Peripheral Polyfunctional PD1+ CD8+ T cells demonstrated strong immune protection in non-small cell lung cancer.

Higher frequencies of polyfunctional PD1+ CD8+ T cells exhibited a stronger capacity to kill tumor cells in vitro and in vivo experiments. These results suggested that peripheral polyfunctional PD1+ CD8+ T cells demonstrated strong immune protection. This study also provided a potential combined treatment strategy with anti-PD1 and CAR-T therapy.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

The dual role of complement in cancers, from destroying tumors to promoting tumor development.

Complement is an important branch of innate immunity; however, its biological significance goes far beyond the scope of simple nonspecific defense and involves a variety of physiological functions, including the adaptive immune response. In this review, to unravel the complex relationship between complement and tumors, we reviewed the high diversity of complement components in cancer and the heterogeneity of their production and activation pathways. In the tumor microenvironment, complement plays a dual regulatory role in the occurrence and development of tumors, affecting the outcomes of the immune response. We explored the differential expression levels of various complement components in human cancers via the Oncomine database. The gene expression profiling interactive analysis (GEPIA) tool and Kaplan-Meier plotter (K-M plotter) confirmed the correlation between differentially expressed complement genes and tumor prognosis. The tumor immune estimation resource (TIMER) database was used to statistically analyze the effect of complement on tumor immune infiltration. Finally, with a view to the role of complement in regulating T cell metabolism, complement could be a potential target for immunotherapies. Targeting complement to regulate the antitumor immune response seems to have potential for future treatment strategies. However, there are still many complex problems, such as who will benefit from this therapy and how to select the right therapeutic target and determine the appropriate drug concentration. The solutions to these problems depend on a deeper understanding of complement generation, activation, and regulatory and control mechanisms.

Nuclear Her2 contributes to paclitaxel resistance in breast cancer cells.

Translocation of full-length Her2 receptor into nucleus was reported by some studies. Here, we tested whether nuclear Her2 contributes to paclitaxel resistance in Her2-overexpressing breast cancer cells. Breast cancer cell was transfected with plasmids containing cDNA of wild-type Her2 or mutant-type Her2 lacking the nuclear localization signal (NLS) sequence which is required for Her2 nuclear transport. Cell resistance to paclitaxel was analyzed. Paclitaxel-resistant breast cancer cell was also developed and nuclear Her2 expression was tested. Then, correlation between nuclear Her2 and resistance to paclitaxel were analyzed. Expression of importin ß1 was decreased to downregulate nuclear Her2 level and cell resistance to paclitaxel was tested. We found that Her2 overexpression increases Her2 nuclear expression and cells resistance to paclitaxel in MCF-7 cells. In the paclitaxel resistant cell (SK-BR-3/R), nuclear Her2 expression is upregulated compared with parental SK-BR-3 cells. Increased expression of nuclear Her2 after short-time (48 h) treatment of paclitaxel was also observed in SK-BR-3 cells. Further downregulation of Her2 nuclear expression through blocking expression of importin ß1 sensitizes the cells to paclitaxel. The analysis showed that the Her2 nuclear expression increases the survivin expression which leads to resistance to paclitaxel. Her2 nuclear expression decreases paclitaxel-induced apoptosis. However, co-immunoprecipitation was applied, and the physical interaction of nuclear Her2 and survivin was not detected. We show for the first time that nuclear Her2 contributes to paclitaxel resistance in breast cancer cells which suggests that nuclear Her2 as a potential target to sensitize breast cancers to paclitaxel treatment.

WASF3 expression correlates with poor prognosis in gastric cancer patients.

