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Purpose: Although gefitinib prolonged the progression-free survival (PFS) of patients with non–small cell lung cancer (NSCLC), unpredictable resistance limited its clinical efficacy. Novel predictive biomarkers with explicit mechanisms are urgently needed. Experimental Design: A total of 282 patients with NSCLC with gefitinib treatment were randomly assigned in a 7:3 ratio to exploratory (n = 192) and validation (n = 90) cohorts. The candidate polymorphisms were selected with Haploview4.2 in Hapmap and genotyped by a MassARRAY system, and the feature variables were identified through Randomforest Survival analysis. Tanswell and clonogenic assays, base editing and cell-derived tumor xenograft model were performed to uncover the underlying mechanism. Results: We found that the germline missense polymorphism rs3742076 (A>G, S628P), located in transactivation domain of FOXM1, was associated with PFS in exploratory (median PFS: GG vs. GA&AA, 9.20 vs. 13.37 months, P = 0.00039, HR = 2.399) and validation (median PFS: GG vs. GA&AA, 8.13 vs. 13.80 months, P = 0.048, HR = 2.628) cohorts. We elucidated that rs3742076_G conferred resistance to gefitinib by increasing protein stability of FOXM1 and facilitating an aggressive phenotype in vitro and in vivo through activating wnt/β-catenin signaling pathway. Meanwhile, FOXM1 level was highly associated with prognosis in patients with EGFR-mutant NSCLC. Mechanistically, FOXM1 rs3742076_G upregulated wnt/β-catenin activity by directly binding to β-catenin in cytoplasm and promoting transcription of β-catenin in nucleus. Remarkably, inhibition of β-catenin markedly reversed rs3742076_G-induced gefitinib resistance and aggressive phenotypes. Conclusions: These findings characterized rs3742076_G as a gain-of-function polymorphism in mediating gefitinib resistance and tumor aggressiveness, and highlighted the variant as a predictive biomarker in guiding gefitinib treatment.

AC0010 Supplementary Figure 2. AC0010 kinase profiling

AC0010 Supplementary Figure 1. AC0010 covalently binds to cysteine 797 in EGFR T790M

AC0010 Supplementary Figure 3. Impact of AC0010 and gefitinib administration on tumor volumes

Supplementary tables Table S1: Patient characteristics. Table S2: Non-synonymous mutations for paired cohort. Table S3: Non-synonymous mutations for unpaired cohort. Table S4: Copy number variants. Table S5: Correlation of principal components with gene expression. Table S6: Pathway enrichment analysis by principal component. Table S7: Gene signature evaluated in this study. Table S8: Tumor genes correlated with EBV genes. Table S9: Pathway enrichment of EBV-correlated genes.

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 (CDKN2A) locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature.Implications: This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. Mol Cancer Res; 15(12); 1722–32. ©2017 AACR.

AC0010 is a pyrrolopyrimidine-based irreversible EGFR inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors, such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR-active and T790M mutations with up to 298-fold increase in potency compared with wild-type EGFR. In a xenograft model, oral administration of AC0010 at a daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR-active and T790M mutations for over 143 days with no weight loss. Three major metabolites of AC0010 were tested and showed no wild-type EGFR inhibition or off-target effects, such as inhibition of IGF-1R. AC0010 is safe in non–small cell lung cancer (NSCLC) patients at a dose range between 50 and 550 mg once per day, and no hyperglycemia or other severe adverse effects were detected, such as grade 3 QT prolongation. The objective responses were observed in NSCLC patients with EGFR T790M mutation. Mol Cancer Ther; 15(11); 2586–97. ©2016 AACR.

AC0010 Supplementary methods; Table S1. IC50 values of AC0010 against representative kinases from biochemistry assay and cell-based ELISA assay; Table S2. List of 55 targets tested to assess the off target effect of AC0010 by an in vitro binding assay; Table S3. IC50 values of AC0010 in cell-based assays against targets with inhibition rate larger than 50% in binding assay; Table S4. Inhibitory activities of EGFR TKIs on proliferation of wild-type NCI-H1975, AC0010-resistant NCI-H1975-P1, NCI-H1975-AVR1 and Osimertinib-resistant NCI-H1975-OSR1 cells; Table S5. Inhibitory activities of AC0010 metabolites M7, MII-2 and MII-6 on proliferation of a panel of cell lines; Table S6. Inhibitory activities of AC0010 and its metabolites on IGF-1R in comparison with rociletinib and its metabolites; Table S7. Baseline demographic and clinical characteristics of 25 patients in dose escalation stage up to date

