Assessing the role of programmed cell death signatures and related gene TOP2A in progression and prognostic prediction of clear cell renal cell carcinoma.

Kidney Clear Cell Carcinoma (KIRC), the predominant form of kidney cancer, exhibits a diverse therapeutic response to Immune Checkpoint Inhibitors (ICIs), highlighting the need for predictive models of ICI efficacy. Our study has constructed a prognostic model based on 13 types of Programmed Cell Death (PCD), which are intertwined with tumor progression and the immune microenvironment. Validated by analyses of comprehensive datasets, this model identifies seven key PCD genes that delineate two subtypes with distinct immune profiles and sensitivities to anti-PD-1 therapy. The high-PCD group demonstrates a more immune-suppressive environment, while the low-PCD group shows better responses to PD-1 treatment. In particular, TOP2A emerged as crucial, with its inhibition markedly reducing KIRC cell growth and mobility. These findings underscore the relevance of PCDs in predicting KIRC outcomes and immunotherapy response, with implications for enhancing clinical decision-making.

Decreased Treg cells induced by bisphenol A is associated with up-regulation of PI3K/Akt/mTOR signaling pathway and Foxp3 DNA methylation in spleen of adolescent mice.

The current study aimed to explore whether bisphenol A (BPA) exposure aggravated the decrease in Tregs induced by ovalbumin (OVA) in adolescent female mouse models of asthma, and whether the process was associated with mTOR-mediated signaling pathways and DNA methylation levels. A total of 40 female C57BL/6 mice at the age of four weeks were used and divided into five groups after 1 week of domestication. Each group consisted of eight mice: the control group, OVA group, OVA + BPA (0.1 µg mL-1) group, OVA + BPA (0.2 µg mL-1) group, and OVA + BPA (0.4 µg mL-1) group. Results revealed that Foxp3 protein levels decreased in the spleens of mice exposed to BPA compared to those in the OVA group. After an elevation in BPA dose, the mRNAs of methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b) were gradually upregulated. The mechanism was related to the activity of TLR4/NF-κB and PI3K/Akt/mTOR signaling pathways and the enhancement of Foxp3 DNA methylation. Our results, collectively, provided a new view for studying the mechanisms underlying BPA exposure-induced immune dysfunction. Investigation of the regulatory mechanisms of DNA methylation in the abnormal Th immune response caused by BPA exposure could help reveal the causes and molecular mechanisms underlying the high incidence of allergic diseases in children in recent years.

The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor.

Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.

Intelligence detection of oil absorption in French fries by surface profiles.

Surface profiles are important evaluation indices for oil absorption behavior of fried foods. This research established two intelligent models of partial least-squares regression (PLSR) and back propagation artificial neural network (BP-ANN) for monitoring the oil absorption behavior of French fries based on the surface characteristics. Surface morphology and texture of French fries by rapeseed oil (RO) and high-oleic peanut oil (HOPO) at different temperatures were investigated. Results showed that oil content of samples increased with frying temperature, accounting for 37.7% and 41.4% of samples fried by RO and HOPO respectively. The increase of crust ratio, roughness and texture parameters (Fm, Nwr, fwr, Wc) and the decrease of uniformity were observed with the frying temperature. Coefficients of prediction set of PLSR and BP-ANN models were more than 0.93, which indicated that surface features combined with chemometrics were rapid and precise methods for determining the oil content of French fries.

GDF-15 alleviates diabetic nephropathy via inhibiting NEDD4L-mediated IKK/NF-κB signalling pathways.

Podocyte inflammatory injury has been indicated to play a pivotal role in the occurrence and development of diabetic nephropathy (DN). However, the pathogenesis of inflammation remains unclear. Recent researches have shown that GDF-15, a member of the transforming growth factor-ß superfamily, were elevated under pathological conditions, such as myocardial ischemia, cancer, as well as inflammation. Here, we demonstrated that GDF-15 could alleviate podocyte inflammatory injury by modulating the NF-κB pathway. GDF-15 and other pro-inflammatory factors, such as TNF-α, IL-1ß, and IL-6 were upregulated in the serum of HFD/STZ rat models. GDF-15 was also elevated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes. The silence of GDF-15 in HG-stimulated podocytes further augmented inflammation and podocyte injury, while overexpression of GDF-15 significantly reduced the inflammatory response in podocytes. Mechanistically, we demonstrated that GDF-15 could inhibit the nuclear translocation of NF-κB through IKK and IκBα by interaction with ubiquitin ligase NEDD4L. Taken together, our data suggested a protective mechanism of elevated GDF-15 in DN through obstruction of ubiquitin degradation of IKK by inhibiting NEDD4L expression, thus decreasing the activation of NF-κB and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN.