Aim: WASF3 has been shown to be required for invasion and metastasis in different cancers, this study is to explore the prognostic value of WASF3 in gastric cancer. Materials & methods: The coexpression of WASF3 and E-cadherin in gastric cancer patients and cells were evaluated. Results: WASF3 was overexpressed and the expression of E-cadherin was decreased in gastric cancer tissues compared with normal tissues (p < 0.001). WASF3 expression is associated with decreased expression of E-cadherin (p = 0.002). Patients with WASF3-positive expression had a poorer prognosis. The multivariate analysis showed that WASF3 expression is an independent prognostic factor related to overall survival (p = 0.027). Conclusion: Our analysis demonstrates that WASF3 expression correlates with poor outcomes and is a potential prognostic factor in gastric cancer patients.

Roles for VEGF-C/NRP-2 axis in regulating renal tubular epithelial cell survival and autophagy during serum deprivation.

Vascular endothelial growth factor C (VEGF-C) is an angiogenic and lymphangiogenic growth factor. Recent research has revealed the role for VEGF-C in regulating autophagy by interacting with a nontyrosine kinase receptor, neuropilin-2 (NRP-2). However, whether VEGF-C participates in regulating cell survival and autophagy in renal proximal tubular cells is unknown. To address this question, we employed a cell modal of serum deprivation to verify the role of VEGF-C and its receptor NRP-2 in regulating cell survival and autophagy in NRK52E cell lines. The results show that VEGF-C rescued the loss of cell viability induced by serum deprivation in a concentration-dependent manner. Furthermore, endogenous VEGF-C was knocked down in NRK52E cells by using specific small-interfering RNAs (siRNA), cells were more sensitive to serum deprivation-induced cell death. A similar increase in cell death rate was observed following NRP-2 depletion in serum-starved NRK52E cells. Autophagy activity in serum-starved NRK52E cells was confirmed by western blot analysis of microtubule-associated protein-1 chain 3 (LC3), immunofluorescence staining of endogenous LC3, and the formation of autophagosomes by electron microscopy. VEGF-C or NRP-2 depletion further increased LC3 expression induced by serum deprivation, suggesting that VEGF-C and NRP-2 were involved in controlling autophagy in NRK52E cells. We further performed autophagic flux experiments to identify that VEGF-C promotes the activation of autophagy in serum-starved NRK52E cells. Together, these results suggest for the first time that VEGF-C/NRP-2 axis promotes survival and autophagy in NRK52E cells under serum deprivation condition. SIGNIFICANCE OF THE STUDY: More researchers had focused on the regulation of autophagy in kidney disease. The effect of VEGF-C on cell death and autophagy in renal epithelial cells has not been examined. We first identified the VEGF-C as a regulator of cell survival and autophagy in NRK52E cell lines. And VEGF-C/NRP-2 may mediate autophagy by regulating the phosphorylation of 4EBP1 and P70S6K. VEGF-C treatment may be identified as a therapeutic target in renal injury repair due to its capacity to promote tubular cell survival in the future.

ß-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10.

Recent studies have demonstrated that ß-catenin in DCs serves as a key mediator in promoting both CD4(+) and CD8(+) T-cell tolerance, although how ß-catenin exerts its functions remains incompletely understood. Here we report that activation of ß-catenin in DCs inhibits cross-priming of CD8(+) T cells by up-regulating mTOR-dependent IL-10, suggesting blocking ß-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8(+) T-cell immunity. However, vaccination of DC-ß-catenin(-/-) (CD11c-specific deletion of ß-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC-ß-catenin(-/-) mice were deficient in generating CD8(+) T-cell immunity despite normal clonal expansion, likely due to impaired IL-10 production by ß-catenin(-/-) DCs. Deletion of ß-catenin in DCs or blocking IL-10 after clonal expansion similarly led to reduced CD8(+) T cells, suggesting that ß-catenin in DCs plays a positive role in CD8(+) T-cell maintenance postclonal expansion through IL-10. Thus, our study has not only identified mTOR/IL-10 as a previously unidentified mechanism for ß-catenin-dependent inhibition of cross-priming, but also uncovered an unexpected positive role that ß-catenin plays in maintenance of CD8(+) T cells. Despite ß-catenin's opposite functions in regulating CD8(+) T-cell responses, selectively blocking ß-catenin with a pharmacological inhibitor during priming phase augmented DC vaccine-induced CD8(+) T-cell immunity and improved antitumor efficacy, suggesting manipulating ß-catenin signaling as a feasible therapeutic strategy to improve DC vaccine efficacy.