Figure S1. The express type of EGFR in S1, S1-MI-80, KB and KBv200 cell lines

Figure Legend for Supplementary Figure 1

Supplementary Figures Figure S1: Subtype identification using random sub-sampling. Figure S2: Subtype robustness. Figure S3: Morphological evaluation of tumors. Figure S4: % Tumor content by subtype. Figure S5: Principle components analysis. Figure S6: Microenvironment signatures. Figure S7: Cytotoxic to T-cell signature ratio and IgD to IgG expression ratio by subtype. Figure S8: Correlation of EBV and tumor gene expression. Figure S9: Mutation and copy number variation for paired and unpaired cohorts. Figure S10: Identification of stromal and intratumoral TILs. Figure S11: Mutation load vs. tumor content.

AC0010 Supplementary Figure 4. The effects of AC0010 and gefitinib administration on rat skins

Tumor suppressor mutations in head and neck squamous cell carcinoma (HNSCC) dominate the genomic landscape, hindering the development of effective targeted therapies. Truncating and missense mutations in NOTCH1 are frequent in HNSCC, and inhibition of PI3K can selectively target NOTCH1 mutant (NOTCH1MUT) HNSCC cells. In this study, we identify several proteins that are differentially regulated in HNSCC cells after PI3K inhibition based on NOTCH1MUT status. Expression of Aurora kinase B (Aurora B), AKT, and PDK1 following PI3K inhibition was significantly lower in NOTCH1MUT cell lines than in wild-type NOTCH1 (NOTCH1WT) cells or NOTCH1MUT cells with acquired resistance to PI3K inhibition. Combined inhibition of PI3K and Aurora B was synergistic, enhancing apoptosis in vitro and leading to durable tumor regression in vivo. Overexpression of Aurora B in NOTCH1MUT HNSCC cells led to resistance to PI3K inhibition, while Aurora B knockdown increased sensitivity of NOTCH1WT cells. In addition, overexpression of Aurora B in NOTCH1MUT HNSCC cells increased total protein levels of AKT and PDK1. AKT depletion in NOTCH1WT cells and overexpression in NOTCH1MUT cells similarly altered sensitivity to PI3K inhibition, and manipulation of AKT levels affected PDK1 but not Aurora B levels. These data define a novel pathway in which Aurora B upregulates AKT that subsequently increases PDK1 selectively in NOTCH1MUT cells to mediate HNSCC survival in response to PI3K inhibition. These findings may lead to an effective therapeutic approach for HNSCC with NOTCH1MUT while sparing normal cells.Significance:Aurora B signaling facilitates resistance to PI3K inhibition in head and neck squamous cell carcinoma, suggesting that combined inhibition of PI3K and Aurora kinase is a rational therapeutic strategy to overcome resistance.

Purpose:Although gefitinib prolonged the progression-free survival (PFS) of patients with non–small cell lung cancer (NSCLC), unpredictable resistance limited its clinical efficacy. Novel predictive biomarkers with explicit mechanisms are urgently needed.Experimental Design:A total of 282 patients with NSCLC with gefitinib treatment were randomly assigned in a 7:3 ratio to exploratory (n = 192) and validation (n = 90) cohorts. The candidate polymorphisms were selected with Haploview4.2 in Hapmap and genotyped by a MassARRAY system, and the feature variables were identified through Randomforest Survival analysis. Tanswell and clonogenic assays, base editing and cell-derived tumor xenograft model were performed to uncover the underlying mechanism.Results:We found that the germline missense polymorphism rs3742076 (A>G, S628P), located in transactivation domain of FOXM1, was associated with PFS in exploratory (median PFS: GG vs. GA&AA, 9.20 vs. 13.37 months, P = 0.00039, HR = 2.399) and validation (median PFS: GG vs. GA&AA, 8.13 vs. 13.80 months, P = 0.048, HR = 2.628) cohorts. We elucidated that rs3742076_G conferred resistance to gefitinib by increasing protein stability of FOXM1 and facilitating an aggressive phenotype in vitro and in vivo through activating wnt/β-catenin signaling pathway. Meanwhile, FOXM1 level was highly associated with prognosis in patients with EGFR-mutant NSCLC. Mechanistically, FOXM1 rs3742076_G upregulated wnt/β-catenin activity by directly binding to β-catenin in cytoplasm and promoting transcription of β-catenin in nucleus. Remarkably, inhibition of β-catenin markedly reversed rs3742076_G-induced gefitinib resistance and aggressive phenotypes.Conclusions:These findings characterized rs3742076_G as a gain-of-function polymorphism in mediating gefitinib resistance and tumor aggressiveness, and highlighted the variant as a predictive biomarker in guiding gefitinib treatment.