Cancer pain intensity and perceived social support in palliative care: 1-week prospective study.

OBJECTIVES: Pain is a complex and multidimensional experience affected by psychosocial factors. Perceived social support (PSS) has been considered as a positive psychosocial resource for effective regulation of cancer patients' well-being. Our study examined the relationship between PSS and pain intensity under 1-week palliative care. METHODS: A prospective study was conducted of terminal cancer inpatients (N=84) recruited from the hospice ward. Pain intensity was assessed on admission and 1 week later, and patients completed self-report questionnaires assessing PSS at admission. The repeated designed analysis of variance was used to explore the correlate of PSS with cancer pain. RESULTS: Pain intensity decreased after 1 week (t=2.303, p=0.024), and 47.62% gained pain relief. For pain intensity, there was a significant PSS group×time interaction effect detected (F=4.544, p=0.036). Pain intensity in the high PSS group was significantly reduced 1 week later (p=0.008), while the change of pain intensity was not significant in the low PSS group (p=0.609). CONCLUSIONS: PSS at admission predicted the 1-week development of pain intensity. Identifying PSS of terminal cancer patients leads to early interventions that are more effective in improving pain management of palliative care.

Endogenous FGF1 Deficiency Aggravates Doxorubicin-Induced Hepatotoxicity.

Doxorubicin (DOX) is a broad-spectrum antineoplastic agent that widely used in clinic. However, its application is largely limited by its toxicity in multiple organs. Fibroblast growth factor 1 (FGF1) showed protective potential in various liver diseases, but the role of endogenous FGF1 in DOX-induced liver damage is currently unknown. Both wild-type (WT) and FGF1 knockout (FGF1-KO) mice were treated with DOX. DOX induced loss of body weight and liver weight and elevation of ALT and AST in WT mice, which were aggravated by FGF1 deletion. FGF1 deletion exacerbated hepatic oxidative stress mirrored by further elevated 3-nitrosative modification of multiple proteins and malondialdehyde content. These were accompanied by blunted compensatively antioxidative responses indicated by impaired upregulation of nuclear factor erythroid 2-related factor 2 and its downstream antioxidant gene expression. The aggravated oxidative stress was coincided with exacerbated cell apoptosis in DOX-treated FGF1-KO mice reflected by further increased TUNEL positive cell staining and BCL-2-associated X expression and caspase 3 cleavage. These detrimental changes in DOX-treated FGF1-KO mice were associated with worsened intestinal fibrosis and increased upregulation fibrotic marker connective tissue growth factor and α-smooth muscle actin expression. However, DOX-induced hepatic inflammatory responses were not further affected by FGF1 deletion. These results demonstrate that endogenous FGF1 deficiency aggravates DOX-induced liver damage and FGF1 is a potential therapeutic target for treatment of DOX-associated hepatoxicity.

SLC39A10 promotes malignant phenotypes of gastric cancer cells by activating the CK2-mediated MAPK/ERK and PI3K/AKT pathways.

Solute carrier family 39 member 10 (SLC39A10) belongs to a subfamily of zinc transporters and plays a key role in B-cell development. Previous studies have reported that its upregulation promotes breast cancer metastasis by enhancing the influx of zinc ions (Zn2+); however, its role in gastric cancer remains totally unclear. Here, we found that SLC39A10 expression was frequently increased in gastric adenocarcinomas and that SLC39A10 upregulation was strongly associated with poor patient outcomes; in addition, we identified SLC39A10 as a direct target of c-Myc. Functional studies showed that ectopic expression of SLC39A10 in gastric cancer cells dramatically enhanced the proliferation, colony formation, invasiveness abilities of these gastric cancer cells and tumorigenic potential in nude mice. Conversely, SLC39A10 knockdown inhibited gastric cancer cell proliferation and colony formation. Mechanistically, SLC39A10 exerted its carcinogenic effects by increasing Zn2+ availability and subsequently enhancing the enzyme activity of CK2 (casein kinase 2). As a result, the MAPK/ERK and PI3K/AKT pathways, two major downstream effectors of CK2, were activated, while c-Myc, a downstream target of these two pathways, formed a vicious feedback loop with SLC39A10 to drive the malignant progression of gastric cancer. Taken together, our data demonstrate that SLC39A10 is a functional oncogene in gastric cancer and suggest that targeting CK2 is an alternative therapeutic strategy for gastric cancer patients with high SLC39A10 expression.

