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Background HBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety, pharmacokinetics, immunogenicity and preliminary efficacy of HBM4003 plus with anti-PD-1 antibody toripalimab in patients with advanced solid tumors, especially focusing on melanoma.Methods The multicenter, open-label phase I trial was divided into two parts: dose-escalation phase (part 1) and dose-expansion phase (part 2). In part 1, HBM4003 was administered at doses of 0.03, 0.1, 0.3 mg/kg in combination with toripalimab with fixed dosage of 240 mg every 3 weeks. The recommended phase II dose (RP2D) was used in the expansion phase. Primary endpoints were safety and RP2D in part 1 and objective response rate (ORR) in part 2. Biomarkers based on cytokines and multiplex immunofluorescence staining were explored.Results A total of 40 patients received study treatment, including 36 patients treated with RP2D of HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week. 36 participants (90.0%) experienced at least one treatment-related adverse event (TRAE), of which 10 (25.0%) patients experienced grade ≥3 TRAEs and 5 (12.5%) experienced immune-mediated adverse events (irAEs) with maximum severity of grade 3. No grade 4 or 5 irAEs occurred. Efficacy analysis set included 32 melanoma patients treated with RP2D and with available post-baseline imaging data. The ORRs of anti-PD-1/PD-L1 treatment-naïve subgroup and anti-PD-1/PD-L1 treatment-failed subgroup were 33.3% and 5.9%, respectively. In mucosal melanoma, the ORR of the two subgroups were 40.0% and 10.0%, respectively. Baseline high Treg/CD4+ratio in the tumor serves as an independent predictive factor for the efficacy of immunotherapy.Conclusions HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week demonstrated manageable safety in solid tumors and no new safety signal. Limited data demonstrated promising antitumor activity, especially in PD-1 treatment-naïve mucosal melanoma.Trial registration number NCT04727164.

Abstract Systemic therapy is typically the primary treatment choice for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. Some patients may achieve partial response (PR) or complete response (CR) with systemic treatment, leading to the possibility of their primary tumor becoming resectable. This study aimed to investigate whether these patients could achieve longer survival through surgical resection of their primary tumor. We retrospectively collected data from 150 HCC patients with extrahepatic metastases treated at 15 different centers from January 1st, 2015, to November 30th, 2022. We evaluated their overall survival (OS) and progress-free survival (PFS) and analyzed risk factors impacting both OS and PFS were analyzed. Patients who received surgical treatment had longer OS compared to those who did not (median OS 16.5 months vs. 11.3 months). However, there was no significant difference in progression-free survival between the two groups. Portal vein invasion (P = 0.025) was identified as a risk factor for poor prognosis in patients, while effective first-line treatment (P = 0.039) and surgical treatment (P = 0.005) were protective factors. No factors showed statistical significance in the analysis of PFS. Effective first-line treatment (P = 0.027) and surgical treatment (P = 0.006) were both independent protective factors for prolonging patient prognosis, while portal vein invasion was an independent risk factor (P = 0.044). HCC patients with extrahepatic metastases who achieve PR/CR with conversion therapy may experience longer OS through surgical treatment. This study is the first to analyze the clinical outcomes of patients receiving surgical treatment for HCC with extrahepatic metastases.

Abstract We demonstrate a novel flat-field, dual-optic imaging EUV—soft X-ray spectrometer and monochromator that attains an unprecedented throughput efficiency exceeding 60% by design, along with a superb spectral resolution of λ/Δλ > 200 accomplished without employing variable line spacing gratings. Exploiting the benefits of the conical diffraction geometry, the optical system is globally optimized in multidimensional parameter space to guarantee optimal imaging performance over a broad spectral range while maintaining circular and elliptical polarization states at the first, second, and third diffraction orders. Moreover, our analysis indicates minimal temporal dispersion, with pulse broadening confined within 80 fs tail-to-tail and an FWHM value of 29 fs, which enables ultrafast spectroscopic and pump-probe studies with femtosecond accuracy. Furthermore, the spectrometer can be effortlessly transformed into a monochromator spanning the EUV—soft X-ray spectral region using a single grating with an aberration-free spatial profile. Such capability allows coherent diffractive imaging applications to be conducted with highly monochromatic light in a broad spectral range and extended to the soft X-ray region with minimal photon loss, thus facilitating state-of-the-art imaging of intricate nano- and bio-systems, with a significantly enhanced spatiotemporal resolution, down to the nanometer–femtosecond level.