Mediator subunit 23 overexpression as a novel target for suppressing proliferation and tumorigenesis in hepatocellular carcinoma.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world. However, the molecular mechanisms involved in HCC are still poorly understood. Here, we study the role of mediator subunit 23 (MED23), a component of the Mediator complex, in hepatocarcinogenesis. METHODS: We detected MED23 expression in HCC samples by real-time polymerase chain reaction (PCR) and immunohistochemistry analysis. We also knocked down and overexpressed MED23 to explore its functional role in hepatoma cell growth. The cell cycle was examined by flow cytometry analysis, and protein expression was examined by Western blot. A xenograft mouse model was used to determine whether MED23 is involved in tumorigenesis. RESULTS: MED23 was frequently upregulated in human HCC tissues compared with paired adjacent non-tumorous liver tissues. The hepatoma cells also showed increased MED23 expression. MED23 knockdown inhibited hepatoma cell growth, whereas overexpression of MED23 promoted cell growth. Knockdown of MED23 induced a G1 to S phase arrest. Moreover, MED23 regulated the expression of p16(INK) (4a) (p16) and the phosphorylation of retinoblastoma protein (Rb). p16 was transcriptionally upregulated, and its promoter was demethylated. The G1 to S phase arrest induced by MED23 knockdown was aborted after p16 was silenced. Furthermore, MED23 knockdown suppressed tumorigenesis and regulated p16/Rb signaling in vivo. CONCLUSIONS: Taken together, our study suggests that MED23 plays an important role in hepatocarcinogenesis, and it may be a novel target for HCC therapy.

Genetic polymorphisms of interleukin-1 beta and osteosarcoma risk.

PURPOSE: Osteosarcoma is the most common childhood bone cancer. Interleukin-1 beta (IL-1B) is crucially involved in osteosarcoma carcinogenesis. Whether genetic polymorphisms of IL-1B also influence osteosarcoma risk is unknown. The aim of this study was to investigate the association between IL-1B gene polymorphisms and osteosarcoma risk in Chinese Han patients. METHODS: A hospital-based case-control study involving 120 osteosarcoma patients and 120 controls was conducted. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect three IL-1B gene polymorphisms (-31 T/C, -511 C/T and +3954 C/T) in these patients. RESULTS: Patients with osteosarcoma had a significantly lower frequency of -31 CC genotype [odds ratio (OR) = 0.40, 95% confidence interval (CI) = 0.17-0.92; P = 0.03] and -31 C allele (OR = 0.67, 95% CI = 0.46-0.99; P = 0.04) than controls. Patients with osteosarcoma had a significantly lower frequency of -511 TT genotype (OR = 0.40, 95% CI = 0.17-0.95; P = 0.04) than controls. The +3954 C/T gene polymorphisms were not associated with a risk of osteosarcoma. When stratified by Enneking stage, tumour location, histological type, tumour metastasis of osteosarcoma and family history of cancer, no statistically significant results were found. CONCLUSIONS: This is the first study to provide evidence for an association of IL-1B gene polymorphisms with osteosarcoma risk.

Suicide among lymphoma patients.