Prolonged Ischemia Increases Complications Among High- and Low-Volume Centers in Lung Transplantation.

BACKGROUND: The effect of prolonged allograft ischemic time on lung transplant outcomes remains controversial, with most studies associating it with increased mortality, but this effect is partly mitigated by center volume. This study sought to evaluate the mechanism of these findings and clarify the impact of ischemic time on short-term outcomes in a national sample. METHODS: Data on lung transplants (January 2010-Janary 2017) were extracted from the Scientific Registry of Transplant Recipients database. Ischemic time was dichotomized as prolonged ischemic time (PIT) or no PIT (N-PIT) at 6 hours. High-volume centers were defined as the top quintile. The primary outcome was 30-day, 1-year, and 3-year mortality; secondary outcomes included in-hospital complications and 72-hour oxygenation. RESULTS: Among 11,809 records, there were significant differences between PIT and N-PIT recipients by demographics, lung allocation score, and donor organ metrics. In a 1:1 propensity score-matched cohort (n = 6422), PIT recipients had reduced survival compared with N-PIT at 3 years (66.5% vs 68.8%, P = .031). On multivariable analysis, this effect persisted among low-volume but not high-volume centers. PIT recipients were more likely to require reintubation, prolonged (>5 days) mechanical ventilation, hemodialysis, longer stay, and acute rejection (all P < .01). Except for reintubation, these disparities were present at both high- and low-volume centers independently. Ischemic time had no effect on 72-hour oxygenation. CONCLUSIONS: PIT remains associated with higher rates of postoperative complications and reduced short-term survival. While center volume ameliorated the survival impact, this was not achieved by reducing postoperative complications. Further research is warranted before broadening ischemic time thresholds among low-volume centers.

Association of pain management and positive expectations with psychological distress and spiritual well­being among terminally ill cancer patients admitted to a palliative care unit.

BACKGROUND: Although palliation of psycho-spiritual distress is of great importance in terminally ill cancer patients, there is a little information about screening patients who benefit from palliative care and identifying the cancer care targets. This study explored the relationship of pain management and positive expectations with depression, anxiety and spiritual well-being (SWB) in terminal cancer patients admitted to a palliative care unit. METHODS: Eighty-four terminal cancer inpatients were recruited from the Hospice Ward, Shengjing Hospital of China Medical University. Optimism and general self-efficacy (GSE) were evaluated at admission. Patients completed self-report questionnaires on SWB, depression, anxiety and pain both on admission and one week later. The repeated designed analysis of variance was used to explore the correlates of depression, anxiety and SWB (meaning, peace, faith). RESULTS: In our sample, only cancer pain diminished significantly one week later. For depression (p = 0.041) and faith (p = 0.013), there was a significant pain group (relieved vs. not relieved) × time interaction effect, such that those with satisfied pain control experienced the improved psycho-spiritual outcomes at 1 week. The relationship between positive expectations, peace and faith was also statistically significant, indicating that the improvement of peace or faith was significant in the low group of optimism and GSE. CONCLUSIONS: Our findings indicated that pain management lied at the center of depression and SWB, meaning that effective pain management may reduce depression, and improve SWB among terminal cancer patients. Moreover, positive expectations, especially for optimism, may be the new target for SWB-related intervention research. Palliative care nurse should require the identification of terminal cancer patients who may more benefit from short-term palliative care, and target them with effective cancer care.

Long-term results of synovectomy in total knee arthroplasty: a prospective, randomized controlled trial.