High-order harmonic generation (HHG) using femtosecond lasers is an efficient and cost-effective method for producing attosecond and femtosecond light in the extreme ultraviolet and soft x-ray regions. This technique generates high-brightness harmonic beams with stable spectra, intensity, and wavefronts, making it a valuable tool for applications such as nanoimaging, material metrology, and studies of ultrafast dynamics. Accurate wavefront measurement of HHG beams is essential for analyzing complex incident fields, understanding atomic responses, and enhancing applications such as attosecond-driven ultrafast processes. However, quantifying the wavefronts of each harmonic component remains a challenge. Here, we present a multicolor wavefront sensing for HHG beams using the Talbot effect, validated theoretically and experimentally. Our method reconstructs individual high-order harmonic wavefronts with a spectral resolution of 4.8 eV, capturing multiple harmonic wavelengths in a single scan along the propagation direction, without the need for additional spectrometers or complex calibrations. This approach surpasses conventional Talbot effect wavefront sensing, which typically relies on quasimonochromatic waves or wavelength-averaging. Additionally, we introduce a high-accuracy centroid detection strategy that reduces tracking errors to the thousandths of a pixel while maintaining high computational efficiency, paving the way for broader applications in imaging and metrology.

Abstract Currently, the optimal lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell (Neo-T) therapy has yet to be determined. We report a single-arm, open-label and non-randomized phase 1 study (NCT02959905) of Neo-T therapy with lymphodepletion at various dose intensity in patients with locally advanced or metastatic solid tumors that are refractory to standard therapies. The primary end point is safety and the secondary end points are disease control rate (DCR), progression-free survival (PFS), overall survival (OS). Results show that the treatment is well tolerated with lymphopenia being the most common adverse event in the highest-intensity lymphodepletion groups. Neo-T infusion-related adverse events are only grade 1–2 in the no lymphodepletion group. The median PFS is 7.1 months (95% CI:3.7-9.8), the median OS is 16.8 months (95% CI: 11.9-31.7), and the DCR is 66.7% (6/9) among all groups. Three patients achieve partial response, two of them are in the no lymphodepletion group. In the group without lymphodepletion pretreatment, one patient refractory to prior anti-PD1 therapy shows partial response to Neo-T therapy. Neoantigen specific TCRs are examined in two patients and show delayed expansion after lymphodepletion treatment. In summary, Neo-T therapy without lymphodepletion could be a safe and promising regimen for advanced solid tumors.

Abstract The current staging method is inadequate to identify high-risk recurrence patients with stage II colon cancer (CC). Using a systematic and comprehensive-biomarker discovery and validation method, we aimed to construct a lncRNA-based signature to improve the prognostic prediction of stage II CC. We identified 1,377 differently expressed lncRNAs by analyzing 16 paired stage II CC tumor tissue and adjacent normal mucosal tissue from the TCGA dataset. Subsequently, using a univariable and step multivariable Cox regression model, we trained an 11-lncRNA signature in the training cohort (n = 141), which could divide patients into high-risk and low-risk groups (AUC at 3 years = 0.801, 95% CI: 0.724–0.877; AUC at 5 years = 0.801, 95% CI: 0.718–0.885). Significantly, patients in the high-risk group had poorer recurrence-free survival (RFS) compared with the low-risk group (log-rank test, P

Programmed cell death ligand 1 (PD-L1) is an immune checkpoint protein frequently expressed in human cancers that contributes to immune evasion through its binding to PD-1 on activated T cells. Unveiling the mechanisms underlying PD-L1 expression is essential for understanding the impact of the immunosuppressive microenvironment and is also crucial for the purpose of reboosting antitumor immunity. However, how PD-L1 is regulated, particularly at translational levels, remains largely unknown. Here, we discovered that a long noncoding RNA (lncRNA), HIF-1α inhibitor at translation level (HITT), was transactivated by E2F transcription factor 1 (E2F1) under IFN-γ stimulation. It coordinated with regulator of G protein signaling 2 (RGS2) in binding to the 5′ UTR of PD-L1, resulting in reduced PD-L1 translation. HITT expression enhanced T cell–mediated cytotoxicity both in vitro and in vivo in a PD-L1–dependent manner. The clinical correlation between HITT/PD-L1 and RGS2/PD-L1 expression was also detected in breast cancer tissues. Together, these findings demonstrate the role of HITT in antitumor T cell immunity, highlighting activation of HITT as a potential therapeutic strategy for enhancing cancer immunotherapy.

Abstract Limited studies have interrogated the genomic landscape of Chinese melanoma in which acral and mucosal melanoma are the mainstay. In this study, we carried out a retrospective analysis on 81 Chinese melanoma patients (15 acral, 25 mucosal and 41 cutaneous melanoma). With the identification of 1114 mutations spanning 248 genes, we summarized that the mutation spectrum varied significantly by subtypes. Acral melanoma and mucosal melanoma had significantly more CNVs. MYC amplification was one of the most commonly detected CNVs, other frequent CNVs in mucosal melanoma included NBN and KDR, which were associated with the poor survival of melanoma patients. A generally low TMB, with a median of only 5.1 mut/Mb, was observed in three groups including cutaneous melanoma. Additionally, over 50% variants in DNA damage repair pathway were detected in all three subtypes, most of which were HRD related genes. Patients with alterations of HRD related genes had a longer survival time after immunotherapy. This study revealed a molecular profiling of Chinese patients with advanced melanoma, and proposed the high variant rate in DDR pathway as a biomarker of immunotherapy, which might provide therapeutic targets and guidance in making clinical decision for different Chinese melanoma.