BACKGROUND: Higher suicide rates were observed in patients diagnosed with lymphoma. In this study, we accurately identified patients with high-risk lymphoma for suicide by constructing a nomogram with a view to effective interventions and reducing the risk of suicide. METHODS: 235,806 patients diagnosed with lymphoma between 2000 and 2020 were picked from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training (N = 165,064) and validation set (N = 70,742). A combination of the Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression identified the predictors that constructed the nomogram. To assess the discrimination, calibration, clinical applicability, and generalization of this nomogram, we implemented receiver operating characteristic curves (ROC), calibration curves, decision curve analysis (DCA), and internal validation. The robustness of the results was assessed by the competing risks regression model. RESULTS: Age at diagnosis, gender, ethnicity, marital status, stage, surgery, radiotherapy, and annual household income were key predictors of suicide in lymphoma patients. A nomogram was created to visualize the risk of suicide after a lymphoma diagnosis. The c-index for the training set was 0.773, and the validation set was 0.777. The calibration curve for the nomogram fitted well with the diagonal and the clinical decision curve indicated its clinical benefit. LIMITATION: The effects of unmeasured and unnoticed biases and confounders were difficult to eliminate due to retrospective studies. CONCLUSION: A convenient and reliable model has been constructed that will help to individualize and accurately quantify the risk of suicide in patients diagnosed with lymphoma.

Black rice diet alleviates colorectal cancer development through modulating tryptophan metabolism and activating AHR pathway.

Consumption of dietary fiber and anthocyanin has been linked to a lower incidence of colorectal cancer (CRC). This study scrutinizes the potential antitumorigenic attributes of a black rice diet (BRD), abundantly rich in dietary fiber and anthocyanin. Our results demonstrate notable antitumorigenic effects in mice on BRD, indicated by a reduction in both the size and number of intestinal tumors and a consequent extension in life span, compared to control diet-fed counterparts. Furthermore, fecal transplants from BRD-fed mice to germ-free mice led to a decrease in colonic cell proliferation, coupled with maintained integrity of the intestinal barrier. The BRD was associated with significant shifts in gut microbiota composition, specifically an augmentation in probiotic strains Bacteroides uniformis and Lactobacillus. Noteworthy changes in gut metabolites were also documented, including the upregulation of indole-3-lactic acid and indole. These metabolites have been identified to stimulate the intestinal aryl hydrocarbon receptor pathway, inhibiting CRC cell proliferation and colorectal tumorigenesis. In summary, these findings propose that a BRD may modulate the progression of intestinal tumors by fostering protective gut microbiota and metabolite profiles. The study accentuates the potential health advantages of whole-grain foods, emphasizing the potential utility of black rice in promoting health.

First-line serplulimab in metastatic colorectal cancer: Phase 2 results of a randomized, double-blind, phase 2/3 trial.

BACKGROUND: Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear. METHODS: This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety. FINDINGS: Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively. CONCLUSIONS: Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC. FUNDING: This work was funded by Shanghai Henlius Biotech, Inc.

Manganese Dioxide/Gold-based Active Tumor Targeting Nanoprobes for Enhancing Photodynamic and Low-Temperature-Photothermal Combination Therapy in Lung Cancer.

Tumor drug resistance caused by the tumor microenvironment is an extremely difficult problem for researchers to solve. Nanoplatforms that integrate diagnosis and treatment have great advantages in tumor treatment, but the design and synthesis of simple and efficient nanoplatforms still face tremendous challenges. In this study, a novel Mn/Au@ir820/GA-CD133 nanoprobe was developed. The manganese dioxide/gold particles were prepared by coprecipitation/assembly, chemically coupled with CD133 antibody, and finally loaded with the photosensitive drug IR820 and the heat shock protein inhibitor Ganetespib. The nanoprobe demonstrated good tumor-targeting ability, increased the level of singlet oxygen produced from laser irradiation by effectively alleviating tumor hypoxia, and decreased the threshold of heat tolerance by downregulating the expression of HSP90 in tumor tissues. This nanoprobe successfully inhibited the growth and progression of tumor tissues in a tumor-bearing mouse model by improving the effectiveness of photodynamic and low-temperature photothermal combination therapy.

Male-Biased Gut Microbiome and Metabolites Aggravate Colorectal Cancer Development.