BACKGROUND: Synovectomy has been introduced into total knee arthroplasty (TKA) with the aim of relieving pain and inflammation of the synovium. However, there are no long-term, comparative data to evaluate the effect of synovectomy in TKA. This study was aimed at assessing pain, function, and complications in patients undergoing synovectomy during TKA for osteoarthritis (OA) at long-term follow-up. METHODS: This was a prospective randomized controlled trial of 42 consecutive patients who underwent staged bilateral TKA. Patients undergoing the first-side TKA were allocated to receive TKA with or without synovectomy followed by a 3-month washout period and crossover to the other strategy for the opposite-side TKA. The overall efficacy of both strategies was evaluated by determination of blood loss, the Knee Society score (KSS), and knee inflammation conditions during a 3-month postoperative period. The postoperative pain, range of motion (ROM), and complications were sequentially evaluated to compare the two groups until 10 years after surgery. RESULTS: At the 10-year follow-up, both groups had a similarly significantly improved ROM (114.88 ±â€Š9.84° vs. 114.02 ±â€Š9.43°, t  = 0.221, P  = 0.815) and pain relief with no differences between the two groups (1.0 [1.0] vs. 1.0 [1.5], U  = 789.500, P  = 0.613). Similar changes in total blood loss, KSS, and knee inflammation were found in both groups during 3 months postoperatively ( P  > 0.05). Additionally, there was no significant difference regarding complications and satisfaction between the two groups ( P  > 0.05). CONCLUSIONS: Synovectomy in conjunction with TKA for primary OA does not seem to provide any benefit regarding postoperative pain, ROM, and satisfaction during a 10-year follow-up. In addition, it may not result in more blood loss and increased incidence of long-term complications. Based on our long-term findings, it should not be performed routinely. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-INR-16008245; https://www.chictr.org.cn/showproj.aspx?proj=13334 .

Precise engineering of disulfide bond-bridged prodrug nanoassemblies to balance antitumor efficacy and safety.

Prodrug-based nanoassemblies, which combine the merits of prodrug technology and nanocarriers, are regarded as promising platforms for cancer treatment. Notably, the chemical structure of prodrugs is closely associated with antitumor efficacy and safety, and the intrinsic relationships among them need further exploration. Herein, paclitaxel was conjugated with 2-octyldodecan-1-ol through different positions of disulfide bond to construct the prodrug nanoassemblies. Interestingly, the minor differences in chemical structure not only dominated the assembly performance and drug release of nanoassemblies, but also significantly impacted the pharmacokinetics, antitumor efficacy, and safety. It was worth noting that prodrug nanoassemblies with one carbon atom between disulfide bond and ester bond had faster drug release and better antitumor effect, while prodrug nanoassemblies with three carbon atoms between disulfide bond and ester bond possessed moderate antitumor effect and better safety. Our findings illustrated the structure-function relationships of self-assembled prodrugs and provided a promising paradigm for the precise engineering of advanced prodrug nanoplatforms. STATEMENT OF SIGNIFICANCE: 1. The major effects of minor differences in prodrug chemical structure on pharmacodynamics and safety were explored, which had important clinical reference significance and value. 2. The in-depth exploration of structure-function relationships to balance efficacy and safety had important guiding significance for the design of prodrug nanoassemblies.

Noninvasive Prediction of Ki-67 Expression in Hepatocellular Carcinoma Using Machine Learning-Based Ultrasomics: A Multicenter Study.

OBJECTIVES: To investigate the ability of ultrasomics to predict Ki-67 expression in hepatocellular carcinoma (HCC). METHODS: A total of 244 patients from three hospitals were retrospectively recruited (training dataset, n = 168; test dataset, n = 43; and validation dataset, n = 33). Lesion segmentation of the ultrasound images was performed manually by two radiologists. In total, 1409 ultrasomics features were extracted. Feature selection was conducted using the intra-class correlation coefficient, variance threshold, mutual information, and recursive feature elimination plus eXtreme Gradient Boosting. The support vector machine was combined with the learning curve and grid search parameter tuning to construct the clinical, ultrasomics, and combined models. The predictive performance of the models was assessed using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity and accuracy. RESULTS: The ultrasomics model performed well on the training, test, and validation datasets. The AUC (95% confidence interval [CI]) for these datasets were 0.955 (0.912-0.981), 0.861 (0.721-0.947), and 0.665 (0.480-0.819), respectively. The combination of ultrasomics and clinical features significantly improved model performance on all three datasets. The AUC (95% CI), sensitivity, specificity, and accuracy were 0.986 (0.955-0.998), 0.973, 0.840, and 0.869 on the training dataset; 0.871 (0.734-0.954), 0.750, 0.829, and 0.814 on the test dataset; and 0.742 (0.560-0.878), 0.714, 0.808, and 0.788 on the validation dataset, respectively. CONCLUSIONS: Ultrasomics was proved to be a potential noninvasive method to predict Ki-67 expression in HCC.