BackgroundPrevious studies indicated the evidence that baseline levels of thyroid antibodies, thyroid status, and serum lactate dehydrogenase (LDH) and M stage may influence the prognosis of patients with advanced or metastatic melanoma treated with immune checkpoint inhibitors that targets programmed cell death-1 (PD-1) or programmed death ligand 1, which reported that dramatic improvements in survival rates were observed; however, the presence of controversy has prevented consensus from being reached. Study objectives were to develop a nomogram to identify several prognostic factors in Chinese patients with metastatic melanoma receiving immunotherapy.MethodsThis retrospective study included 231 patients from Sun Yat-sen University Cancer Center, and patients were split into internal cohort (n = 165) and external validation cohort (n = 66). We developed a nomogram for the prediction of response and prognosis on the basis of the levels of serum thyroid peroxidase antibody (A-TPO), free T3 (FT3), and LDH and M stage that were measured at the baseline of anti–PD-1 infusion. In addition, the follow-up lasted at least until 5 years after the treatment or mortality. RECIST v1.1 was used to classify treatment responses.ResultsChi-square test showed that PD-1 antibody was more effective in patients with melanoma with high level baseline FT4 or earlier M stage. A multivariate Cox analysis showed that baseline FT3 (P = 0.009), baseline A-TPO (P = 0.016), and LDH (P = 0.013) levels and M stage (P < 0.001) independently predicted overall survival (OS) in patients with melanoma. The above factors are integrated, and a prediction model is established, i.e., nomogram. Survival probability area-under-the-curve values of 1, 2, and 3 years in the training, internal validation, and external validation cohorts showed the prognostic accuracy and clinical applicability of nomogram (training: 0.714, 0.757, and 0.764; internal validation: 0.7171963, 0.756549, and 0.7651486; external validation: 0.748, 0.710, and 0.856). In addition, the OS of low-risk (total score ≤ 142.65) versus high-risk (total score > 142.65) patients varied significantly in both training group (P < 0.0001) and external validation cohort (P = 0.0012).ConclusionsAccording to this study, baseline biomarkers are associated with response to immunotherapy and prognosis among patients with metastatic melanoma. Treatment regimens can be tailor-made on the basis of these biomarkers.

IntroductionImmune checkpoint blockade inhibitor (ICI) therapy offers significant survival benefits for malignant melanoma. However, some patients were observed to be in disease progression after the first few treatment cycles. As such, it is urgent to find convenient and accessible indicators that assess whether patients can benefit from ICI therapy.MethodsIn the training cohort, flow cytometry was used to determine the absolute values of 66 immune cell subsets in the peripheral blood of melanoma patients (n=29) before treatment with anti-PD-1 inhibitors. The least absolute shrinkage and selection operator (LASSO) Cox regression model was followed for the efficacy of each subset in predicting progression-free survival. Then we validated the performance of the selected model in validation cohorts (n=20), and developed a nomogram for clinical use.ResultsA prognostic immune risk score composed of CD1c+ dendritic cells and three subsets of T cells (CD8+CD28+, CD3+TCRab+HLA-DR+, CD3+TCRgd+HLA-DR+) with a higher prognostic power than individual features (AUC = 0.825). Using this model, patients in the training cohort were divided into high- and low-risk groups with significant differences in mean progression-free survival (3.6 vs. 12.3 months), including disease control rate (41.2% vs. 91.7%), and objective response rate (17.6% vs. 41.6%). Integrating four-immune cell-subset based classifiers and three clinicopathologic risk factors can help to predict which patients might benefit from anti-PD-1 antibody inhibitors and remind potential non-responders to pursue effective treatment options in a timely way.ConclusionsThe prognostic immune risk score including the innate immune and adaptive immune cell populations could provide an accurate prediction efficacy in malignant melanoma patients with ICI therapy.

Survival is generally poor for Chinese patients with advanced melanoma because of high rates of acral and mucosal melanoma and limited therapeutic options. The first analysis of the phase 1b KEYNOTE-151 study showed second-line pembrolizumab was well tolerated and had clinically meaningful antitumor activity in Chinese patients with advanced melanoma. Three-year follow-up is presented. Eligible patients were of Chinese descent and had unresectable stage III/IV melanoma that progressed after first-line therapy. Patients received pembrolizumab 2 mg/kg every 3 weeks for ≤35 cycles. Primary end points were safety and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Response was assessed per RECIST v1.1 by blinded independent central review. Subgroup analyses were conducted by melanoma subtype and BRAF and PD-L1 status (acral melanoma only). 103 patients were enrolled; median follow-up duration (time from first dose to data cutoff [July 13, 2020]) was 44.6 months (IQR, 39.1–46.2). Any-grade treatment-related adverse events (TRAEs) occurred in 85.4% of patients, and grade 3/4 TRAEs in 12.6%. No grade 5 TRAEs occurred. Three patients discontinued pembrolizumab because of TRAEs (immune-mediated hepatitis, pneumonia, and arthritis). Immune-mediated AEs and infusion reactions occurred in 34.0% (grade 3/4, 2.9%). ORR was 17.6% (95% CI, 10.8–26.4; 1 complete response/17 partial responses), and median DOR was 13.8 months (range, 2.7–37.4+). Median PFS was 2.8 months (95% CI, 2.7–3.5) and 36-month PFS rate was 5.0%. Median OS was 13.2 months (95% CI, 10.4–16.5) and 36-month OS rate was 22.3%. Median OS for patients with known melanoma subtype was 14.8 months for acral, 13.5 months for nonacral cutaneous, and 7.4 months for mucosal melanoma. Among the acral subgroup, median OS was 22.8 months for PD-L1–positive disease, 8.4 months for PD-L1–negative disease, 18.5 months for BRAF wild-type disease, and 5.8 months for BRAF-mutant disease. Over 3 years’ follow-up, second-line pembrolizumab continued to show manageable safety, clinically meaningful antitumor activity, and durable responses in Chinese patients with advanced melanoma. Subgroup analysis suggested particular benefit in PD-L1–positive and BRAF wild-type acral melanoma, although small subgroup sizes preclude definitive conclusions.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT02821000.

