Serum cytokines and creatinine/cystatin C ratio as prognostic biomarkers in advanced cancer patients treated with anti-PD-1/PD-L1 therapy.

OBJECTIVE: Immune checkpoint inhibitors (ICIs), specifically targeting the programmed cell death protein-1 or its ligand (PD-1/PD-L1), have been extensively used in the treatment of a spectrum of malignancies, although the predictive biomarkers remain to be elucidated. This study aims to investigate the association between baseline circulating levels of cytokines and the creatinine/cystatin C ratio (CCR) with the treatment outcomes of ICIs in patients with advanced cancer. METHODS: The pre-treatment circulating levels of 10 cytokines (PD-L1, CTLA4, CXCL10, LAG3, HGF, CCL2, MIG, GRANB, IL-18, and IL-6) were measured via automated capillary-based immunoassay platform in the serum of 65 advanced cancer patients treated with anti-PD-1/PD-L1-based systemic therapy and 10 healthy volunteers. The levels of cytokines and CCR were quantified and categorized into high and low groups based on the median value. The associations of serum cytokines and CCR with response to treatment, survival, and immune-related adverse events were assessed. RESULTS: Elevated circulating levels of 6 cytokines (PD-L1, CXCL10, HGF, CCL2, MIG, and IL-6) were observed in cancer patients compared with that in healthy volunteers. The correlation coefficients between cytokines, CCR and nutritional risk index were also calculated. In the cancer cohort (N = 65), low circulating HGF (P = 0.023, P = 0.029), low IL-6 (P = 0.002, P < 0.001), and high CCR (P = 0.031, P = 0.008) were associated with significantly improved progression-free survival (PFS) and overall survival (OS). Multi-variable COX analyses adjusted for clinicopathological factors revealed that low HGF, low IL-6, and high CCR were independent favorable prognostic factors for PFS (P = 0.028, P = 0.010, and P = 0.015, respectively) and OS (P = 0.043, P = 0.003, and P = 0.026, respectively). Grade 2 irAEs occurred more frequently in patients with low levels of circulating CCL2 and LAG3. CONCLUSIONS: Pre-treatment circulating levels of serum IL-6, HGF, and CCR may serve as independent predictive and prognostic biomarkers in advanced cancer patients treated with ICIs-based systemic therapy. These findings might help to identify potential patients who would benefit from these therapies.

Ginsenoside Rg3 decreases breast cancer stem-like phenotypes through impairing MYC mRNA stability.

Breast cancer stem cells (BCSCs) are responsible for breast cancer metastasis, recurrence and treatment resistance, all of which make BCSCs potential drivers of breast cancer aggression. Ginsenoside Rg3, a traditional Chinese herbal medicine, was reported to have multiple antitumor functions. Here, we revealed a novel effect of Rg3 on BCSCs. Rg3 inhibits breast cancer cell viability in a dose- and time-dependent manner. Importantly, Rg3 suppressed mammosphere formation, reduced the expression of stemness-related transcription factors, including c-Myc, Oct4, Sox2 and Lin28, and diminished ALDH(+) populations. Moreover, tumor-bearing mice treated with Rg3 exhibited robust delay of tumor growth and a decrease in tumor-initiating frequency. In addition, we found that Rg3 suppressed breast cancer stem-like properties mainly through inhibiting MYC expression. Mechanistically, Rg3 accelerated the degradation of MYC mRNA by enhancing the expression of the let-7 family, which was demonstrated to bind to the MYC 3' untranslated region (UTR). In conclusion, our findings reveal the remarkable suppressive effect of Rg3 on BCSCs, suggesting that Rg3 is a promising therapeutic treatment for breast cancer.

Intracranial complete remissions in an aumolertinib-treated EGFR mutation-positive non-small cell lung cancer (NSCLC) patient with symptomatic brain metastases and Eastern Cooperative Oncology Group performance status (ECOG PS) up to 4: a case report.