Nitroreductase-induced bioorthogonal ligation for prodrug activation: A traceless strategy for cancer-specific imaging and therapy.

Prodrug development is of great interest in cancer therapy. From bio-friendly standpoints, traceless prodrug activation would be an ideal approach for cancer treatment owning to the avoidance of byproduct which might induce side effects in living system. Here, we report a fully traceless strategy for cancer imaging and therapy via a metal-free bioorthogonal ligation triggered by nitroreductase (NTR) overexpressed in solid tumors. The reduction of nitro substrates to amines by NTR and further condensation of amines with aldehydes can be seamlessly combined to yield imine-based resveratrol (RSV) with water as the only byproduct. In comparison with RSV, this precursor exhibited not only the same level of anticancer efficiency both in vitro and in vivo under hypoxia, but also a high sensitivity to hypoxia and much lower perturbation towards normal cells, which holds a great potential of theranostic prodrug for cancer therapy.

Effects of arbuscular mycorrhizal inoculation on the phytoremediation of PAH-contaminated soil: A meta-analysis.

Inoculation with arbuscular mycorrhizal (AM) fungi can accelerate the phytoremediation process by increasing plant biomass and improving soil physicochemical and biological characteristics. However, a quantitative, data-based conclusion is yet to be derived on the roles of AM fungi in remediating soils polluted by polycyclic aromatic hydrocarbons (PAHs), and the impact factors are unclear. To address these issues, we performed a meta-analysis of 45 articles to estimate the effects of AM inoculation on the phytoremediation of soils polluted by PAHs and to examine the influence of experimental conditions on these effects. Our results showed that AM inoculation significantly decreased the residual soil PAHs concentration at all PAHs levels, and the largest effect of AM treatment was 48.5% compared to the non-mycorrhizal treatment. This should be attributed to increased plant growth and PAHs uptake, and soil biological activity in the rhizosphere induced by AM symbionts. Compared to the non-mycorrhizal treatment, the largest AM effects on the total plant biomass, root PAHs concentration, shoot PAHs concentration, soil bacterial biomass, soil catalase activity, and soil polyphenol oxidase activity were 51.7%, 565%, 53.1%, 141%, 100% and 51.9%, respectively. Although these effects on the above mentioned parameters varied with AM fungi (genus, species, and inoculation mode), soil PAHs (source, concentration, and type), plant type (dicots and monocots), and experimental conditions (experimental duration, soil sterilization and additional factors), few negative AM effects were observed. This study confirmed the feasibility of using AM fungi to enhance the phytoremediation of PAHs-contaminated soil.

Neoadjuvant Therapy for Locally Advanced Esophageal Cancers.

Esophageal carcinoma is one of the most aggressive malignant diseases. At present, neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy are regarded as the standard modalities for the treatments of locally advanced esophageal cancers based on several landmark trials. However, the optimal regimen, radiation dose, and surgical intervals are uncertain and the rate of recurrence after neoadjuvant therapy is high. Patients receiving neoadjuvant therapy and reaching a pathological complete response have been reported to have a better survival benefit and a fewer recurrence risk than those non-pathological complete responses. Nevertheless, less than half of patients will reach a pathological complete response after neoadjuvant therapy, and the methods to evaluate the efficacy after neoadjuvant therapy accurately are limited. Immune checkpoint inhibitors have been recommended for the treatments of advanced esophageal cancers. Recently, research has been beginning to evaluate the safety and efficacy of immunotherapy combined with neoadjuvant therapy. Here, we will review and discuss the development of the neoadjuvant therapy of locally advanced esophageal cancers and unsolved clinical problems.

Myocardial extracellular volume assessed by cardiovascular magnetic resonance may predict adverse left ventricular remodeling in rheumatic heart disease after valvular surgery.