Background Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments.Methods Blood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STINGflox/flox, TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture.Results Increased STING, CCL22 level, FOXP3+ cells but decreased CD8+ cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STINGflox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3+ cells but higher CD8+ cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-β) signals to promote CD4+CD25highFOXP3+ iTreg differentiation from both human and murine CD4+-naïve T cells from WT and IFNAR−/− mice but not TKO or IRF3−/− mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4+-naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-β. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-β, cyclic GMP-AMP synthase and 2’-3’-cGAMP, leading to iTreg expansion.Conclusions These findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.

Abstract p53 and NF-κBp65 are essential transcription factors (TFs) in the cellular response to stress. Two signaling systems can often be entwined together and generally produce opposing biological outcomes in a cell context-dependent manner. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) has the potential to inhibit both p53 and NF-κBp65, yet how such activities of iASPP are integrated with cancer remains unknown. Here, we utilized different cell models with diverse p53/NF-κBp65 activities. An iASPP(295–828) mutant, which is exclusively located in the nucleus and has been shown to be essential for its inhibitory effects on p53/NF-κBp65, was used to investigate the functional interaction between iASPP and the two TFs. The results showed that iASPP inhibits apoptosis under conditions when p53 is activated, while it can also elicit a proapoptotic effect when NF-κBp65 alone is activated. Furthermore, we demonstrated that iASPP inhibited the transcriptional activity of p53/NF-κBp65, but with a preference toward p53, thereby producing an antiapoptotic outcome when both TFs were simultaneously activated. This may be due to stronger binding between p53 and iASPP than NF-κBp65 and iASPP. Overall, these findings provide important insights into how the activities of p53 and NF-κBp65 are modulated by iASPP. Despite being a well-known oncogene, iASPP may have a proapoptotic role, which will guide the development of iASPP-targeted therapies to reach optimal outcomes in the future.

It is widely approved that emotions play a critical role in language education. This inspires EFL teachers to establish a classroom oriented toward students’ emotions and senses involved in the teaching/learning processes. Such an emotioncy-based pedagogy can bring about various positive outcomes in second/foreign language education. In tune with this, the present study briefly reviews the definitions, models, roots, and potentials of emotioncy in stopping student’ boredom and pessimism. Moreover, it makes some references to empirical inquiries in this line of research to strengthen its scientific basis. Finally, the study presents a number of implications for teachers, teacher educators, and researchers in language education urging them to focus on students’ emotions and senses more than before.

Abstract Background We have previously developed a unique metastasis‐associated signature consisting of six long non‐coding RNAs (lncRNAs), including a novel lncRNA, namely LINC02323. In the present study, we aimed to investigate the underlying roles of LINC02323 in the migration, invasion and TGF‐β‐induced epithelial‐mesenchymal transition (EMT) of lung adenocarcinoma (LUAD) cells. Methods The distribution of LINC02323 was detected by the nuclear‐plasma separation experiment. Cell proliferation was assessd by MTT assay, and cell migration and invation were detected by transwell assays. EMT was detected by RT‐qPCR and western blotting. Interaction between miRNA and LINC02323 was predicted by starBase v2.0 and confirmed by the double luciferase reporting system. Results LINC02323 was distributed in the cytoplasm and nucleus. The overexpression or deletion of LINC02323 did not affect the proliferation of LUAD cells, while significantly affected the migration and invasion of LUAD cells. TGF‐β‐induced EMT process was significantly affected by both RNA interference (RNAi) and overexpression of LINC02323. The predicted results showed that there were binding sites between LINC02323 and miR‐1343‐3p. The expression of LINC02323 was found to be negatively correlated with miR‐1343‐3p in LUAD by analyzing The Cancer Genome Atlas (TCGA) database. The double luciferase reporting system, RT‐qPCR and western blotting experiments confirmed that LINC02323 could bind to miR‐1343‐3p, which bound to TGF‐β receptor 1 (TGFBR1). Inhibition of miR‐1343‐3p reversed LINC02323 silencing‐mediated suppression of migration, invasion and EMT. Conclusions LINC02323 acts as a competing endogenous RNA (ceRNA), which sponged miR‐1343‐3p to upregulate the TGFBR1 expression and promote the EMT and metastasis in LUAD. Key points Significant findings of the study LINC02323 promotes epithelial‐mesenchymal transition and metastasis via sponging miR‐1343‐3p in lung adenocarcinoma. What this study adds LINC02323 is a key molecule in the process of invasion and metastasis of LUAD and might be used as a potential target in metastatic cancer.

