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Graphical abstract, Highlights • The expression of DOK family genes is related to overall survival (OS), clinical stage, tumor mutation, methylation, CNV, and SNV. • DOK family genes are significantly associated with poor prognosis of UVM. • DOK1-DOK3 has obvious correlation with tumor immunity and tumor microenvironment. • DOK family gene is significantly related to tumor stemness and drug sensitivity. • The expression of DOK family genes is related to the activation of EMT and hormone ER pathways, and is related to the inhibition of DNA damage response, cell cycle, and hormone AR pathways. • DOK1 and DOK3, DOK2 and DOK3 have the significant correlation., Introduction DOK is a new type of regulatory protein family that participates in the regulation of tumor cell growth. However, most of the studies are conducted in cell lines, and systematic studies have not been conducted in human tumors. Objectives We conducted a comprehensive analysis of DOK based on its expression profile and its relationship with patient survival, immune infiltration, tumor microenvironment, and drug sensitivity. Methods We used the TCGA database to analyze the correlation between DOK family gene expression and prognosis and clinical stage. The protein expression of DOK in tumor tissues was analyzed by immunohistochemistry. Use the cBioPortal database to analyze the alteration frequency in DOK family genes in human tumors. In addition, we used ESTIMATE algorithm and TIMER website to analyze the correlation between DOK family genes and tumor immunity. Finally, we further analyzed the relationship between DOK family genes and tumor stemness and the sensitivity of cancer cells to chemotherapy. Results We conducted a comprehensive analysis of DOK family genes based on its expression profile and its relationship with patient survival. We also confirmed this conclusion by immunohistochemistry. The expression of DOK family genes is related to OS, clinical stage, tumor mutation, methylation, CNV, and SNV. DOK family genes are significantly associated with poor prognosis of UVM. DOK1-DOK3 has obvious correlation with tumor immunity. DOK2 can increase the sensitivity of chemotherapy drugs, while DOK4 reduces the sensitivity of multiple chemotherapy drugs. In addition, the expression level of DOK family genes is significantly correlated with the activity of cancer marker-related pathways. Conclusions DOK plays a role of tumor suppressor gene or tumor-promoting gene in different tumors. However, DOK family genes play a role in promoting cancer in UVM. DOK family genes are significantly associated with drug sensitivity.

Bone marrow stromal cells (BMSCs) have been implicated in multiple myeloma (MM) progression. However, the underlying mechanisms remain largely elusive. Therefore, we aimed to explore key factors in BMSCs that contribute to MM development. RNA-sequencing was used to perform gene expression profiling in BMSCs. Enzyme-linked immunosorbent assays (ELISAs) were performed to determine the concentrations of PGE2 and TNFα in sera and conditioned media (CM). Western blotting, qRT-PCR and IHC were used to examine the expression of cyclooxygenase 2 (COX2) in BMSCs and to analyze the regulation of TNFα by COX2. Cell growth and adhesion assays were employed to explore the function of COX2 in vitro. A 5T33MMvt-KaLwRij mouse model was used to study the effects of COX2 inhibition in vivo. COX2 was found to be upregulated in MM patient-derived BMSCs and to play a critical role in BMSC-induced MM cell proliferation and adhesion. Administration of PGE2 to CM derived from BMSCs promoted MM cell proliferation and adhesion. Conversely, inhibition of COX2 in BMSCs greatly compromised BMSC-induced MM cell proliferation and adhesion. PCR array-based analysis of inflammatory cytokines indicated that COX2 upregulates the expression of TNFα. Subsequent rescue assays showed that an anti-TNFα monoclonal antibody could antagonize COX2-mediated MM cell proliferation and adhesion. Administration of NS398, a specific COX2 inhibitor, inhibited in vivo tumor growth and improved the survival of 5TMM mice. Our results indicate that COX2 contributes to BMSC-induced MM proliferation and adhesion by increasing the secretion of PGE2 and TNFα. Targeting COX2 in BMSCs may serve as a potential therapeutic approach of treating MM.

OBJECTIVE Diabetes is common in COVID-19 patients and associated with unfavorable outcomes. We aimed to describe the characteristics and outcomes and to analyze the risk factors for in-hospital mortality of COVID-19 patients with diabetes. RESEARCH DESIGN AND METHODS This two-center retrospective study was performed at two tertiary hospitals in Wuhan, China. Confirmed COVID-19 patients with diabetes (N = 153) who were discharged or died from 1 January 2020 to 8 March 2020 were identified. One sex- and age-matched COVID-19 patient without diabetes was randomly selected for each patient with diabetes. Demographic, clinical, and laboratory data were abstracted. Cox proportional hazards regression analyses were performed to identify the risk factors associated with the mortality in these patients. RESULTS Of 1,561 COVID-19 patients, 153 (9.8%) had diabetes, with a median age of 64.0 (interquartile range 56.0–72.0) years. A higher proportion of intensive care unit admission (17.6% vs. 7.8%, P = 0.01) and more fatal cases (20.3% vs. 10.5%, P = 0.017) were identified in COVID-19 patients with diabetes than in the matched patients. Multivariable Cox regression analyses of these 306 patients showed that hypertension (hazard ratio [HR] 2.50, 95% CI 1.30–4.78), cardiovascular disease (HR 2.24, 95% CI 1.19–4.23), and chronic pulmonary disease (HR 2.51, 95% CI 1.07–5.90) were independently associated with in-hospital death. Diabetes (HR 1.58, 95% CI 0.84–2.99) was not statistically significantly associated with in-hospital death after adjustment. Among patients with diabetes, nonsurvivors were older (76.0 vs. 63.0 years), most were male (71.0% vs. 29.0%), and they were more likely to have underlying hypertension (83.9% vs. 50.0%) and cardiovascular disease (45.2% vs. 14.8%) (all P values CONCLUSIONS COVID-19 patients with diabetes had worse outcomes compared with the sex- and age-matched patients without diabetes. Older age and comorbid hypertension independently contributed to in-hospital death of patients with diabetes.