Supplementary figures with figure legends

Detailed individual characteristics of each patient

Supplementary Figure from FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non–Small Cell Lung Cancer

Supplementary data tables

Supplementary Table from FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non–Small Cell Lung Cancer

Supplementary Figures S1-8

Purpose:Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood.Experimental Design:We performed genomic profiling of 78 patients with non–small cell lung cancer (NSCLC) who underwent anti–PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response.Results:We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's ρ = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32–4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09–4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types.Conclusions:We identified novel genomic biomarkers that were predictive of response to anti–PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.

The transcription factor ABSCISIC ACID INSENSITIVE5 (ABI5) plays a crucial role in abscisic acid (ABA) signaling during seed germination. However, how ABI5 is regulated during this process is poorly understood. Here, we report that the ubiquitin E3 ligase MIEL1 and its target transcription factor MYB30 modulate ABA responses in Arabidopsis thaliana during seed germination and seedling establishment via the precise regulation of ABI5. MIEL1 interacts with and ubiquitinates ABI5 to facilitate its degradation during germination. The transcription factor MYB30, whose turnover is mediated by MIEL1 during seed germination, also interacts with ABI5 to interfere with its transcriptional activity. MYB30 functions downstream of MIEL1 in the ABA response, and both are epistatic to ABI5 in ABA-mediated inhibition of seed germination and postgerminative growth. ABA treatment induces the degradation of MIEL1 and represses the interaction between MIEL1 and ABI5/MYB30, thus releasing both ABI5 and MYB30. Our results demonstrate that MIEL1 directly mediates the proteasomal degradation of ABI5 and inhibits its activity via the release of its target protein MYB30, thus ensuring precise ABA signaling during seed germination and seedling establishment.

Immunotherapy plays a compelling role in cancer treatment and has already made remarkable progress. However, many patients receiving immune checkpoint inhibitors fail to achieve clinical benefits, and the response rates vary among tumor types. New approaches that promote anti-tumor immunity have recently been developed, such as small molecules, bispecific antibodies, chimeric antigen receptor T cell products, and cancer vaccines. Small molecule drugs include agonists and inhibitors that can reach the intracellular or extracellular targets of immune cells participating in innate or adaptive immune pathways. Bispecific antibodies, which bind two different antigens or one antigen with two different epitopes, are of great interest. Chimeric antigen receptor T cell products and cancer vaccines have also been investigated. This review explores the recent progress and challenges of different forms of immunotherapy agents and provides an insight into future immunotherapeutic strategies.

This study explores the mechanism of miR-36a in the hypoxia-reoxygenation process and its engagement in the repair of cardiomyocytes via modulating bone marrow mesenchymal stem cells (BMSCs). Thirty-two patients with myocardial injury were enrolled after hospitalization. Meanwhile, 32 normal patients were recruited as controls. The miR-36a levels were quantified via ELISA. BMSCs were isolated and cultured. The qRT-PCR was employed to determine the expression of genes involved in myocardial injury and hypoxia-reoxygenation, including KGF, SpB, SpA, CK18, SpC and Occludin. Specific mRNAs related to myocardial damage repair were also measured after miR-36a was knockdown and overexpressed during the process of repair induction. The expression of miR-36a in 32 patients with myocardial injury was elevated compared to that in controls. BMSCs can quantitatively retard the expression of hypoxia-reoxygenation-related genes. The knockdown of miR-36a can significantly enhance the expression of hypoxia-reoxygenation-related genes which were engaged in myocardial injury. miR-36a overexpression can significantly impede the expression of the hypoxia-reoxygenation-related genes which were involved in myocardial injury. miR-36a contributes to the repair of myocardial injury via functionally enhancing BMSCs’ function and interfering with the hypoxia-reoxygenation process.