Abstract Background The chemokine receptor CCR5 is one of the co-receptor of HIV-1 infection. People with homozygous CCR5Δ32 deletion resist HIV-1 infection, which makes the CCR5 an important target for HIV-1 gene therapy. Although the CRISPR/Cas9 has ever been used for HIV-1 study, the newly developed CRISPR/AsCpf1 has never been utilized in HIV-1 co-receptor disruption. The CRISPR/Cpf1 system shows many advantages over CRISPR/Cas9, such as lower off-target, small size of nuclease, easy sgRNA design for multiplex gene editing, etc. Therefore, the CRISPR/Cpf1 mediated gene editing will confer a more specific and safe strategy in HIV-1 co-receptor disruption. Results Here, we demonstrated that CRISPR/AsCpf1 could ablate the main co-receptor of HIV-1 infection-CCR5 efficiently with two screened sgRNAs via different delivery strategies (lentivirus, adenovirus). The edited cells resisted R5-tropic HIV-1 infection but not X4-tropic HIV-1 infection compared with the control group in different cell types of HIV-1 study (TZM.bl, SupT1-R5, Primary CD4+T cells). Meanwhile, the edited cells exhibited selective advantage over unedited cells while under the pressure of R5-tropic HIV-1. Furthermore, we clarified that the predicted off-target sites of selected sgRNAs were very limited, which is much less than regular using sgRNAs for CRISPR/Cas9, and no evident off-target was observed. We also showed that the disruption of CCR5 by CRISPR/AsCpf1 took no effects on cell proliferation and apoptosis. Conclusions Our study provides a basis for a possible application of CCR5-targeting gene editing by CRISPR/AsCpf1 with high specific sgRNAs against HIV-1 infection.

Abstract Background Local relapses and metastases are primary causes of death in lung cancer patients. In the present study, we aimed to develop a prognostic signature based on metastasis‐associated lncRNAs in patients with lung adenocarcinoma (LUAD). Methods Firstly, the potential metastasis‐associated lncRNAs were identified by analyzing high‐throughput data from The Cancer Genome Atlas (TCGA), and based on which, an lncRNA signature was constructed for prediction of relapse in LUAD patients using Cox proportional hazards regression analysis. Moreover, the prognostic performance of the lncRNA signature was evaluated using Kaplan‐Meier survival analysis, time‐dependent receiver operating characteristic (ROC) curve and Cox analysis, respectively. In addition, the potential metastasis‐associated function of these six lncRNAs was confirmed by lncRNA over‐expression or depletion and in vitro transwell assays in LUAD cells. Results An lncRNA signature consisting of six most important prognostic factors (LINC01819, ZNF649‐AS1, HNF4A‐AS1, FAM222A‐AS1, LINC02323 and LINC00672) was developed. The signature was an independent predictor for patients' relapse‐free survival (RFS), which could provide higher tumor relapse prediction capability compared with the TNM staging system at three years and five years, respectively (P = 0.0209 and P = 0.0468). Furthermore, the combination of this lncRNA signature and TNM stage had better prognostic value than TNM stage alone at three and five years, respectively (P = 0.0006 and P = 0.0096). Additionally, all the lncRNAs of the signature had a regulatory role in the LUAD cell mobility. Conclusions This novel six‐lncRNA signature had considerable prognostic value for prediction of relapse in LUAD patients. Key points Significant findings of the study The unique metastasis‐associated lncRNA signature was related to tumor metastasis and prognosis in LUAD patients. What this study adds This signature had considerable prognostic value for prediction of relapse in LUAD patients.

Abstract Background Acral and mucosal melanomas are rarely seen in Caucasians but common in China. There are limited data on the recurrence characteristics for these patients. This study aimed to identify the recurrence pattern for localized melanoma in China, especially acral and mucosal subtypes. Methods Patients with localized melanoma who underwent radical resection between January 1999 and December 2014 in southern China were retrospectively reviewed. Survival and annual recurrence hazard were analyzed by Kaplan–Meier method and hazard function, respectively. Results Totally, 1012 patients were included (acral melanoma 400; chronic sun-induced damage (CSD)/non-CSD melanoma 314; mucosal melanoma 298). Recurrence was recorded in 808 patients (localized 14.1%; regional 29.6%, and distant 56.3%). Mucosal melanoma had local and M1c stage recurrence more frequently than cutaneous melanoma, but less frequent regional node relapse. There was no difference in recurrent site distribution between acral and CSD/non-CSD melanoma. The annual recurrence hazard curve for the entire cohort showed a double-peaked pattern with the first major peak in the second year after surgery and the second peak near the seventh year. Mucosal melanoma had a higher recurrence risk than cutaneous melanoma. Acral melanoma had a lower flat recurrence peak than CSD/non-CSD melanoma. Tumor thickness > 4.0 mm, ulceration, positive regional nodes, and wound infection were associated with a higher recurrence risk in cutaneous melanoma. Adjuvant therapy reduced the recurrence risk of cutaneous melanoma but not of mucosal melanoma. Conclusions This is a large cohort about the rule of recurrence risk in acral and mucosal melanoma and will provide an initial framework for development of surveillance and adjuvant strategy for Chinese melanoma patients.