Background: Brain metastases happen in approximately 70% of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients. It negatively impacts the survival and quality of life, with the median survival time for untreated patients is just 2.9 months. Nevertheless, no extensive research data is available for symptomatic brain metastases because asymptomatic brain metastases patients are usually included in the clinical trials then. Case Description: Here, we report a 74-year-old male lung cancer patient with symptomatic brain metastases and performance status (PS) score of ~4. The patient was presented to our clinic on July 19 2020 with dizziness for one day, convulsions in the right lower limb for 2 hours, nausea, and severe vomiting. Further tissue and imaging analysis revealed EGFR-mutant stage IV (cT2N3M1) NSCLC with multiple brain metastases and cerebral edema. Initially, he was treated with bevacizumab on July 24th for one cycle, then with novel third-generation EGFR-tyrosine kinase inhibitor (TKI) aumolertinib at 110 mg daily from July 31st until disease control. Systemic partial remission (PR) and complete intracranial remission had been achieved in the lung and intracranial lesions. Notably, the PS score has detected as a level 4 at the time of diagnosis. After 2 weeks of aumolertinib administration, the patient showed significant improvement, and the PS score returned to 0. Interestingly, the patient significantly recovered from brain metastases and living a healthy daily life; nevertheless, he is currently receiving aumolertinib monotherapy for NSCLC and being follow-up for clinical updates. Conclusions: Our case presented a patient with EGFR-mutant NSCLC with symptomatic brain metastases. Aumolertinib proved to be a highly effective and well-tolerated treatment option for sustained disease control and comprehensive future studies are needed to confirm its efficacy in a larger population.

A Novel Punch Technique for Facial Pigmented Melanocytic Nevus.

The punch tool is a swift and practical instrument in the facial pigmented melanocytic nevus. However, few studies have evaluated the efficacy of the method for facial pigmented nevus. The aim of this study was to evaluate the practicability and effectiveness of removing facial pigmented nevus by punch biopsy technique. This was an observational study of patients with facial pigmented nevus in the Hospital of Plastic Surgery, Weifang Medical University. The ages of patients ranged from 15 to 36 years (average, 25 y). The outcome evaluations included Vancouver Scar Scale (VSS) score, esthetic appearance, and patient satisfaction. Following standard procedures, preoperative surgical excision was performed with safety margins. Anatomopathologic analysis of the surgical specimen was used as the gold standard to evaluate the accuracy of diagnosis by punch biopsy. From January 2019 to January 2020, this punch technique was carried out on 96 patients (151 pigmented nevus) with 35 melanocytic nevus on the forehead, 39 on the cheek, 21 on the eyelid, and 45 on the nose, whereas 11 were on nasolabial folds. The diameters of pigmented nevus are 0.5 to 10 mm on the face. All patients were evaluated at a follow-up visit ranging from 6 to 20 months (average, 11±1.5 mo) and healed with no complication. The histopathological examinations of the skin lesions showed benign outcomes. The mean Vancouver Scar Scale were 1.1±0.4. Ideal cosmetic and functional outcomes were achieved in 94 patients (97.9%). All patients achieved complete satisfaction except 2 patients with partial satisfaction. No recurrences and complications were recorded. This study demonstrated that the punch technique is an effective method to remove facial pigmented melanocytic nevus with acceptable functional and esthetic outcomes without relapse.

Infection with a human-derived enteroinvasive Escherichia coli strain altered intestinal barrier function in guinea pigs / La infección con una cepa enteroinvasiva de Escherichia coli de origen humano alteró la función de la barrera intestinal en cobayos

Background/aims: The aim was to characterize a bacterium causing intestinal mucosal barrier damage and to identify the possible invasion mechanism. Materials and methods: The intestinal permeability and tight junction protein levels were detected in guinea pigs infected with Escherichia coli D-09 via immunofluorescence analysis and western blotting. In order to explain this invasion mechanism at the gene level, whole genome sequencing analysis was performed on this bacterium. Results: The results showed an increased intestinal permeability and upregulated expression of the leaky protein claudin-2 in both the colon and liver of the infected animals. In addition, the draft genome of E. coli D-09 comprised 42 scaffolds (size, > 645 bp) with a total size of 4,679,567 bp. A total of 4379 protein coding genes were identified, which contained 45 antibiotic resistance and 86 virulence-related genes and covered 88.0% of the whole genome. Conclusions: This study verified that the human-derived enteroinvasive E. coli strain could destroy intestinal barrier function in guinea pigs. Additionally, our data first characterized the genome features of E. coli O124:K72 D-09, which may provide new insights into the possible invasion mechanism.(AU)

Norcantharidin overcomes vemurafenib resistance in melanoma by inhibiting pentose phosphate pathway and lipogenesis via downregulating the mTOR pathway.