Men demonstrate higher incidence and mortality rates of colorectal cancer (CRC) than women. This study aims to explain the potential causes of such sexual dimorphism in CRC from the perspective of sex-biased gut microbiota and metabolites. The results show that sexual dimorphism in colorectal tumorigenesis is observed in both ApcMin/ + mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice with male mice have significantly larger and more tumors, accompanied by more impaired gut barrier function. Moreover, pseudo-germ mice receiving fecal samples from male mice or patients show more severe intestinal barrier damage and higher level of inflammation. A significant change in gut microbiota composition is found with increased pathogenic bacteria Akkermansia muciniphila and deplets probiotic Parabacteroides goldsteinii in both male mice and pseudo-germ mice receiving fecal sample from male mice. Sex-biased gut metabolites in pseudo-germ mice receiving fecal sample from CRC patients or CRC mice contribute to sex dimorphism in CRC tumorigenesis through glycerophospholipids metabolism pathway. Sexual dimorphism in tumorigenesis of CRC mouse models. In conclusion, the sex-biased gut microbiome and metabolites contribute to sexual dimorphism in CRC. Modulating sex-biased gut microbiota and metabolites could be a potential sex-targeting therapeutic strategy of CRC.

Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study.

We report a multicenter, phase 2 study evaluating the efficacy of pucotenlimab, an anti-PD-1 antibody, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, and potential biomarkers for response. Overall, 100 patients with previously treated, advanced solid tumors centrally confirmed as dMMR or MSI-H received pucotenlimab at 200 mg every 3 weeks. The most common cancer type is colorectal cancer (n = 71). With a median follow-up of 22.5 months, the objective response rate is 49.0% (95% confidence interval 38.86%-59.20%) as assessed by the independent review committee, while the median progression-free survival and overall survival have not been reached. Grade ≥3 treatment-related adverse events were observed in 18 patients. For the biomarker analysis, responders are enriched in patients with mutations in the KMT2D gene. Pucotenlimab is an effective treatment option for previously treated advanced dMMR/MSI-H solid tumors, and the predictive value of KMT2D mutation warrants further research. This study is registered with ClinicalTrials.gov: NCT03704246.

Overexpression of HMGB3 and its prognostic value in breast cancer.

Background: High mobility group protein B3 (HMGB3) is abundantly expressed in a number of malignancies, contributing to tumor cell growth and predicting poor outcomes. More research on the connection between HMGB3 and breast cancer is needed. The prognostic significance of HMGB3 in breast cancer was examined and validated in this study. Methods: Using The Cancer Genome Atlas (TCGA) database RNA sequencing and clinical data, we investigated the associations between HMGB3 expression and tumor mutations, prognosis, and immune infiltration in breast cancer. The Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), breast cancer gene-expression miner (bc-GenExMiner), UALCAN, OncoLnc, cBio Cancer Genomics Portal (cBioPortal), and LinkedOmics databases were applied to examine the levels of expression, mutation, coexpression, and immune correlation of HMGB3 in breast cancer. cBioPortal and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) were used for coexpression and enrichment analyses, respectively. Experimental tests and a separate cohort of breast cancer patients in our center were used for validation. To determine independent risk factors affecting breast carcinoma prognosis, multivariate Cox regression analysis was performed. The Kaplan-Meier method was applied to analyze the connection between HMGB3 expression and overall survival time in breast cancer. Results: Pan-cancer investigation using the GEPIA and UALCAN databases revealed a high level of HMGB3 expression in different malignancies, including breast cancer. HMGB3 might be a potential diagnostic biomarker, according to the receiver operating characteristic (ROC) curve (AUC=0.932). And immunohistochemistry confirmed higher HMGB3 protein expression in breast cancer tissues in clinical samples. Experimental tests also showed that breast cancer cells have higher expression of HMGB3, and knockdown of HMGB3 can promote the proliferation of breast cancer cells and increase sensitivity to chemotherapy. Human epidermal growth factor receptor 2 (HER2), Nottingham Prognostic Index (NPI), basal-like status, nodal status (N+), triple-negative status, and Scarff-Bloom-Richardson (SBR) grade all showed positive correlations with HMGB3 expression. Conversely, HMGB3 expression was negatively associated with the expression of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer. Breast cancer patients with high HMGB3 expression had poor overall survival, which was validated by an analysis of a separate cohort of breast cancer patients in our center. Cox regression analysis identified high HMGB3 expression as an independently associated risk factor for breast carcinoma. The amount of immunological infiltration was substantially linked with the high expression of HMGB3. The chromosome centromeric region, ATPase activity, and the cell cycle are critical areas where HMGB3 is involved, according to enrichment analysis. Therefore, we suspected that HMGB3 might be a potential biomarker for detecting and treating breast carcinoma. Conclusion: Breast cancer tissues had higher HMGB3 expression than normal breast tissues. HMGB3 overexpression may serve as an indicator for poor breast cancer outcomes.