ObjectivesTo examine the long-term survival outcome of dabrafenib in combination with trametinib in Chinese patients with unresectable or metastatic acral/cutaneous melanoma with BRAF-V600 mutation and to explore potential predictors of effectiveness.MethodsThis was a long-term follow-up of Chinese patients with unresectable or metastatic BRAF V600-mutant acral/cutaneous melanoma administered dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) in an open-label, multicenter, single-arm, phase IIa study (NCT02083354). Efficacy endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The impacts of baseline characteristics on PFS and OS were analyzed.ResultsA total of sixty patients were included. The median age was 48 years, and 24 patients (40.0%) were male. Totally 12 individuals (20.0%) had acral melanoma, and 45 (75.0%) had failed previous systemic therapy. Up to July 2020, the median duration of follow-up was 37.0 (95% confidence interval [CI] 29.1-44.9) months. The updated ORR was 71.7% (95%CI 60.3%-83.1%). The 3-year OS rate was 28.8% (95%CI 19.1-43.6%) in the overall population, and 35.7% (95%CI 15.5–82.4%) in acral melanoma patients. The median DOR was 7.5 months (95%CI 4.5 to 10.5). Baseline normal lactic dehydrogenase (LDH), metastatic organ sites

Melanoma, the most threatening cancer in the skin, has been considered to be driven by the carcinogenic RAF-MEK1/2-ERK1/2 signaling pathway. This signaling pathway is usually mainly dysregulated by mutations in BRAF or RAS in skin melanomas. Although inhibitors targeting mutant BRAF, such as vemurafenib, have improved the clinical outcome of melanoma patients with BRAF mutations, the efficiency of vemurafenib is limited in many patients. Here, we show that blood bilirubin in patients with BRAF-mutant melanoma treated with vemurafenib is negatively correlated with clinical outcomes. In vitro and animal experiments show that bilirubin can abrogate vemurafenib-induced growth suppression of BRAF-mutant melanoma cells. Moreover, bilirubin can remarkably rescue vemurafenib-induced apoptosis. Mechanically, the activation of ERK-MNK1 axis is required for bilirubin-induced reversal effects post vemurafenib treatment. Our findings not only demonstrate that bilirubin is an unfavorable for patients with BRAF-mutant melanoma who received vemurafenib treatment, but also uncover the underlying mechanism by which bilirubin restrains the anticancer effect of vemurafenib on BRAF-mutant melanoma cells.

Abstract Background Hepatitis B virus (HBV) reactivation is a serious complication in patients with cancers and HBV infection undergoing immunosuppressant treatment or chemotherapy. However, the safety of anti-programmed cell death (PD) -1 and anti-programmed cell death-ligand 1 (PD-L1) therapy in these patients is unknown because they were excluded from clinical trials of immunotherapy. Methods This retrospective cohort study involved consecutive hepatitis B surface antigen (HBsAg) -positive cancer patients who were referred to Sun Yat-sen University Cancer Center and received an anti-PD-1/PD-L1 antibody between January 1, 2015 and July 31, 2018. The primary end point was the rate of the occurrence of HBV reactivation. Results In total, 114 eligible patients were included, among whom 90 (79%) were male, and the median (range) age was 46 (16–76) years. Six patients (5.3%) developed HBV reactivation, occurring at a median of 18 weeks (range, 3–35 weeks) from the commencement of immunotherapy. Among these patients, all of them had undetectable baseline HBV DNA; one had prophylactic antiviral therapy while five did not; four were positive for Hepatitis B e antigen while the other two were negative. At reactivation, the median HBV DNA level was 3.89 × 104 IU/mL (range, 1.80 × 103–6.00 × 107 IU/mL); five had HBV-related hepatitis and one exhibited increasing HBV DNA level without alanine transaminase elevation. No HBV-related fatal events occurred. The lack of antiviral prophylaxis was the only significant risk factor for HBV reactivation (odds ratio, 17.50 [95% CI, 1.95–157.07], P = .004). Conclusions HBV reactivation occurs in a subset of HBsAg-positive cancer patients undergoing anti-PD-1 or anti-PD-L1 immunotherapy. Regular monitoring of HBV DNA and antiviral prophylaxis are advised to prevent this potentially fatal complication.