Melanoma is the most aggressive type of skin cancer with a high incidence and low survival rate. More than half of melanomas present the activating BRAF mutations, along which V600E mutant represents 70%-90%. Vemurafenib (Vem) is an FDA-approved small-molecule kinase inhibitor that selectively targets activated BRAF V600E and inhibits its activity. However, the majority of patients treated with Vem develop acquired resistance. Hence, this study aims to explore a new treatment strategy to overcome the Vem resistance. Here, we found that a potential anticancer drug norcantharidin (NCTD) displayed a more significant proliferation inhibitory effect against Vem-resistant melanoma cells (A375R) than the parental melanoma cells (A375), which promised to be a therapeutic agent against BRAF V600E-mutated and acquired Vem-resistant melanoma. The metabolomics analysis showed that NCTD could, especially reverse the upregulation of pentose phosphate pathway and lipogenesis resulting from the Vem resistance. In addition, the transcriptomic analysis showed a dramatical downregulation in genes related to lipid metabolism and mammalian target of the rapamycin (mTOR) signaling pathway in A375R cells, but not in A375 cells, upon NCTD treatment. Moreover, NCTD upregulated butyrophilin (BTN) family genes, which played important roles in modulating T-cell response. Consistently, we found that Vem resistance led to an obvious elevation of the p-mTOR expression, which could be remarkably reduced by NCTD treatment. Taken together, NCTD may serve as a promising therapeutic option to resolve the problem of Vem resistance and to improve patient outcomes by combining with immunomodulatory therapy.

Infection with a human-derived enteroinvasive Escherichia coli strain altered intestinal barrier function in guinea pigs.

BACKGROUND/AIMS: The aim was to characterize a bacterium causing intestinal mucosal barrier damage and to identify the possible invasion mechanism. MATERIALS AND METHODS: The intestinal permeability and tight junction protein levels were detected in guinea pigs infected with Escherichia coli D-09 via immunofluorescence analysis and western blotting. In order to explain this invasion mechanism at the gene level, whole genome sequencing analysis was performed on this bacterium. RESULTS: The results showed an increased intestinal permeability and upregulated expression of the leaky protein claudin-2 in both the colon and liver of the infected animals. In addition, the draft genome of E. coli D-09 comprised 42 scaffolds (size, > 645 bp) with a total size of 4,679,567 bp. A total of 4379 protein coding genes were identified, which contained 45 antibiotic resistance and 86 virulence-related genes and covered 88.0% of the whole genome. CONCLUSIONS: This study verified that the human-derived enteroinvasive E. coli strain could destroy intestinal barrier function in guinea pigs. Additionally, our data first characterized the genome features of E. coli O124:K72 D-09, which may provide new insights into the possible invasion mechanism.

Age-Based Disparities in Metastatic Melanoma Patients Treated in the Immune Checkpoint Inhibitors (ICI) Versus Non-ICI Era: A Population-Based Study.

