophage. In addition, compounds 2-6, and 14 showed superior α-glucosidase inhibitory activity (IC50 = 5.0-21.2 µM) compared to the clinical α-glucosidase inhibitor, acarbose (IC50 = 289.9 µM). This is the first report of the anti-AGE effects of compounds 2-6 and 9-12, and α-glucosidase inhibitory activities of compounds 3-6, 9, 11 and 14. The current study supports the role of phenolics in the antidiabetic properties attributed to this edible berry, and warrants further animal studies to evaluate their potential as dietary agents for the prevention and/or therapy of hyperglycemia-mediated diseases.

Hypoglycemic and hypolipidemic effects of triterpenoid-enriched Jamun (Eugenia jambolana Lam.) fruit extract in streptozotocin-induced type 1 diabetic mice.

The edible berries of Eugenia jambolana Lam. (known as Jamun) are consumed in various parts of the world. Our previous studies revealed that a triterpenoid-enriched Jamun fruit extract (TJFE) showed beneficial effects on glucose homeostasis in non-diabetic mice. Herein, the anti-diabetic effects of TJFE (100 mg kg-1 by oral gavage for ten days) were evaluated in streptozotocin (STZ)-induced type 1 diabetic mice. TJFE significantly attenuated STZ-induced hyperglycemia and glucose intolerance, suppressed the abnormal elevation of hepatic gluconeogenesis, and improved dyslipidemia in the mice. Histopathology and mechanism-based studies revealed that TJFE preserved the architecture and function of pancreatic islets, attenuated insulin secretion deficiency, enhanced insulin/Akt signaling transduction, reduced lipogenic gene expression, and prevented the abnormal activation of Erk MAPK in the liver tissues of the STZ-induced diabetic mice. The current study adds to previously published data supporting the potential beneficial effects of this edible fruit on diabetes management.

[Effect of Tiaoshen Kaiyu Acupuncture (Regulating Vitality and Dredging Stasis) Combined with Psychological Intervention on Patients of Mild Depression After Stroke].

OBJECTIVE: To observe the effect of Tiaoshen Kaiyu acupuncture (regulating vitality and dredging stasis) combined with psychological intervention for treating mild depression after stroke. METHODS: Ninety-four patients were enrolled and were randomly divided into acupuncture (48 cases) and control (46 cases) groups. Patients in the control group were given standard treatment plus psychological intervention, while patients in the acupuncture group were treated with Tiaoshen Kaiyu acupuncture plus standard treatment and psychological intervention. Acupoints of Sishencong(EX-HN 1), Baihui(GV 20), and Yintang(EX-HN 3) were selected in the acupuncture group. Each group received treatment once daily, five times weekly, for a total of 6 weeks. A self-rating depression scale (SDS), Hamilton depression scale (HAMD), simplified Fugl-Meyer motor function assessment (FMA), and modified Barthel index (MBI) were used before and after treatment to evaluate the efficacy. RESULTS: After the treatment the four indexes were improved significantly compared with those before treatment in the acupuncture and control groups (P<0.01). The FMA and MBI scores in the acupuncture group were higher than those in the control group (P<0.05). The HAMD and SDS scores were significantly lower in the acupuncture group than in the control group (P<0.01). In both the acupuncture and control groups, the differences before and after treatment of the HAMD and FMA scores (rs＝0.332, P<0.01) and the HAMD and MBI scores (rs＝0.356, P<0.01) were positively correlated. CONCLUSION: Tiaoshen Kaiyu acupuncture combined with psychological intervention is more effective than psychological intervention therapy alone. The efficacy is correlated with motor function and mild depression scores of patients after stroke.

New Sesquiterpenoids from Eugenia jambolana Seeds and Their Anti-microbial Activities.

Twenty four sesquiterpenoids, 1-24, including 11 new sesquiterpenoids, jambolanins A-K, and two new norsesquiterpenoids, jambolanes A and B, along with six known triterpenoids, were isolated from the seeds of Eugenia jambolana fruit. Their structures were elucidated on the basis of NMR and MS spectrometry data analysis. Among the isolates, compound 13 possessed a rare 6,7-seco-guaiene skeleton, and compounds 14 and 15 were norsesquiterpenoids containing a spiro[4.4]nonane skeleton. Antimicrobial assay evaluation revealed that sesquiterpenoids, 4, 5/6, 17, 19, 21, 23, and 24 inhibited the growth of the Gram-positive bacterium, Staphylococcus aureus. The current study advances scientific knowledge of E. jambolana phytochemicals and suggests that its sesquiterpenoids may contribute, in part, to the anti-infective effects attributed to the edible fruit of this plant.

Heparin-derived oligosaccharide inhibits vascular intimal hyperplasia in balloon-injured carotid artery.