Background: Pembrolizumab shows robust antitumor activity and favorable safety in metastatic melanoma. KEYNOTE-151 evaluated pembrolizumab in Chinese patients, who have more aggressive melanoma subtypes than other populations. Methods: Chinese patients aged ≥18 years with advanced melanoma previously treated with one line of therapy received pembrolizumab 2 mg/kg every 3 weeks for 35 cycles or until confirmed disease progression, intolerable toxicity, or study withdrawal. Primary end points were objective response rate (ORR) per RECIST v1.1 by blinded independent central review and safety. Key secondary end points included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 and overall survival (OS). Results: Median age was 52 years (N = 103); 37.9% had acral and 14.6% had mucosal melanoma. Median follow-up was 7.9 months at data cutoff (December 27, 2017). ORR was 16.7% (95% CI, 10.0–25.3%) (1 complete, 16 partial responses). Disease control rate was 38.2%. ORR was 15.8% for acral, 13.3% for mucosal melanoma. Median DOR was 8.4 months; 65.6% of patients had response duration ≥6 months. Median PFS was 2.8 months (95% CI, 2.7–3.5 months); 6-month rate was 20.4%. Median OS was 12.1 months (95% CI, 9.6 months–not reached); 6-month rate, 75.7%; 12-month rate, 50.6%. Treatment-related AEs (TRAEs) occurred in 87 (84.5%) patients; 9 (8.7%) experienced grade 3/4 TRAE and 2 (1.9%) discontinued because of TRAE; none died. Two deaths occurred that were unrelated to treatment. Conclusions: Pembrolizumab was well tolerated and provided clinically meaningful antitumor activity as second-line therapy in Chinese patients with advanced melanoma.

Abstract Background Melanoma is a rare, deadly disease without effective treatment options in China. Vemurafenib is a selective inhibitor of oncogenic BRAF V600 kinase approved in more than 90 countries, based on results obtained primarily in Caucasian patients. Limited data are available regarding the efficacy and safety of vemurafenib in Asian patients. Methods This phase I study investigated the pharmacokinetics, efficacy, and tolerability of vemurafenib (960 mg twice daily) in Chinese patients with BRAF V600 mutation–positive unresectable or metastatic melanoma. The study included two cohorts: a pharmacokinetic cohort (n = 20) and an expansion cohort (n = 26). Results After 21 days of dosing, vemurafenib demonstrated marked accumulation and relatively constant steady-state exposure over the dosing period. Confirmed best overall response rate was 52.2% (95% CI 37.0–67.1%). Median progression-free survival was 8.3 months (95% CI 5.7–10.9%); median overall survival was 13.5 months (95% CI 12.2%–not estimable). The most common adverse events were dermatitis acneiform, arthralgia, diarrhea, blood cholesterol level increase, blood bilirubin level increase, melanocytic nevus, and alopecia. A total of nine grade 3 or 4 adverse events were reported in seven patients (15.2%). Conclusion Overall, vemurafenib showed a favorable benefit-risk profile among Chinese patients. Pharmacokinetics, safety, and efficacy were generally consistent with those reported in Caucasian patients. Trial registration ClinicalTrials.gov identification: NCT01910181. Registered 29 July 2013, prospectively registered.

Anticancer immunotherapy has undergone a long evolving journey for decades, and has been dramatically applied to mainstream treatments in oncology in recent 5 years. This progress represents an advanced milestone following cytotoxic medicine and targeted therapy. Cellular immunity plays a pivotal role in the immune responses of hosts to tumor antigens. Such immunity is notably suppressed during neoplastic progression due to immuno-editing processes. Cellular immunity can also be selectively re-activated to combat malignancies while exploiting the advantages of contemporary scientific breakthroughs in molecular immunology and genetic engineering. The rapid advancement of cellular immunity-based therapeutic approaches has achieved high efficacy in certain cancer patients. Consequently, the landscape of oncologic medicine and pharmaceutical innovation has transformed recently. In this regard, we present a comprehensive update on clinically established anti-cancer treatments with cell immunity augmentation as the major mechanism of action.

High-speed underwater vehicles are subjected to complex multiphase turbulent processes, such as the growth, development, shedding, and collapse of cavitation bubbles. To study the cavity evolution and pressure pulsation characteristics, in this paper, cloud cavitation over a conical axisymmetric test body with four pressure sensors is investigated. A multi-field simultaneous measurement experiment method for the natural cavitation of underwater vehicles is proposed to understand the relationship between cavity evolution and instantaneous pressure. The results show that the evolution of cloud cavitation can be mainly divided into three stages: (I) the growth process of the attached cavity, (II) the shedding process of the attached cavity, and (III) the collapse of detached cavities. The evolution of the attached cavity and collapse of the large-scale shedding cavity will cause strong pressure pulsations. It is found that the cavitation number plays an important role in cavitation evolution and pressure pulsation. Interestingly, as the cavitation number decreases, the fluctuation intensity of cavitation increases significantly and gradually presents obvious periodicity. Moreover, the unstable cavitating flow patterns are highly correlated with the time domain and frequency domain characteristics of pressure. Especially, as the cavitation number decreases, the main frequency becomes lower and the pressure band becomes more concentrated.

