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Background Depression is a common, easily ignored, accompanied disease of gastric cancer (GC) patients and is often observed with elevated plasma catecholamine levels. Depression frequently promotes GC progression and leads to poor clinical outcomes; however, the molecular mechanisms underlying depression‐induced GC progression remain poorly understood. We aimed to study the effects of depression on GC progression and explore possible mechanisms mediating the action of depression‐associated catecholamines on GC. Methods Depression states of GC patients were graded using the Patient Health Questionnaire‐9, and plasma catecholamine levels were examined by high performance liquid chromatography coupled with tandem mass spectrometry. Migrative and invasive GC cells were examined using transwell assays, and metastatic GC niches were imaged using bioluminescence technology in a depression mouse model established with chronic unpredictable mild stress. Mouse depression‐like behaviors were assessed through sucrose preference, forced swimming, and tail suspension tests. Characteristics of the neuroendocrine phenotype were observed via RT‐PCR, Western blotting, flow cytometry, and transmission electron microscopy. Results Fifty‐one GC patients (age: 53.61 ± 1.79 years; cancer duration: 3.71 ± 0.33 months; depression duration: 2.37 ± 0.38 months; male‐to‐female ratio: 1.55:1) were enrolled in the study. Depression grade was significantly higher in GC patients showing higher plasma levels of catecholamines (epinephrine: P = 0.018; noradrenaline: P = 0.009), higher oncogene metastasis‐associated in colon cancer‐1 (MACC1) level (P = 0.018), and metastasis (P < 0.001). Further, depression‐associated catecholamine specifically bound to the beta‐2 adrenergic receptor (β2‐AR) and upregulated MACC1 expression, and thus promoting neuroendocrine phenotypic transformation through direct binding between MACC1 and synaptophysin. Eventually, the neuroendocrine phenotypic transformation accelerated GC invasion in vitro and metastasis in vivo. However, β2‐AR antagonist ICI‐118,551 or MACC1 silencing effectively blocked the catecholamine‐induced neuroendocrine phenotypic transformation and eliminated depression‐enhanced GC migration and invasion. Moreover, β2‐AR blocking or MACC1 silencing prevented GC metastasis attributed to a neuroendocrine phenotype in a depression mouse model. Conclusions Catecholamine‐induced neuroendocrine phenotypes of GC cells led to depression‐accelerated GC invasion and metastasis via the β2‐AR/MACC1 axis, while β2‐AR antagonist or MACC1 silencing could reverse it, showing promising potential therapeutic strategies for improving the outcome of GC patients with comorbid depression.

Chemotherapy is currently the main treatment for unresectable or advanced postoperative gastric cancers. However, its efficacy is negatively affected by the occurrence of chemoresistance, which severely affects patient prognosis. Recently, dysregulation in autophagy has been suggested as a potential mechanism for chemoresistence, and long noncoding RNA (lncRNA) also shows its regulatory role in cancer drug resistance. Using RNA sequencing, we found that lncRNA EIF3J-DT was highly expressed in drug-resistant gastric cancer cells. In-vitro and in-vivo experiments showed that EIF3J-DT activated autophagy and induced drug resistance in gastric cancer cells by targeting ATG14. Bioinformatics and experimental results showed that EIF3J-DT regulated the expression of ATG14 through direct binding to enhance stabilization of ATG14 mRNA and via blocking the degradation of ATG14 mRNA through competitively binding with microRNA (miRNA) MIR188-3p. Therefore, EIF3J-DT increased the expression of ATG14, contributing to activation of autophagy and chemoresistance. Furthermore, it was confirmed that EIF3J-DT and ATG14 were highly expressed in gastric cancer patients resistant to chemotherapy, and this was closely associated with patient prognosis. In conclusion, EIF3J-DT is involved in the regulation of autophagy and chemoresistance in gastric cancer cells by targeting ATG14. It may be a suitable new target for enhancing chemosensitivity and improving prognosis.Abbreviations: 3-MA: 3-methyladenine; 5-Fu: 5-fluorouracil; ATG: autophagy related; C-CASP3: cleaved caspase 3; C-CASP7: cleaved caspase 7; C-PARP: cleaved PARP; CQ: chloroquine; CR: complete response; DIG: digoxigenin; ESR1: estrogen receptor 1; FBS: fetal bovine serum; FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; ISH: in situ hybridization; lncRNA: long noncoding RNA; miRNA: microRNA; MUT: mutant; NC: negative control; OXA: oxaliplatin; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TEM: transmission electron microscopy; WT: wild type.