CD137L-macrophage induce lymphatic endothelial cells autophagy to promote lymphangiogenesis in renal fibrosis.

Renal lymphangiogenesis is a new field of international nephrology in recent years and plays an important role in the progression of chronic renal disease. CD137 was originally described as a surface molecule present on activated T and NK cells and detected on hypoxic endothelial cells and inflamed blood vessels, but its function on lymphatic endothelial cells remains unclear. We investigated the relationships among CD137, lymphangiogenesis and macrophages, which are involved in interstitial fibrosis. Similar to other chronic inflammatory diseases, we found lymphangiogenesis and expression of CD137 in the renal tissue of patients with IgA nephropathy. CD137-positive lymphatic vessels were involved in the development process of IgA nephropathy and positively correlated with serum creatinine, serum urea nitrogen, serum uric acid, and urinary 24 h total protein. The expression of these indicators was negatively correlated with eGFR, plasma albumin, and HB. In mouse models of UUO, we verified that CD137 expression was significantly elevated during lymphangiogenesis and that its ligand CD137L was released by macrophages after VEGF-C stimulation in the kidney. In vitro, recombinant CD137L significantly enhanced LEC proliferation, migration and tube formation, and these effects were inhibited by CD137 siRNA. Mechanistically, the CD137L interaction with CD137 induced the transition from LC3-I to LC3-II and the expression of Atg5, Atg7, Atg12 and p62 proteins by activating the PI3K/AKT/mTOR pathway to promote autophagy. Knockdown of Atg5 and Atg7 blocked CD137L-induced autophagy. Thus, we propose that CD137L secretion by macrophages interacts with CD137 on lymphatic endothelial cells to prompt lymphangiogenesis in the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the CD137-CD137L pathway is a novel therapeutic approach for obstructive nephropathy.

Notoginsenoside R1 induces oxidative stress and modulates LPS induced immune microenvironment of nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor with high incidence. Notoginsenoside R1 (NGR1) is the main active compound of total Panax notoginseng saponin, and has multiple anti-tumor effects. This study aimed to investigate the effect and mechanism of NGR1 in NPC. MATERIALS: NPC cells were treated with different doses of NGR1. The NGR1 function in NPC was evaluated using Cell Counting Kit-8, Transwell, Western blot, flow cytometry, immunofluorescence assay, and quantitative real-time PCR. Meanwhile, the NGR1 mechanism in NPC was assessed by rescue experiments. Furthermore, the NGR1 function in vivo was determined by constructing an NPC xenotransplantation model, TUNEL, and immunohistochemistry assays. RESULTS: NGR1 repressed NPC cell growth and invasion but facilitated NPC cell apoptosis and oxidative stress. Also, NGR1 alleviated inflammation in NPC cells. Mechanistically, NGR1 restrained NPC cell growth and induced oxidative stress in NPC cells, while these effects were abolished after lipopolysaccharide (an activator of the TRAF6/NF-κB pathway) treatment, implying that NGR1 reduced NPC cell growth and induced oxidative stress in NPC cells by the inactivation of TRAF6/NF-κB axis. Moreover, in vivo studies further proved the palliative effect of NGR1 on NPC. CONCLUSION: NGR1 inhibited NPC cell growth and induced oxidative stress in NPC cells by inactivating TRAF6/NF-κB axis.