The present study investigated the influence of energy ratio on microstructure and mechanical properties in the transition zone of hybrid laser-MIG welded 316L/AH36 joints. The region between the laser zone and hybrid zone was defined as the transition zone. The ratio of laser to arc energy was defined as energy ratio. Similar microstructure types including ferrite, austenite, and martensite were observed in the transition zone under each energy ratio. However, obvious difference in microstructure distribution and crystallographic characteristic in transition zone was found in varying energy ratio. With the energy ratio decreasing from 2:1 to 1:2, the fraction of martensite was decreased from 83.1% to 65.6%, the fraction of high angle grain boundaries was increased from 44.8% to 61.3% and the average grain size was increased from 3.62 to 17.20 μm. The phenomenon was attributed to the improvement of cooling rate and reduction of filler metal. Therefore, the highest average microhardness value of 445 HV in the fusion zone was obtained under the highest energy ratio compared to that of 223 HV under the lowest energy ratio. Besides, the low-temperature impact absorption energy was increased from 41 to 90 J and the tensile fracture mode was changed from cleavage fracture mode to ductile fracture mode as the energy ratio decreased from 2:1 to 1:2.

In recent years, tumor metabolism has become a prevalent research topic for scientists and pharmaceutical companies. As research in the field has progressed, the metabolism-based therapy of tumors has ushered in new opportunities. Most tumors emerge and evolve under selective pressure from their microenvironment, which promotes the diversification of both neoplastic and non-neoplastic compartments of the tumor microenvironment (TME), and finally reaches a certain degree of intratumoral heterogeneity. As a result of the tumor intratumoral heterogeneity, tumor cells often possess a complex energy metabolism phenotype. During tumor progression, the metabolism for both tumor parenchyma and stroma is reprogrammed. The tumor stroma mainly consists of the extracellular matrix, fibroblasts, and immune cells. Interestingly, tumor-infiltrating immune cells utilize different metabolites based on their subtype and function, and these immunometabolic pathways can be modified in the TME. In particular, interleukins play a vital role in the activation and differentiation of immune cells and have exhibited multiple effects on tumor cell neoplasia, invasion, and metastasis. In this review, we summarize the common mechanisms of interleukins affecting the tumor and tumor-infiltrating immune cells metabolically and discuss how these mechanisms may lead to novel therapeutic opportunities. This review might contribute to the novel development of cancer immunotherapy.

Purpose This paper aims to investigate the mechanism of Ni particles distribution in the liquid Sn3.5Ag melt under the external static magnetic field. The control steps of Ni particles and the Sn3.5Ag melt metallurgical process were studied. After aging, the microhardness of pure Sn3.5Ag, Sn3.5Ag containing randomly distributed Ni particles and Sn3.5Ag containing columnar Ni particles were compared. Design/methodology/approach Place the sample in a crucible for heating. After the sample melts, place a magnet directly above and below the sample to provide a magnetic field. Sn3.5Ag with the different morphological distribution of Ni particles was obtained by holding for different times under different magnetic field intensities. Finally, pure Sn3.5Ag, Sn3.5Ag with random distributed Ni particles and Sn3.5Ag with columnar Ni particles were aged and their microhardness was tested after aging. Findings The experimental results show that with the increase of magnetic field strength, the time for Ni particle distribution in Sn3.5Ag melt to reach equilibrium is shortened. After aging, the microhardness of Sn3.5Ag containing columnar nickel particles is higher than that of pure Sn3.5Ag and Sn3.5Ag containing randomly distributed nickel particles. A chemical reaction is the control step in the metallurgical process of nickel particles and molten Sn3.5Ag. Originality/value Under the action of the magnetic field, Ni particles in Sn3.5Ag melt will be arranged into columns. With the increase of magnetic field strength, the shorter the time for Ni particles in Sn3.5Ag melt to arrange in a column. With the extension of the service time of the solder joint, if Sn3.5Ag with columnar nickel particles is used as the solder joint material, its microhardness is better than Sn3.5Ag with arbitrarily distributed nickel particles and pure Sn3.5Ag.

Microstructure evolution of friction stir processed 2507 duplex stainless steel was investigated at rotational speed of 400 rpm and traverse speed of 100 mm/min. The microstructural evolution in processed zone was studied by optical microscopy and electron backscattered diffraction. Regions in the stir zone and the thermo-mechanically affected zone experienced different microstructure evolution due to different thermo-mechanical processes. The results showed that static recrystallization, dynamic recrystallization, and dynamic recovery occurred in the processed zone. And the ferrite was occurred the recrystallization prior to the austenite.

Introduction Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. Methods Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. Results A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation. Conclusions Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL. Trial Registration NCT02824458.