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of systemic autoinflammatory/autoimmune diseases, generally systemic juvenile idiopathic arthritis and adult-onset Still's disease. It is characterized by an excessive proliferation of macrophages and T lymphocytes. Recent research revealed that cytokine storm with elevated pro-inflammatory cytokines, including IFN-γ, IL-18, and IL-6, may be central to the pathogenesis of MAS. Though the mainstream of MAS treatment remains corticosteroids and cyclosporine, targeted therapies with anti-cytokine biologics are reported to be promising for controlling systemic inflammation in MAS.

The heterogeneity in prognoses and chemotherapeutic responses of colon cancer patients with similar clinical features emphasized the necessity for new biomarkers that help to improve the survival prediction and tailor therapies more rationally and precisely. In the present study, we established a stroma‐related lncRNA signature (SLS) based on 52 lncRNAs to comprehensively predict clinical outcome. The SLS model could not only distinguish patients with different recurrence and mortality risks through univariate analysis, but also served as an independent factor for relapse‐free and overall survival. Compared with the conventionally used TNM stage system, the SLS model clearly possessed higher predictive accuracy. Moreover, the SLS model also effectively screened chemotherapy‐responsive patients, as only patients in the low‐SLS group could benefit from adjuvant chemotherapy. The following cell infiltration and competing endogenous RNA (ceRNA) network functional analyses further confirmed the association between the SLS model and stromal activation‐related biological processes. Additionally, this study also identified three phenotypically distinct colon cancer subtypes that varied in clinical outcome and chemotherapy benefits. In conclusion, our SLS model may be a significant determinant of survival and chemotherapeutic decision‐making in colon cancer and may have a strong clinical transformation value.

Background: In recent decades, immune checkpoint inhibitors (ICIs) have become a conspicuous promising treatment. However, there are still some problems such as limited effective rate and undefined suitable patients. With increasing attention to the influence of baseline tumor burden on the therapeutic efficacy of ICIs, most researchers are currently of the view that patients with high-baseline tumor burden (HTB) have shorter overall survival and poor immunotherapy efficacy; nevertheless, recent studies have been limited to clinical phenomena without deep mechanistic exploration. Methods: RNA-seq and Single-cell RNA sequencing were used to reveal the difference of microenvironment between low-baseline tumor burden (LTB) and HTB tumor. Mice model construction, flow cytometry and cytokine antibody array were used to identify the phenomenon and mechanism of HTB effects on tumor immune microenvironment (TIME) and ICIs effcacy.Results: HTB caused a significantly higher infiltration with M2-type macrophages expressing a high level of programmed death-ligand 1 (PD-L1) to block the infiltration by CD8+ T cells and impaired the therapeutic effect of ICIs. HTB-derived IGFBP2 induced the macrophages’ polarization and PD-L1 expression via signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, these HTB–activated macrophages exerted a pro-tumor effect by inhibiting proliferation and cytotoxic function of CD8+ T cells in a PD-L1-dependent fashion. Disappointingly, total tumor burden did not affect the microenvironment or the immunotherapy efficacy of any single tumor. Moreover, macrophage inhibitor in HTB and palliative surgery were not able to increase the therapeutic efficacy in HTB. Only in the early stage of tumor with LTB, the macrophage inhibitor PLX3397 significantly improved the efficacy of ICIs on HTB. Conclusions: Our study has demonstrated that HTB induced the production of PD-L1+ M2-macrophages through the IGFBP2–STAT3 signaling pathway to generate the suppressive TIME, thereby reducing the efficacy of ICIs. These results further clarify the effects and illuminate a novel mechanism of HTB effects on ICI efficacy, and also provide functional evidence for an earlier use of macrophage inhibitors or combination treatment to reshape the tumor microenvironment.