Immune checkpoint inhibitors (ICIs) have revolutionized metastatic melanoma treatment, but our knowledge of ICI activity across age groups is insufficient. Patients in different age groups with advanced melanoma were selected based on the ICI approval time in this study. Patients with melanoma were identified in the Surveillance, Epidemiology, and End Result (SEER) database program 2004-2016. The results showed that 4,040 patients had advanced melanoma before the advent of ICI (referred to as the "non-ICI era"), whereas there were 6,188 cases after ICI approval (referred to as the "ICI era"). In all age groups, the cases were dominated by men. The differences between the first (20-59 years) and second (60-74 years) age groups in both eras were significant in terms of surgery performance and holding of insurance policies (p = 0.05). The first and second groups (20-59 and 60-70 years old, respectively) showed no difference in survival (median = 8 months) during the non-ICI era, but the difference was evident in the first, second, and third age groups in the ICI era, with the younger group (20-59 years) having significantly better survival (median = 18, 14, and 10 months, respectively, p = 0.0001). Multivariate analysis of the first group (the youngest) in the ICI era revealed that surgery was significantly associated with an increase in survival among patients compared with those who did not undergo surgery (p < 0.0001). Furthermore, having an insurance policy among all age groups in the ICI era was associated with favorable survival in the first (20-59 years) and second (60-74 years) age groups (p = 0.0001), while there were no survival differences in the older ICI group (>74 years). Although there were differences in survival between the ICI era and the non-ICI era, these results demonstrate that ICI positively affected the survival of younger patients with advanced melanoma (first age group) than it had beneficial effects on older patients. Moreover, having had cancer surgery and holding an insurance policy were positive predictors for patient survival. This study emphasizes that adequate clinical and preclinical studies are important to enhance ICI outcomes across age groups.

Administration of a Probiotic Mixture Ameliorates Cisplatin-Induced Mucositis and Pica by Regulating 5-HT in Rats.

Probiotic-based therapies have been shown to be beneficial for chemotherapy-induced mucositis. Previous research has demonstrated that a probiotic mixture (Bifidobacterium brevis, Lactobacillus acidophilus, Lactobacillus casei, and Streptococcus thermophilus) can ameliorate chemotherapy-induced mucositis and dysbiosis in rats, but the underlying mechanism has not been completely elucidated. We aimed to determine the inhibitory effects of the probiotic mixture on cisplatin-induced mucositis and pica and the underlying mechanism, focusing on the levels of 5-hydroxytryptamine (5-HT, serotonin) regulated by the gut microbiota. A rat model of mucositis and pica was established by daily intraperitoneal injection of cisplatin (6 mg/kg) for 3 days. In the probiotic+cisplatin group, predaily intragastric injection of the probiotic mixture (1 × 109 CFU/kg BW) was administrated for 1 week before cisplatin injection. This was then followed by further daily probiotic injections for 6 days. Histopathology, pro-/anti-inflammatory cytokines, oxidative status, and 5-HT levels were assessed on days 3 and 6. The structure of the gut microbiota was analyzed by 16S rRNA gene sequencing and quantitative PCR. Additionally, 5-HT levels in enterochromaffin (EC) cells (RIN-14B cell line) treated with cisplatin and/or various probiotic bacteria were also determined. The probiotic mixture significantly attenuated kaolin consumption, inflammation, oxidative stress, and the increase in 5-HT concentrations in rats with cisplatin-induced intestinal mucositis and pica. Cisplatin markedly increased the relative abundances of Enterobacteriaceae_other, Blautia, Clostridiaceae_other, and members of Clostridium clusters IV and XIVa. These levels were significantly restored by the probiotic mixture. Importantly, most of the genera increased by cisplatin were significantly positively correlated with colonic 5-HT. Furthermore, in vitro, the probiotic mixture had direct inhibitory effects on the 5-HT secretion by EC cells. The probiotic mixture protects against cisplatin-induced intestine injury, exhibiting both anti-inflammatory and antiemetic properties. These results were closely related to the reestablishment of intestinal microbiota ecology and normalization of the dysbiosis-driven 5-HT overproduction.

PD-1/PDL-1 Inhibitors and Cardiotoxicity; Molecular, Etiological and Management Outlines.

Background: The US Food and Drug Administration (FDA) has approved several immunotherapeutic drugs for cancer since 2010, and many more are still being evaluated in other clinical studies. These inhibitors significantly increase response rates and result in the treatment of patients with advanced cancer. However, cancer immunotherapy leads to essential cardiac toxicity properties that have become distinct from other cancer patients' care and are mostly related to their etiology. Aim of review: As potential implications, the occurrence of cardiovascular adverse events is particularly challenging and needs a comprehensive understanding of overall cancer-related etiology, clinical outcomes with different variable severity, and management. Key scientific concepts of review: In terms of improving the overall survival of patients with cancer, clinicians should be careful in selecting either programmed cell death-1 (PD-1) or its programmed cell death ligand (PDL-1) inhibitors by evaluating their risk and clinical benefit for early intervention and decrease the level of morbidity and mortality of their patients. This review focuses on the effectiveness of PD-1/PL-1 antibodies and associated cardiotoxicity adverse events, including etiological mechanisms, diagnosis, and treatment.