The aims of the present study were to determine the effects of heparin-derived oligosaccharides (HDOs) on vascular intimal hyperplasia (IH) in balloon-injured carotid artery and to elucidate the underlying mechanisms of action. An animal model was established by rubbing the endothelia within the common carotid artery (CCA) in male rabbits. The rabbits were fed a high-cholesterol diet. Arterial IH was determined by histopathological changes to the CCA. Serum lipids were detected using an automated biochemical analysis. Expressions of mRNAs for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), scavenger receptor class B type I (SR-BI), and ATP-binding cassette transporter A1 (ABCA-1) were analyzed using reverse transcription polymerase chain reaction assays. Expressions of VEGF, VCAM-1, MCP-1, SR-BI and ABCA-1 proteins were analyzed by Western blotting. Enzyme-linked immunosorbent assays were used to quantify expression levels of VEGF and bFGF. Our results showed that administration of HDO significantly inhibited CCA histopathology and restenosis induced by balloon injury. The treatment with HDOs significantly decreased the mRNA and protein expression levels of VEGF, bFGF, VCAM-1, MCP-1, and SR-BI in the arterial wall; however, ABCA-1 expression level was elevated. HDO treatment led to a reduction in serum lipids (total cholesterol, triglycerides, high-density and low-density lipoproteins). Our results from the rabbit model indicated that HDOs could ameliorate IH and underlying mechanism might involve VEGF, bFGF, VCAM-1, MCP-1, SR-BI, and ABCA-1.

Two new diterpenoid lactones isolated from Andrographis paniculata.

In the present study, two new diterpenoid lactones, 3-deoxy-andrographoside (1) and 14-deoxy-15-methoxy-andrographolide (2), were isolated from the aerial parts of Andrographis paniculata. Their structures were elucidated by combination of NMR, MS, and chemical methods. The configurations of 1 and 2 were established based on the analysis of ROESY data and single crystal X-ray diffraction experiment.

Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration.

PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC50 > 9), and by careful manipulation of the pKa and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated.

Aflatoxin B1 can be complexed with oxidised tea polyphenols and the absorption of the complexed aflatoxin B1 is inhibited in rats.

BACKGROUND: Aflatoxin B1 (AFB1) is the most prevalent and carcinogenic form of the aflatoxins. In this report, we explored the interaction between AFB1 and oxidised tea polyphenols (OTP). Then, the influence of OTP on the absorption and toxicity of AFB1 in rats was investigated. RESULTS: We found that AFB1 can be complexed with OTP, and a transmembrane bidirectional transport experiment verified the absorption of complexed AFB1 (C-AFB1) was inhibited by OTP dramatically (P < 0.001). Animal experiments results showed that the AFB1 plus OTP group had significantly (P < 0.05) decreased AFB1-albumin (AFB1-alb) compared to the AFB1 group at 4 h after ingestion. OTP could significantly (P < 0.01) promote the elimination of AFB1 in faeces. Moreover, the liver injury induced by AFB1 was significantly inhibited by OTP. CONCLUSION: Our results demonstrated AFB1 can be complexed with OTP and the absorption of the C-AFB1 is inhibited in rats. Consequently, the liver injury induced by AFB1 can be inhibited by OTP. These results provide insight that consuming OTP-containing products, like fermented Pu-er tea, can protect damage from AFB1, and OTP may be used as a kind of food additive. © 2016 Society of Chemical Industry.

[HPLC Specific Fingerprint of Alcohol Extract of Andrographis paniculata].

OBJECTIVE: To establish the specific fingerprint of alcohol extract of Andrographis paniculata by HPLC. METHODS: The analysis was performed on Cosmosil 5C18 -MS-II (250 mm x 4. 6 mm, 5 µm) column, with gradient phase consisting of acetonitrile and water at the flow rate of 1. 0 mL/min. The UV detection wavelength was set at 225 nm, and column temperature was 30 °C. RESULTS: The specific fingerprint chromatogram was established and seven common peaks were identified by comparison with the reference standards and LC-MS. The relative retention times were 1. 00 (No. 1, andrographolide), 1. 04 (No. 2, deoxyandrographoside), 1. 07 (No. 3, isoandrographolide), 1. 10 (No. 4, 14-deoxy-11, 12-didehydroandrographoside), 1. 50 (No. 5, neoandrographolide), 1. 75 ( No. 6, deoxyandrographolide) and 1. 79 (No. 7, dehydroandrographolide). CONCLUSION: The method is simple and reproducible with high precision, which can provide the basis for the quality control and evaluation of alcohol extract of Andrographis paniculata and its preparations.

Pre-clinical characterization of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, combined with ionizing radiation for head and neck squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) is over-expressed in nearly all cases of squamous cell carcinoma of the head and neck (SCCHN), and is an important driver of disease progression. EGFR targeted therapies have demonstrated clinical benefit for SCCHN treatment. In this report, we investigated the pre-clinical efficacy of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, both alone and in combination with ionizing radiation (IR), a primary curative modality for SCCHN. One normal oral epithelial (NOE) and three SCCHN (FaDu, UT-SCC-8, UT-SCC-42a) cell lines were used to conduct cell viability, clonogenic survival, cell cycle, and immunoblotting assays in vitro, using increasing doses of Dacomitinib (10-500 nM), both with and without IR (2-4 Gy). The FaDu xenograft model was utilized for tumor growth delay assays in vivo, and immunohistochemical analyses were conducted on extracted tumors. A dose-dependent reduction in cell viability and clonogenic survival after Dacomitinib treatment was observed in all three SCCHN models. Treatment led to a significant reduction in EGFR signalling, with a subsequent decrease in phosphorylation of downstream targets such as ERK, AKT, and mTOR. In vivo, Dacomitinib treatment delayed tumor growth, while decreasing phospho-EGFR and Ki-67 immunoexpression. These effects were further enhanced when combined with IR, both in vitro and in vivo. The preclinical data support the further evaluations of Dacomitinib combined with IR for the future management of patients with SCCHN.