415 Background: Clinical trials support the efficacy of immune checkpoint blockades (ICBs) plus chemotherapy in a subset of patients with metastatic gastric cancer (mGC). With the aim of identifying determinants of response, we developed a TMEscore assay (PCR assay with 30 genes) to assess tumor microenvironment, which was previously proved to be a robust predictive biomarker for patients treated with ICBs. Methods: Advanced GC patients treated with ICB combined with chemotherapy as first-line regimen were included in this multi-center prospective clinical trial (NCT#04850716). 65 tumor specimens obtained from 8 medical centers before treatment were applied to estimate TMEscore, PD-L1(CPS) and mismatch repair deficiency (MMR). Of 65 patients, 43 patients with treatment response and 34 patients with progression-free survival (PFS) were used to compare the predictiveness of biomarkers. Results: Theoverall response rate (ORR) and median PFS of this cohort were 39.9% and 4.67 months.Enhanced ORR was observed in TMEscore-high mGC patients (ORR = 61%), but only 16.7% in the low group. Regressive tumors (partial response, PR) had markedly higher TMEscore than stable and progressive tumors (stable disease, SD; progressive disease, PD, P = 0.001). By applying ROC curve analysis, the TMEscore was found to be an encouraging predictive biomarker that surpassed MMR and CPS statistically (AUC = 0.863, 0.525, and 0.519, respectively; Delong test, P = 0.003). Importantly, the Kaplan-Meier survival analysis demonstrated that a high TMEscore was significantly related to a more favorable PFS ( P = 0.0026, HR=0.18, 95%CI 0.06-0.55). Compared to TMEscoreA (immune score), TMEscoreB (stromal score) presented a dramatically higher hazard ratio for PFS (HR = 12.25, P = 0.0001), implicating stromal activation as a critical mechanism of intrinsic resistance to ICB plus chemotherapy. Meanwhile, PD-L1 (CPS) was not statistically associated with PFS, whether 1 or 5 were used as a cutoff to divide patients ( P = 1 and 0.22). Conclusions: This prospective clinical study indicated that the TMEscore assay is a robust biomarker for screening mGC patients who may derive survival benefit from ICB plus chemotherapy. Our data also suggest that TMEscore may be a more accurate predictive biomarker than MSI and CPS (PD-L1) for mGC patients, which warrants additional investigations in larger cohorts. Clinical trial information: NCT#04850716 .

Tyrosine kinase inhibitors (TKI) play a pivotal role in the treatment of non-small-cell lung cancer (NSCLC) with mutations in epidermal growth factor receptor (EGFR) and rearrangements in anaplastic lymphoma kinase (ALK). However, the influences of TKIs on the tumor immune microenvironment (TIM), especially dynamic changes of responders, have not yet been fully elucidated. Therefore, RNA sequencing and whole-exome sequencing were performed on EGFR/ALK-positive NSCLC samples before and after TKI treatment. In combination with neoantigen and mutational-load estimations, xCell and single-sample gene set enrichment analysis (ssGSEA) were used to assess tumor immune-cell infiltration and activity. Furthermore, weighted-gene correlation network analysis and the bottleneck method were used to identify the hub genes that affected treatment-related immune responses. We found that TKI treatment remodeled the TIM in treatment-responsive samples. Profound increases in the rate of anti-tumor cell infiltration and cytotoxicity was observed following TKI treatment, while antigen presentation was limited in ALK-rearranged samples. However, no significant change in anti-tumor cell infiltration or cytotoxicity was found between pre-treatment and post-progression samples. Subsequently, we found that neurofilament heavy (NEFH) mutations were enriched in samples after TKI treatment and were associated with reduced neutrophil infiltration. The cytotoxicity of EGFR-mutant NSCLCs with co-driver TP53 mutation and ALK-rearranged samples with wild-type TP53 seems to be more easily induced by TKI. Finally, the immune-associated score generated by hub genes was positively correlated with immune infiltration, immune activation, and a favorable prognosis. In conclusion, the dynamic changes in the TIM provide clues to drug selection and timing for TKI-immunotherapy combinations.