Efficacy and safety of endostatin in combination with chemotherapy in small cell lung cancer: a phase 2 single-arm multicenter open-label trial.

BACKGROUND: Small-cell lung cancer (SCLC) is a type of lung cancer with high invasiveness and poor prognosis. Although SCLC is effective for initial treatment, the vast majority of patients will relapse, the efficacy of posterior line therapy is limited, and there is a lack of effective treatment. At the same time, in the past 30 years, there has been little progress in first-line treatment. With the progress of antiangiogenic therapy, whether it can be used in the treatment of SCLC is worth exploring. Therefore, a single-arm multicenter clinical study was conducted on the efficacy, optimization, and safety of endostatin combined chemotherapy in SCLC. METHODS: This study is a prospective non-blind single-arm multicenter study. From January 2016 to July 2019, a total of 22 patients with histologically diagnosed SCLC were enrolled in three centers. The treatment regimen was as follows: continuous intravenous pump infusion of endostatin (90 mg) for 72 hours, 3 days before chemotherapy, and continuous pump infusion of endostatin (120 mg) for 96 hours the next day following the infusion of chemotherapeutic drugs; the chemotherapy regimen was administered with standard platinum combined with etoposide once every 21 days. After six cycles, endostatin maintenance therapy was used until the disease progressed or intolerable adverse reactions occurred. The therapeutic effect was evaluated by imaging and oncology markers every two cycles, and the adverse reactions, tumor progression time, and patient survival time were recorded. RESULTS: Among the 21 patients analyzed, the median progression-free survival (PFS) was 8.0 months, the median overall survival (OS) was 13.6 months, the objective effective rate (ORR) was 61.9%, and the disease control rate (DCR) was 95.2%. All patients tolerated the treatment. The main adverse reactions were myelosuppression, albuminuria, nausea, and vomiting. The incidence of grade 3 or 4 adverse reactions was 7.2%, which could be relieved by symptomatic support treatment. There were no treatment-related deaths. CONCLUSIONS: Endostatin combined with platinum-etoposide is safe and effective in the treatment of SCLC.

Diversity-Oriented Synthesis of Aliphatic Fluorides via Reductive C(sp3 )-C(sp3 ) Cross-Coupling Fluoroalkylation.

Monofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel-catalyzed monofluoromethylation of unactivated alkyl halides using a low-cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross-coupling of two alkyl halides. Results with 1-bromo-1-fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp3 )-C(sp3 ) cross-coupling fluoroalkylation. These transformations demonstrate high efficiency, mild conditions, and excellent functional-group compatibility, especially for a range of pharmaceuticals and biologically active compounds. Mechanistic studies support a radical pathway. Kinetic studies reveal that the reaction is first-order dependent on catalyst and alkyl bromide whereas the generation of monofluoroalkyl radical is not involved in the rate-determining step. This strategy provides a general and efficient method for the synthesis of aliphatic fluorides.

Diverse Synthesis of Chiral Trifluoromethylated Alkanes via Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Fluoroalkylation.

The trifluoromethyl group represents one of the most functional and widely used fluoroalkyl groups in drug design and screening, while the drug candidates containing chiral trifluoromethyl-bearing carbons are still few due to the lack of efficient methods for the asymmetric introduction of trifluoromethyl group into organic molecules. Herein, we described a nickel-catalyzed asymmetric trifluoroalkylation of aryl iodides, for the first time, by utilizing reductive cross-coupling in enantioselective fluoroalkylation. This novel method has demonstrated high efficiency, mild conditions, and excellent functional group tolerance, especially for substrates containing diverse pharmaceutical and bioactive molecules moieties. This strategy provided an efficient and facile way for diversity-oriented synthesis of chiral trifluoromethylated alkanes.

Overall Survival in Heart Disease-Related Death in Non-Small Cell Lung Cancer Patients: Nonimmunotherapy Versus Immunotherapy Era: Population-Based Study.