Background: Only a few studies to date have focused on the application of cardiovascular magnetic resonance (CMR) in rheumatic heart disease (RHD); in particular, research on the application of T1-mapping CMR sequences is limited. This study aimed to investigate whether diffuse myocardial fibrosis evaluated using preoperative T1 mapping and extracellular volume (ECV) fraction measurement could predict the progression of adverse left ventricular remodeling (LVR) after surgery. Methods: A total of 32 adult patients with RHD and 30 healthy controls were recruited. Baseline clinical characteristics, CMR findings, and T1 mapping measurements were compared between the two groups. Transthoracic echocardiography measurements were collected before and after surgery. Patients with an increase in left ventricular end-diastolic volume of >15% or a decrease in left ventricular ejection fraction of >10% were classified into the adverse remodeling group; otherwise, patients were categorized into the non-adverse remodeling group. Results: Compared with the healthy controls, patients with RHD had impaired biventricular function, enlarged ventricular volume, and increased native T1 and ECV values. Patients in the adverse remodeling group had higher ECV values than those in the non-adverse remodeling group (33.25%±3.67% vs. 28.45%±4.46%, P=0.002). Binary logistic regression analysis showed that the ECV value was associated with adverse LVR (odds ratio: 1.273, P=0.045). ECV was found to be a sensitive biomarker for predicting adverse LVR (area under the curve: 0.78; sensitivity: 75.0%; specificity: 77.3%). Conclusions: ECV has potential value for predicting the progression of adverse LVR and for identifying non-responders among patients with RHD undergoing surgery.

ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase.

BACKGROUND: Mannose, a natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI). However, its function in thyroid cancer still remains elusive. METHODS: MTT, colony formation and flow cytometry assays were performed to determine the response of thyroid cancer cells to mannose. Meanwhile, mouse models of subcutaneous xenograft and primary papillary thyroid cancer were established to determine in vivo anti-tumor activity of mannose. The underlying mechanism of mannose selectively killing thyroid cancer cells was clarified by a series of molecular and biochemical experiments. RESULTS: Our data demonstrated that mannose selectively suppressed the growth of thyroid cancer cells, and found that enzyme activity of PMI rather than its protein expression was negatively associated with the response of thyroid cancer cells to mannose. Besides, our data showed that zinc ion (Zn2+) chelator TPEN clearly increased the response of mannose-insensitive cells to mannose by inhibiting enzyme activity of PMI, while Zn2+ supplement could effectively reverse this effect. Further studies found that the expression of zinc transport protein ZIP10, which transport Zn2+ from extracellular area into cells, was negatively related to the response of thyroid cancer cells to mannose. Knocking down ZIP10 in mannose-insensitive cells significantly inhibited in vitro and in vivo growth of these cells by decreasing intracellular Zn2+ concentration and enzyme activity of PMI. Moreover, ectopic expression of ZIP10 in mannose-sensitive cells decrease their cellular response to mannose. Mechanistically, mannose exerted its anti-tumor effect by inhibiting cellular glycolysis; however, this effect was highly dependent on expression status of ZIP10. CONCLUSION: The present study demonstrate that mannose selectively kills thyroid cancer cells dependent on enzyme activity of PMI rather than its expression, and provide a mechanistic rationale for exploring clinical use of mannose in thyroid cancer therapy.

Role of Rho guanine nucleotide exchange factors in non-small cell lung cancer.

Conventionally, Rho guanine nucleotide exchange factors (GEFs) are known activators of Rho guanosine triphosphatases (GTPases) that promote tumorigenesis. However, the role of Rho GEFs in non-small cell lung cancer (NSCLC) remains largely unknown. Through the screening of 81 Rho GEFs for their expression profiles and correlations with survival, four of them were identified with strong significance for predicting the prognosis of NSCLC patients. The four Rho GEFs, namely ABR, PREX1, DOCK2 and DOCK4, were downregulated in NSCLC tissues compared to normal tissues. The downregulation of ABR, PREX1, DOCK2 and DOCK4, which can be attributfed to promoter methylation, is correlated with poor prognosis. The underexpression of the four key Rho GEFs might be related to the upregulation of MYC signaling and DNA repair pathways, leading to carcinogenesis and poor prognosis. Moreover, overexpression of ABR was shown to have a tumor-suppressive effect in PC9 and H1703 cells. In conclusion, the data reveal the unprecedented role of ABR as tumor suppressor in NSCLC. The previously unnoticed functions of Rho GEFs in NSCLC will inspire researchers to investigate the distinct roles of Rho GEFs in cancers, in order to provide critical strategies in clinical practice.