Adult-onset Still disease (AOSD) is a rare autoinflammatory condition. The presence of an evanescent, salmon-pink, nonpruritic rash is one of the major diagnostic criteria for the disease. The rash occurs with fever and subsides with defervescence. The presence of dyskeratotic keratinocytes in the upper one-third layer of the epidermis is a distinctive histopathological feature of persistent pruritic lesions associated with AOSD. Here, we report 2 cases of AOSD characterized by persistent pruritic lesions resembling those observed in dermatomyositis. Identifying the clinical and histopathological manifestation of the cutaneous lesions is essential for the early diagnosis of AOSD and for differentiating this condition from those presenting with dyskeratotic cells in the epidermis.

Chemotherapy is currently the main treatment for unresectable or advanced postoperative gastric cancers. However, its efficacy is negatively affected by the occurrence of chemoresistance, which severely affects patient prognosis. Recently, dysregulation in autophagy has been suggested as a potential mechanism for chemoresistence, and long noncoding RNA (lncRNA) also shows its regulatory role in cancer drug resistance. Using RNA sequencing, we found that lncRNA EIF3J-DT was highly expressed in drug-resistant gastric cancer cells. In-vitro and in-vivo experiments showed that EIF3J-DT activated autophagy and induced drug resistance in gastric cancer cells by targeting ATG14. Bioinformatics and experimental results showed that EIF3J-DT regulated the expression of ATG14 through direct binding to enhance stabilization of ATG14 mRNA and via blocking the degradation of ATG14 mRNA through competitively binding with microRNA (miRNA) MIR188-3p. Therefore, EIF3J-DT increased the expression of ATG14, contributing to activation of autophagy and chemoresistance. Furthermore, it was confirmed that EIF3J-DT and ATG14 were highly expressed in gastric cancer patients resistant to chemotherapy, and this was closely associated with patient prognosis. In conclusion, EIF3J-DT is involved in the regulation of autophagy and chemoresistance in gastric cancer cells by targeting ATG14. It may be a suitable new target for enhancing chemosensitivity and improving prognosis. Abbreviations: 3-MA: 3-methyladenine; 5-Fu: 5-fluorouracil; ATG: autophagy related; C-CASP3: cleaved caspase 3; C-CASP7: cleaved caspase 7; C-PARP: cleaved PARP; CQ: chloroquine; CR: complete response; DIG: digoxigenin; ESR1: estrogen receptor 1; FBS: fetal bovine serum; FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; ISH: in situ hybridization; lncRNA: long noncoding RNA; miRNA: microRNA; MUT: mutant; NC: negative control; OXA: oxaliplatin; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TEM: transmission electron microscopy; WT: wild type.

Gold nanoparticles (AuNPs) are a promising nanomaterial due to their drug-delivery properties and inherent anti-neoplastic activity. Here, we focused on the anti-neoplastic effects of an improved targeting polymer and folic acid-modified gold nanoparticles (AuNPP-FA) without therapeutic drugs. AuNPP-FA inhibited tumor proliferation both in vitro and in vivo, and tumor metastasis was controlled in vivo. We also found that, in addition to inhibiting tumor angiogenesis, AuNPP-FA normalized tumor vasculature by increasing pericyte coverage and strengthening tight junctions by upregulating VE-cadherin (VE-cad) levels on endothelial cells. This decreased vascular permeability, improved vascular perfusion, and alleviated tissue hypoxia. The immunotherapeutic response was enhanced due to the increased infiltration of CD3+CD8+ T lymphocytes. AuNPP-FA increased the expression and secretion of semaphorin 3A (SEMA3A) in cancer cells to further inhibit Smad2/3 signaling in human umbilical vein endothelial cells (HUVECs). This normalized tumor vasculature and inhibited metastasis. In conclusion, AuNPP-FA normalized tumor vasculature; therefore, AuNPP-FA has great potential for future clinical applications.