Ultrasonic assisted friction stir welding (UaFSW) and conventional friction stir welding (FSW) were conducted on AA6061 and Ti6Al4V alloys. Smaller waves and larger flashes were obtained by UaFSW w...

Systemic inflammation plays an important role in carcinogenesis and is associated with overall survival in patients with different cancer types, including those treated with immune checkpoint blockade (ICB). Serum Amyloid A (SAA) is an acute-phase protein and a marker of persistent inflammation. We hypothesized that circulating SAA may predict outcomes in advanced non-small cell lung (aNSCLC) patients treated with PD-1/PD-L1 ICB.This retrospective study included 91 aNSCLC patients who received anti-PD-(L)1 monotherapy in Sun Yat-sen University Cancer Center (Guangzhou, China) between August 2016 and June 2018. We examined the impact of circulating SAA at baseline and 8 (±2) weeks later on overall survival (OS). X-tile program was used to determine the cut-off values which optimized the significance of the split between Kaplan-Meier survival curves. Kaplan-Meier methodology and Cox regression analyses were conducted for survival analyses.The optimal cut-off value of baseline SAA for OS stratification was 137.6 mg/L. In univariate analysis, both high level of baseline SAA (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.47-5.18; P = 0.002) and lack of early SAA descent (HR, 1.51; 95% CI, 1.11-2.06; P = 0.009) were significantly associated with inferior OS. In multivariate analysis, gender, smoking status, performance status, liver metastasis, neutrophil-to-lymphocyte ratio, baseline SAA and early changes in SAA independently predicted OS (all with P0.05). A combined baseline SAA ≥ 137.6 mg/L and without early SAA descent identified a small cohort with remarkably worse OS (median, 3.2 months).Both high baseline and lack of early decline in circulating SAA are significantly associated with inferior outcomes in aNSCLC patients treated with PD-1/PD-L1 ICB. Combined these two SAA indexes provided improved risk stratification. The prognostic value of this simple, readily-available, and cost-effective biomarker warrants larger, prospective validation before definitive recommendation can be made.

Biguanides are a class of anti-diabetic drugs that includes phenformin and metformin, however, the former was withdrawn from approval in many countries due to its toxicity. Findings from retrospective epidemiological studies in diabetic populations and pre-clinical laboratory models have demonstrated that biguanides possess anti-tumor activities that suggest their repurposing for cancer prevention and treatment. However, a better understanding of how these biguanides behave as anti-tumor agents is needed to guide their improved applications in cancer therapy, spurring increased interest in their pharmacology. Here, we present evidence for proposed mechanisms of action related to their anti-tumor activity, including their effects on central carbon metabolism in cancer cells and immune-modulating activity, and then review progress on biguanide repurposing in cancer therapeutics and the possible re-evaluation of phenformin as a cancer therapeutic agent.

Pruritus is one of the most common and challenging side effects of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and has impaired patients' quality of life and treatment compliance. Our study evaluated the efficacy and safety of aprepitant in managing EGFR-TKIs-related pruritus.This randomized, double-blind, placebo-controlled study was conducted between December 2016 and August 2020 in China. Patients were eligible if they were 18 years or older and had histologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) with first onset of moderate to severe pruritus during EGFR-TKI treatment.A total of 130 eligible patients were randomly assigned to aprepitant (n = 65) or desloratadine (n = 65) groups. The median (interquartile range [Q1, Q3]) age was 63 (54, 70) years, and 79 (60.8%) were women. Mean visual analog scale scores at baseline were 6.35 (95% confidence interval [CI], 5.89-6.82) in the aprepitant group and 5.94 (95% CI, 5.56-6.32) in the desloratadine group. After 1 week of treatment, 33 (53.2%) patients responded to aprepitant, which was significantly higher than that of 14 (23.7%) patients responded to desloratadine (p = .001). Moreover, patients in the aprepitant group had a significantly shorter response time than patients in the desloratadine group (mean [days], 13.39 [95% CI, 11.08-15.70] vs. 16.67 [95% CI, 14.19-19.13], p = .04). The most frequent drug-related adverse events in aprepitant group and desloratadine were constipation and dry mouth, and all adverse events were grade 1-2.To the authors' knowledge, this is the first study to prospectively present that aprepitant elicited a better and faster response and mild toxicity for managing EGFR-TKI induced pruritus than desloratadine.ClinicalTrials.gov Identifier: NCT02646020.