The cardiotoxicity during immunotherapy administration leads to mortality by more than 42% and heart disease-related mortality among immunotherapy-linked cancers is still considered to be underestimated. In this study, the advanced stage of non-small cell lung cancer (NSCLC) with heart disease-related death was selected in accordance with immunotherapy approval time. NSCLC was searched on the Surveillance, Epidemiology, and End Results (SEER) program. Results show that 538 advanced NSCLC cases, those dominated by men and elderly people aged more than 70 years, had a high percentage of heart disease-related death in both eras. The difference between contemporary groups was fairly nonsignificant (P = > 0.05). The overall survival (OS) of all-cause mortality difference showed improved survival in the immunotherapy group (P = 0.0001). In the study of heart disease-related death survival with adjusted data, the NSCLC patients show significant lower survival in the immunotherapy era compared with the nonimmunotherapy era (P = 0.003; hazard ratio [HR] = 1.31; 95% CI = 1.099-1.57). In the multivariate analysis of NSCLC-related immunotherapy, histology revealed that the non-squamous cell type had an independent risk for lower OS than the squamous cell type (P = 0.04; HR= 0.74; CI = 0, 55- 0.99). The results demonstrate the survival benefits for NSCLC in immunotherapy; however, in heart disease-related death, immunotherapy in patients with NSCLC shows decreased OS. This study highlights that NSCLC patients should be highly monitored during immunotherapy administration, and further assessment is needed.

Intratumoral and peritumoral radiomics analysis for preoperative Lauren classification in gastric cancer.

BACKGROUND: Preoperative prediction of the Lauren classification in gastric cancer (GC) is very important to the choice of therapy, the evaluation of prognosis, and the improvement of quality of life. However, there is not yet radiomics analysis concerning the prediction of Lauren classification straightly. In this study, a radiomic nomogram was developed to preoperatively differentiate Lauren diffuse type from intestinal type in GC. METHODS: A total of 539 GC patients were enrolled in this study and later randomly allocated to two cohorts at a 7:3 ratio for training and validation. Two sets of radiomic features were derived from tumor regions and peritumor regions on venous phase computed tomography (CT) images, respectively. With the least absolute shrinkage and selection operator logistic regression, a combined radiomic signature was constructed. Also, a tumor-based model and a peripheral ring-based model were built for comparison. Afterwards, a radiomic nomogram integrating the combined radiomic signature and clinical characteristics was developed. All the models were evaluated regarding classification ability and clinical usefulness. RESULTS: The combined radiomic signature achieved an area under receiver operating characteristic curve (AUC) of 0.715 (95% confidence interval [CI], 0.663-0.767) in the training cohort and 0.714 (95% CI, 0.636-0.792) in the validation cohort. The radiomic nomogram incorporating the combined radiomic signature, age, CT T stage, and CT N stage outperformed the other models with a training AUC of 0.745 (95% CI, 0.696-0.795) and a validation AUC of 0.758 (95% CI, 0.685-0.831). The significantly improved sensitivity of radiomic nomogram (0.765 and 0.793) indicated better identification of diffuse type GC patients. Further, calibration curves and decision curves demonstrated its great model fitness and clinical usefulness. CONCLUSIONS: The radiomic nomogram involving the combined radiomic signature and clinical characteristics holds potential in differentiating Lauren diffuse type from intestinal type for reasonable clinical treatment strategy.

Importin 13 promotes NSCLC progression by mediating RFPL3 nuclear translocation and hTERT expression upregulation.