STAT3 as a target for sensitizing prostate cancer cells to irradiation.

Radioresistance of prostate cancer (PCa) is a major factor leading to local failure of radiotherapy. STAT3 is an oncogenic protein that was recently found to be activated in PCa tumors. This study aimed to investigate the radiosensitization effect of targeting STAT3 in PCa tumors. Here, the radiosensitization effect of STAT3 blockade was investigated by clonogenic assay, flow cytometry and western blot analysis in human PCa cells in vitro and in vivo. We demonstrated that STAT3 blockade with a STAT3 inhibitor or siRNA increased the radiosensitivity of PCa cells and that radiation together with STAT3 blockade induced more apoptosis and double-strand breaks (DSBs) than radiation alone in LNCaP cells. In addition, radiation induced STAT3 activation and survivin expression in PCa cells, which was inhibited by STAT3 blockade. Transfection with survivin cDNA attenuated the radiosensitization effect of STAT3 blockade. These effects were further confirmed by in vivo studies, which showed that the STAT3 inhibitor enhanced the treatment efficacy of radiation on LNCaP xenografts with decreased STAT3 activation and survivin expression. These findings suggest that STAT3 blockade radiosensitizes PCa cells through regulation of survivin. Thus, our study has revealed STAT3 as a potential sensitizer for irradiation in PCa cells. Its clinical application as an adjuvant in radiotherapy of PCa should be explored in the future.

Apatinib plus 5-fluorouracil as a third or subsequent-line treatment option for metastatic colorectal cancer: a phase-II, single-arm, prospective study.

Background: For metastatic colorectal cancer (mCRC) patients for whom at least 2 lines of previous standard therapies have failed, the prognosis is often unfavorable due to very limited subsequent treatment options. We sought to explore the efficacy of apatinib, an oral small-molecule vascular endothelial growth factor receptor-2 inhibitor, plus 5-fluorouracil (5-FU) as a third- or subsequent-line treatment for mCRC. Methods: In this phase-II, single-arm, prospective study, the eligible patients had been histologically confirmed to have adenocarcinoma of the colon or rectum for which at least 2 previous regimens of standard therapies had failed. All the patients were treated with a daily dose of 250 mg of apatinib, in combination with capecitabine, Tegafur Gimeracil Oteracil Potassium Capsule (S-1), or 5-FU, until disease progression, unacceptable toxicity, or consent withdrawal. Results: From June 2017 to April 2018, 16 patients were enrolled in this study. Among them, 4 achieved partial response, 7 had stable disease, and 5 had progression disease, resulting in an objective response rate of 25.00% [95% confidence interval (CI): 7.27-52.38%], and a disease control rate of 68.75% (95% CI: 41.34-88.98%). The median progression-free survival (PFS) was 4.83 months (95% CI: 2.17-8.90 months), and the median overall survival (OS) was 9.10 months (95% CI: 5.59-15.18 months). The common treatment-related adverse events (AEs) were hand-foot syndrome (56.25%), hypertension (37.50%), proteinuria (37.50%), gingival bleeding (18.75%) and abdominal pain (18.75%). Grade 3 AEs, including hand-foot syndrome (18.75%), hypertension (12.50%), and proteinuria (12.50%), were observed in 7 patients. Conclusions: The combination regimen of apatinib plus 5-FU had encouraging anti-tumor efficacy, and is a feasible third- or subsequent-line treatment option for mCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT03210064.