Achieving strong joining of aluminum alloy to carbon fiber thermoplastic composites (CFRTP) using laser heating was an essential method to reduce the weight of structure and save energy. In current study, a silane coupling agent was adopted on the aluminum alloy surface to improve the bonding strength of the laser joining of aluminum alloy to CFRTP. Substrate characteristics of the aluminum alloy after treatment including surface morphology, surface roughness and wettability as well as chemical composition were then studied. For comparison, identical experiments were also performed for the polished and sanded aluminum alloy. Compared to the aluminum alloy polished, the surface roughness of aluminum alloy sanded and silane treated was increased, whereas the wettability was both decreased. The rougher surface led to a worse wettability of aluminum alloy surface for these two specimens. In addition, the detected organo-functional group for the latter was also responsible for the increase of water contact angle on the aluminum alloy surface. Compared to the polished specimens, the tensile shear force of joints for sanded and silane-treated substrates averaged 1106.9N and 2959.4N respectively, which represents a respective increase of 1.2 times and 3.3 times than the polished state. Correspondingly, the tensile shear strength of joints was 6.3MPa and 16.8MPa, which was increased by 1.1 times and 2.9 times, respectively. The improved mechanical interlocking induced by increasing the surface roughness in both sanded and silane treated cases was considered to strengthen the bonding strength at the interface. Moreover, for the joints fabricated by aluminum alloy silane treated and CFRTP, the remarkable enhancement of joint strength was also related to the formation of silane coupling film on the aluminum alloy surface. The tensile shear properties of joints were also found to have a positive influence in increasing the adhesion amount of CFRTP on the fractured surface of aluminum alloy. Finally, the silane treatment was expected to play a significant role in joining aluminum alloy to CFRTP.

Fiber laser joining of 6061 aluminium alloy and carbon fiber reinforced thermoplastic composite (CFRTP) was performed in this work. The effect of three process parameters including laser power, traveling speed and defocus distance on the bonding interface and joint properties was investigated. Shear tests were performed to evaluate the joint strength in different variables. X-ray photoelectron spectroscopy (XPS) was adopted to confirm the chemical states of elements at the interface. The results indicated that the shear strength of joints first increased and then decreased with the increase of heat input. Insufficient flow of CFRTP could not fill the grooves of aluminium alloy surface at low heat input. The resin was decomposed at excessisvely high heat input, causing pores remained at the interface. The fracture mode was determined as the interface failure. XPS result revealed that no new chemical bond was found at the interface, and the mechanical interlocking between aluminium alloy and CFRTP was main bonding mechanism. The maximum shear strength was 23.8 MPa, which was obtained as laser power, traveling speed and defocus distance was 1100 W, 5 mm/s and +10 mm, respectively.

Despite the revolution provided by immunotherapy, sustained clinical benefit has yet to be achieved for most of patients with advanced solid tumors. Myeloid cells readily accumulate in tumors, in some cases contributing up to 75% of the tumor mass. While supporting tumor growth and being associated with unfavorable prognosis, myeloid cells can mediate phagocytosis of cancer cells and cytotoxic tumor killing and promote adaptive immune responses through antigen presentation and co-stimulation, therefore representing promising targets in cancer therapy. The ability to engineer circulating and tumor associated myeloid cells to activate their ability to elicit anti-tumor adaptive immunity is an attractive approach to harness systemic anti-tumor immunity. However, it remains challenging to specifically target and activate myeloid cells in vivo. To overcome this hurdle, we have developed a novel in vivo myeloid cell engineering platform in which a chimeric antigen receptor (CAR) is generated by fusing a tumor recognition scFv with the alpha chain of human Fc receptors (CD89). The stable expression and function of these receptors requires the endogenously expressed common Fc receptor gamma chain (FcRγ), which expression is mostly restricted to myeloid cells. For in vivo engineering, the construct is encapsulated and delivered in lipid nanoparticles (LNP). Trophoblast cell surface antigen 2 (TROP2) is overexpressed in most human solid epithelial cancers, as compared to low expression in corresponding normal tissue. Increased TROP2 expression has been linked to increased tumor growth and has been implicated as a prognostic marker in these cancers, supporting the development of therapies targeting TROP2. Intravenous infusion of LNP encapsulating mRNA encoding the anti-TROP2-CD89 fusion protein results in the uptake of the LNPs and expression of the chimeric receptor fusion protein in myeloid cells. In immunodeficient xenograft models of hepatocellular carcinoma and triple negative breast cancer, delivery of LNP mRNA encoding GPC3-CD89 or TROP2-CD89 fusion proteins resulted in anti-tumor efficacy, confirming the ability of this approach to program myeloid cells. Repeat dosing studies showed significant anti-tumor efficacy following bi-weekly administration of TROP2-CD89. Furthermore, in the B16/10 syngeneic melanoma model, treatment with the melanoma antigen gp75-CD89 fusion protein was also associated with the initiation of broad systemic immune responses, characterized by tumor infiltration by activated CD8+ T cells, reduced tumor-associated Tregs and activation of antigen presenting cells in spleen. When infused in cynomolgus monkeys, TROP2-CD89 LNP led to cell surface expression of anti-TROP2 CAR in myeloid cells. Together these studies highlight the potential of in vivo delivery of CD89 fusion proteins to program myeloid cells to recognize and kill cancer. Citation Format: Thomas E. Prod'homme, Shannon Argueta, Hongyun Zhao, Michael Gorgievski, Neha Diwangi, Edward Cochran, Bruce McCreedy, Yuxiao Wang, Daniel Getts. In vivo delivery of novel CD89 fusion receptor to myeloid cells by mRNA activates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB027.