Background: Sweet syndrome is a neutrophilic dermatosis that could be associated with malignancy, especially hematologic malignancy. Few studies have systematically elaborated on this disorder and its features related with hematologic malignancy. Objective: This study aimed to describe the clinicopathological characteristics, treatment, and outcome of Sweet syndrome and to evaluate patient characteristics associated with hematologic malignancy. Methods: We retrospectively reviewed patients with Sweet syndrome at the Department of Dermatology, the First Affiliated Hospital of Zhejiang University from October 2010 to February 2019. Results: The study included 37 patients (16 men and 21 women), with a mean age of 53 years. Ten patients (27%) were classified as having malignancy-associated Sweet syndrome: nine with a hematologic malignancy including acute myeloid leukemia (4/9, 44%), myelodysplastic syndrome (4/9, 44%), and multiple myeloma (1/9, 11%) and one with a solid tumor diagnosed with liver carcinoma. The mean hemoglobin and platelet levels (P = 0.007 and P = 0.013, respectively), were significantly lower in patients with hematologic malignancy than in those with Sweet syndrome only. No significant difference in histopathology was found between patients with and without hematologic malignancy. Systemic corticosteroids were the most frequently used treatment (24/37, 65%). Higher mortality was found in patients with hematologic malignancy. Conclusion: It is important to assess Sweet syndrome patients who have laboratory evidence of lower hemoglobin and platelet levels for a hematologic malignancy.

Due to its invisibility, NIR (Near-infrared) flash has been widely used to capture the images of wild animals in the night. Although the animals can be captured without notice, the gray NIR images are short of color and texture information and thus is difficult to analyze, for both human and machine. In this paper, we propose to use CycleGAN (Generative Adversarial Networks) to translate NIR image to the incandescent domain for visual quality enhancement. Example translations show that both color and texture can be well recovered by the proposed CycleGAN model. The recognition performance of a SSD based detector on the translated incandescent images is also significantly better than that on the original NIR images. Taking Wildebeest and Zebra for example, an increase of \(16\%\) and \(8\%\) in recognition accuracy has been observed.

Background Early recognition and treatment for severe drug eruption are important in improving clinical outcomes. A few studies have reported laboratory parameters to evaluate the severity of drug eruptions. This study aimed to determine the association between serum ferritin and the severity of drug eruptions. Methods We retrospectively reviewed patients diagnosed with drug eruptions in our hospital from 2013 to 2018. Results We identified 85 patients (mean age 53.4 years), 20 in the severe cutaneous adverse drug reactions (SCADRs) group and 65 in the non‐SCADRs group. Serum ferritin level was higher in the SCADRs group compared with that in the CADRs group (P

Adult-onset Still's disease (AOSD) is a rare multisystem autoinflammatory disorder of unknown etiology. AOSD is generally characterized by high spiking fever, arthralgia or arthritis, skin rash, leukocytosis, and hyperferritinemia. Traditionally, AOSD has been treated with non-steroidal anti-inflammatory drugs, corticosteroids, and immunosuppressants. An increasing number of studies have shown that proinflammatory cytokines, such as interleukin-1β, -18, -6, and tumor necrosis factor-α, play key roles in AOSD and may serve as therapeutic targets. In the current review, we provided insights into the roles of these cytokines in the pathogenesis of AOSD and also provided a commentary on the clinical studies of biologic therapy against AOSD.

Drug-loaded nanoparticles from 'Ershiwuwei Shanhu' Pill (ESP) inducing cellular swelling of the SH-SY5Y neuroblastoma cells were investigated. Electron microscope was used to observe nanoparticles existing in the freeze-dried supernatant of 'Ershiwuwei Shanhu' Pill. Drug-free nanoparticles were obtained from the solution of drug-loaded nanoparticles via dialysis. The size and zeta potential of two kinds of nanoparticles were tested by granularmetric analysis and surface charge analysis. Results showed that nanoparticles could penetrate into cellular nucleus and caused cell swelling. CCK8 analysis implied that low concentration of drug-free nanoparticles from 'Ershiwuwei Shanhu' Pill can induce cell proliferation of the SH-SY5Y neuroblastoma cells, while drug-loaded nanoparticles can reduce cell viability through NF-κB pathway. Drug-loaded nanoparticles existed in 'Ershiwuwei Shanhu' pill might play a vital role during pharmacotherapy, which served as nanocarriers in delivering drugs into cells.