In this study, construction of conductive and biocompatible three-dimensional nickel scaffolds (NiF) with electrodeposited chitosan (CS) for tissue engineering. The scaffolds were characterized by scanning electron microscopy (SEM), mechanical testing, water absorption, retention capacity and conductive sensitivity. Three-dimensional nickel scaffolds with electrodeposited chitosan (NiFC-n) exhibited uniformly filling structure on their surfaces and the inner structure and good mechanical property. When the versatile NiFC-n sensors were attached to different deformation, they could detect a variety of motion signals. MTT assay, Cells were stained with carboxyfluoresceinsuccinimidyl ester (CFSE) assay, apoptosis experiment and cell culture experiment results showed that NiFCn had good biocompatibility. The results indicated that the NiFC2 had a low immunogenicity, and can promote cell proliferation and support cell adhesion. This work provides a safe and feasible electrodeposition method to construct conductive and biocompatible three-dimensional nickel scaffolds with electrodeposited chitosan for tissue engineering. Therefore, NiFCn had potential application as biomaterials that may contact with real time measurement of rehabilitation for tissue engineering.

Cavitation involves complex multiphase turbulence and has important research significance. In this study, the Schnerr–Sauer cavitation model was used to model cavitation, and the detached-eddy simulation (DES) method was used to calculate the unsteady natural cavitating flow. The predicted results are in good agreement with experimentally measured cavity evolution and pressure values, demonstrating the effectiveness of this numerical method. Low temperature causes changes in the properties of water. The density of water at 0° is 999.84 kg/m3 and the density of water at 25° is 997.04. Cavitation evolution and shedding are analyzed at temperatures of 0 °C and 25 °C. The results showed that lower temperature increased the frequency of cavitation and enhanced pressure pulsation. At the same time, low temperature also increases the frequency of cavity shedding and shortens the cycle. In addition, based on the Ω method, the difference between vortex dynamics at various temperatures was studied, and it was found that different cavity stages showed different vortex structure characteristics, and lower temperature would aggravate the change of wake vortex structure. At the same time, the analysis of the turbulence characteristics in the downstream of the cavity shows that the lower temperature reduces the velocity pulsation and reduces the turbulence integral scale. At the end of the model, large-scale pulsations are transformed into small-scale pulsations.

The objective of this article is to investigate the flow structure of the ventilated cavitation around an under-water vehicle. In the experiments, a high-speed camera system is used to observe cavity evolution of the unsteady cavitation flow, the velocity field is measured by the particle image velocimetry technique, and dynamic pressure measurement systems are used to measure pressure fluctuations under different cavitation numbers. We seek to investigate the mechanism of the re-entrant flow and shock wave phenomenon during the cavity evolution. The study concludes that the ventilated cavity is insufficient to overcome the re-entrant jet intrusion and the re-entrant jet moves upstream straightly as well as curvilinearly. Then, the vortex structure rotating clockwise forms on the vehicle surface and the cavity area with low velocity represents the vortex. The re-entrant jet rolls back after the re-entrant jet reaches the front of the cavity. The experimental results also show that the pressure signals at different instants destabilize on the vehicle surface; fluctuant pressure peak is detected at the closure region of the cavity and pressure peak increases as the cavitation number is decreased. Surface pressure fluctuations travel on the vehicle surface from the collapse of cloud cavitation. The variation in shedding frequency for different cavitation numbers is discussed at the end of the article.

BACKGROUND:Accumulated evidences demonstrated that single nucleotide polymorphisms (SNPs) in mRNA 3'-untranslated region (3'-UTR) may impact microRNAs (miRNAs)-mediated expression regulation of oncogenes and tumor suppressors. There is a TNFAIP2 3'-UTR rs8126 T>C genetic variant which has been proved to be associated with head and neck cancer susceptibility. This SNP could disturb binding of miR-184 with TNFAIP2 mRNA and influence TNFAIP2 regulation. However, it is still unclear how this polymorphism is involved in development of esophageal squamous cell carcinoma (ESCC). Therefore, we hypothesized that the functional TNFAIP2 rs8126 SNP may affect TNFAIP2 expression and, thus, ESCC risk. METHODS:We investigated the association between the TNFAIP2 rs8126 variant and ESCC risk as well as the functional relevance on TNFAIP2 expression in vivo. Genotypes were determined in a case-control set consisted of 588 ESCC patients and 600 controls. The allele-specific regulation on TNFAIP2 expression by the rs8126 SNP was examined in normal and cancerous tissue specimens of esophagus. RESULTS:We found that individuals carrying the rs8126 CC or CT genotype had an OR of 1.89 (95%CI = 1.23-2.85, P = 0.003) or 1.38 (95%CI = 1.05-1.73, P = 0.017) for developing ESCC in Chinese compared with individual carrying the TT genotype. Carriers of the rs8126 CC and CT genotypes had significantly lower TNFAIP2 mRNA levels than those with the TT genotypes in normal esophagus tissues (P