Our previous studies have reported that RFPL3 protein exerts its unique function as a transcriptional factor of hTERT promoter after being transported into the lung cancer cell nucleus. However, the detailed mechanism by which RFPL3 undergoes nuclear transport has not been reported yet. Here, we identified RFPL3 as a potential import cargo for IPO13, which was found to be overexpressed in NSCLC cells and tissues. IPO13 interacted with RFPL3 in lung cancer cells, and the knockdown of IPO13 led to the cytoplasmic accumulation of RFPL3, the decreased anchoring of RFPL3 at hTERT promoter, and the downregulation of hTERT expression. Moreover, IPO13 silencing suppressed tumor growth in vitro and in vivo. IHC analysis confirmed the positive correlation between the expression levels of IPO13 and hTERT in the tumor tissues from patients with lung cancer. Furthermore, the mechanistic study revealed that IPO13 recognized RFPL3 via a functional nuclear localization signal (NLS), which is located in the B30.2 domain at the C-terminal region of RFPL3. Of note, the presence of EGFR mutations was significantly related to the increased IPO13 expression. The EGFR-TKI Osimertinib downregulated IPO13 expression level in NSCLC cell lines with EGFR mutations, but not in EGFR wild-type ones. In summary, our data suggest that inhibition of IPO13 transport activity itself might be an alternative and potential therapeutic strategy for NSCLC.

LncRNA SLC7A11-AS1 Contributes to Lung Cancer Progression Through Facilitating TRAIP Expression by Inhibiting miR-4775.

PURPOSE: Long non-coding RNAs (lncRNAs) are important regulators of lung cancer. This article introduced a novel lncRNA, SLC7A11-AS1, whose effects on lung cancer development have been explored. METHODS: Lung cancer tissues and normal tissues of 47 patients were collected. Bronchial epithelial cell line (BEAS-2B) and lung cancer cell lines (H520, H596, A549 and H1299) were cultured. H1299 and A549 cells were transfected with siSLC7A11-AS1 or siNC. The proliferation, migration and invasion of H1299 and A549 cells were detected by CCK-8 assay and Transwell experiment. Caspase-3 activity in H1299 and A549 cells was researched using caspase-3 activity detection kit. Dual-luciferase reporter gene assay and RNA pull-down assay were performed to explore the relationship between SLC7A11-AS1 and miR-4775. SLC7A11-AS1, miR-4775 and TRAIP mRNA expressions in tissues/cells were detected by qRT-PCR. RESULTS: The up-regulated SLC7A11-AS1 in lung cancer patients was associated with metastasis and advanced tumor stage (P < 0.05). SLC7A11-AS1 was significantly up-regulated in lung cancer cells (P < 0.05). Silencing of SLC7A11-AS1 prominently inhibited H1299 and A549 cells proliferation, migration and invasion in vitro (P < 0.05). SLC7A11-AS1 acted as a sponge to inhibit miR-4775 expression in H1299 and A549 cells. Meanwhile, TRAIP expression in H1299 and A549 cells was directly and negatively regulated by miR-4775. Inhibition of miR-4775 or overexpression of TRAIP in H1299 and A549 cells remarkably reversed the reduced proliferation, migration and invasion induced by SLC7A11-AS1 silencing (P < 0.05). CONCLUSION: SLC7A11-AS1 promoted lung cancer development by enhancing TRAIP expression via suppressing miR-4775.

Role of fucosyltransferase IV in the migration and invasion of human melanoma cells.

Malignant melanoma is one of the most aggressive human tumor types, mainly due to its high invasion capability, metastatic properties, and the absence of effective treatments. Glycosylation serves a pivotal role in the migration and invasion of melanoma. However, differences in glycosylation between high and low metastatic melanoma cells and how these regulate migration and invasion by altering the expression of fucosyltransferases (FUTs) remain unclear. In the present study, matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS) analysis revealed that the composition profiling of fucosylated N-glycans differed between high metastatic C8161 and low metastatic A375P cells. Further analysis revealed that FUT4 expression was significantly increased in C8161 cells. Melanoma tissue arrays further demonstrated that FUT4 was overexpressed in metastatic samples. Altered FUT4 expression was accompanied by a change in the migration and invasion capacity of the cells. In addition, the migration and invasion potential of melanoma cells were decreased in C8161 and increased in A375P cells upon altering FUT4 expression levels by small interfering RNA or complementary DNA transfection. Furthermore, regulating FUT4 expression markedly modulated the activity of the phosphoinositide-3-kinase/Akt (PI3K/Akt) signaling pathway, which affected melanoma cell migration and invasion. In conclusion, FUT4 is a novel biomarker and regulator of the migration and invasion of melanoma cells and may serve as a therapeutic target for melanoma.