3568 Background: Identifying patterns of pathological tumor resistant to treatment regimens and improving tumor’s chemotherapy sensitivity from longitudinal and multi-omics data integration are of paramount importance in order to provide the best chances of cure, especially, for colorectal cancer liver metastases. Methods: We elucidated genomic (ctDNA and whole exome sequencing), immunomic (DNA-based T cell receptor sequencing) and transcriptomic changes from liver metastases, peripheral blood and match primary tumors that accompany the evolution of colorectal cancer liver metastases. In total, 197 histopathologically distinct areas of liver metastases and 72 peripheral blood samples at multiple time points from 15 patients with colorectal cancer were analysis in this study. Results: In responding patients, mutation load from plasma were reduced from baseline ( P < 0.001), but changed slightly in tumor tissues ( P = 0.351). Transcriptomic analysis and immunohistochemistry revealed that increased infiltration of neutrophils and monocytes were associated with worse outcomes and insensitive response to chemotherapy (Neutrophils: P = 0.003; Monocytes: P = 0.032). Activation of fatty acid metabolism, JAK-STAT, PPAR, insulin and TGF-β signaling pathway were observed in progressive tumor. TCR diversity in response metastatic regions was significantly increased compared with non-responder ( P = 0.008). Combination of bevacizumab with chemotherapy facilitated T cell infiltrating to the tumor microenvironment which might consequently benefit from checkpoint immunotherapy ( P = 0.006). Conclusions: Our integrative and comparative genomic analysis provides a new paradigm for understanding the evolution and treatment resistance of colorectal cancer liver metastases, with implications for identifying ways to advance treatment regimen and monitoring treatment response of colorectal cancer liver metastases.

e15026 Background: Colorectal cancer has been one of the most diagnosed cancers worldwide, and circulating tumor cells (CTCs), resulting in colorectal liver metastases (CLM), relate to its mortality. Although the mechanism and prognostication of metastasis has attracted a broad interest, the definite relationship between CLM and different phenotype of CTC is still not sufficient. Our objective is to investigate the clinical implication of different phenotype of CTCs. Methods: Twenty-one patients with CLM were enrolled in this study. Peripheral venous (PeV) and portal vein (PoV) blood specimens were collected from each patient. Through real-time ultrasound-guided percutaneous portal vein access, Pov blood was collected. Then CTC detection technology was employed to isolate CTCs for categorization. Results: No difference in the number of total CTCs between PoV and PeV, while strikingly, the number of epithelial CTCs was higher in PoV. In patients with unresected primary lesions, epithelial CTCs in PoV were more than that in PeV, while there was no difference in resected ones. Furthermore, we demonstrate that the percentage of epithelial CTCs in PoV relate to the number of liver metastatic nodules. In addition, the increased percentage of epithelial CTCs in the PoV relates to low amounts of lymphocytes. Conclusions: Our study shows that high proportion of epithelial CTCs in Pov relates to increasing number of liver metastatic nodules in CLM.

In this paper, we first provide a comprehensive investigation of four online job recommender systems (JRSs) from four different aspects: user profiling, recommendation strategies, recommendation output, and user feedback. In particular, we summarize the pros and cons of these online JRSs and highlight their differences. We then discuss the challenges in building high-quality JRSs. One main challenge lies on the design of recommendation strategies since different job applicants may have different characteristics. To address the aforementioned challenge, we develop an online JRS, iHR, which groups users into different clusters and employs different recommendation approaches for different user clusters. As a result, iHR has the capability of choosing the appropriate recommendation approaches according to users’ characteristics. Empirical results demonstrate the effectiveness of the proposed system.

In this paper, we propose a dynamic user profile-based job recommender system. To address the challenge that the job applicants do not update the user profile in a timely manner, we update and extend the user profile dynamically based on the historical applied jobs and behaviors of job applicants. In particular, the statistical results of basic features in the applied jobs are used to update the job applicants'. In addition, feature selection is employed in the text information of jobs that applied by the job applicant for extending the feature. Then a hybrid recommendation algorithm is employed according to the characteristics of user profiles for achieving the dynamic recommendation.