Comprehensive studies in second primary cancer (SPC) after the initial primary human papillomavirus (HPV)‐related cancer still remain warranted. We aimed to analyze the incidence and risk factors of SPC after HPV‐related cancer. We identified 86 790 patients diagnosed with initial primary HPV‐related cancer between 1973 and 2010 in the SEER database. Standardized incidence ratio (SIR) and cumulative incidence were calculated to assess the risk of SPC after HPV‐related cancer. The SIR of SPC after HPV‐related cancer was 1.60 (95% confidence interval [CI], 1.55‐1.65) for male and 1.25 (95% CI, 1.22‐1.28) for female. SIR of second primary HPV‐related cancer (7.39 [95% CI, 6.26‐8.68] male and 4.35 [95% CI, 4.04‐4.67] female) was significantly higher than that of HPV‐unrelated cancer (1.54 [95% CI, 1.49‐1.60] male and 1.16 [95% CI, 1.13‐1.19] female). The 5‐year cumulative incidence of SPC was 7.22% (95% CI, 6.89‐7.55%) for male and 3.72% (95% CI, 3.58‐3.88%) for female. Risk factors for SPC included being married and having initial primary cancer (IPC) diagnosed at earlier stage for both genders, and IPC diagnosed at older age as well as surgery performed for female. Patients diagnosed with HPV‐related cancer are more likely to develop another primary cancer, compared with the age‐specific reference population., Our study performed a systematic estimation of the incidence of second primary cancer in HPV‐related cancer patients. This figure displayed the distribution of second primary cancer sites after the specific initial primary HPV‐related cancer. The result may provide some accordance for the surveillance of second primary cancer after initial primary HPV‐related cancer.

Oscillating laser welding of 2-mm-thick 6061-T6 aluminum alloy and AISI304 steel in overlap configuration was performed under various oscillation amplitudes of 0, 3, and 5 mm. The experimental results indicated that the welding window of Al/steel dissimilar joints was improved with increasing oscillation amplitudes. The beam oscillation broadened weld width and interfacial bonding width while reducing weld depth. In the joint produced under 0-mm oscillation, a multi intermetallic compound (IMC) layer formed with a thickness of about 90 μm. In the joint produced under 3-mm oscillation, the IMC layer with the compositions of η-Fe2Al5+block-shaped θ-Fe4Al13) was obtained and its corresponding thickness reduced to 20 μm. When the oscillation amplitude further increased to 5 mm, only a η-Fe2Al5+little θ-Fe4Al13 layer with a thickness of 5 μm generated. Simulation results for the temperature history indicated that an oscillating laser beam would disperse laser energy, restraining the steel penetrating. Besides, dispersed heat energy depressed the melting of lower aluminum sheets and interfacial element diffusion. Thus, the formation of IMCs was suppressed. The limited IMCs and increased bonding width led to an improvement in the tensile–shear properties. The maximum fracture load of the joint under 5-mm oscillation was 185 N/mm, which was twice higher than that of joints welded without beam oscillation. Less Al atoms dissolved into the fusion zone under beam oscillation, resulting in lower microhardness and better toughness. Fracture locations changed from the fusion zone to the interface due to weakened steel penetration and improved toughness.