Background Gut microbiome alterations are closely related to human health and linked to a variety of diseases. Although great efforts have been made to understand the risk factors for multiple myeloma (MM), little is known about the role of the gut microbiome and alterations of its metabolic functions in the development of MM. Results Here, in a cohort of newly diagnosed patients with MM and healthy controls (HCs), significant differences in metagenomic composition were discovered, for the first time, with higher bacterial diversity in MM. Specifically, nitrogen-recycling bacteria such as Klebsiella and Streptococcus were significantly enriched in MM. Also, the bacteria enriched in MM were significantly correlated with the host metabolome, suggesting strong metabolic interactions between microbes and the host. In addition, the MM-enriched bacteria likely result from the regulation of urea nitrogen accumulated during MM progression. Furthermore, by performing fecal microbiota transplantation (FMT) into 5TGM1 mice, we proposed a mechanistic explanation for the interaction between MM-enriched bacteria and MM progression via recycling urea nitrogen. Further experiments validated that Klebsiella pneumoniae promoted MM progression via de novo synthesis of glutamine in mice and that the mice fed with glutamine-deficient diet exhibited slower MM progression. Conclusions Overall, our findings unveil a novel function of the altered gut microbiome in accelerating the malignant progression of MM and open new avenues for novel treatment strategies via manipulation of the intestinal microbiota of MM patients.

NEK2 is associated with drug resistance in multiple cancers. Our previous studies indicated that high NEK2 confers inferior survival in multiple myeloma (MM); thus, a better understanding of the mechanisms by which NEK2 induces drug resistance in MM is required. In this study, we discovered that NEK2 enhances MM cell autophagy, and a combination of autophagy inhibitor chloroquine (CQ) and chemotherapeutic bortezomib (BTZ) significantly prevents NEK2‐induced drug resistance in MM cells. Interestingly, NEK2 was found to bind and stabilize Beclin‐1 protein but did not affect its mRNA expression and phosphorylation. Moreover, autophagy enhanced by NEK2 was significantly prevented by knockdown of Beclin‐1 in MM cells, suggesting that Beclin‐1 mediates NEK2‐induced autophagy. Further studies demonstrated that Beclin‐1 ubiquitination is decreased through NEK2 interaction with USP7. Importantly, knockdown of Beclin‐1 sensitized NEK2‐overexpressing MM cells to BTZ in vitro and in vivo. In conclusion, we identify a novel mechanism whereby autophagy is activated by the complex of NEK2/USP7/Beclin‐1 in MM cells. Targeting the autophagy signaling pathway may provide a promising therapeutic strategy to overcome NEK2‐induced drug resistance in MM., Autophagy is associated with bortezomib resistance in multiple myeloma (MM). Here, we show that NEK2 stabilizes Beclin‐1 through USP7‐mediated deubiquitination, thereby enhancing autophagy and eventually inducing bortezomib resistance in MM cell. Moreover, knockdown of Beclin‐1 profoundly inhibits NEK2‐mediated bortezomib resistance. These findings indicate that NEK2 induces autophagy‐mediated bortezomib resistance through stabilizing Beclin‐1 in MM cell.

The blood-testis barrier (BTB) separates the seminiferous epithelium into the apical and basal compartments. The BTB has to operate timely and accurately to ensure the correct migration of germ cells, meanwhile maintaining the immunological barrier. Testin was first characterized from primary Sertoli cells, it is a secretory protein and a sensitive biomarker to monitor junctions between Sertoli and germ cells. Till now, the functions of testin on BTB dynamics and the involving mechanisms are unknown. Herein, testin acts as a regulatory protein on BTB integrity. In vitro testin knockdown by RNAi caused significant damage to the Sertoli cell barrier with no apparent changes in the protein levels of several major tight junction (TJ), adhesion junction, and gap junction proteins. Also, testin RNAi caused the diffusion of two TJ structural proteins, occludin and ZO-1, diffusing away from the Sertoli cell surface into the cytoplasm. Association and colocalization between ZO-1 and occludin were decreased after testin RNAi, examined by Co-IP and coimmunofluorescent staining, respectively. Furthermore, testin RNAi induced a dramatic disruption on the arrangement of actin filament bundles and a reduced F-actin/G-actin ratio. The actin regulatory protein ARP3 appeared at the Sertoli cell interface after testin RNAi without its protein level change, whereas overexpressing testin in Sertoli cells showed no effect on TJ barrier integrity. The above findings suggest that besides as a monitor for Sertoli-germ cell junction integrity, testin is also an essential molecule to maintain Sertoli-Sertoli junctions.

Chemoresistance seriously hinders the treatment efficiency of human cancers, including prostate cancer (PCa). Multiple long noncoding RNAs (lncRNAs) were involved in drug resistance in PCa. We aimed to explore the function of transient receptor potential cation channel subfamily M member 2 (TRPM2) antisense RNA (TRPM2-AS) in paclitaxel (PTX) resistance in PCa. Our results showed that TRPM2-AS was increased in PTX-resistant PCa cells. TRPM2-AS knockdown accelerated cell apoptosis and inhibited cell proliferation, migration, invasion, and PTX resistance in PTX-resistant PCa cells. MiR-497-5p was bound to TRPM2-AS and its inhibition reversed the effects of TRPM2-AS knockdown on cell progression and PTX resistance in PTX-resistant PCa cells. FOXK1 was identified as a target of miR-497-5p and FOXK1 overexpression showed similar effects on cell progression and PTX resistance with miR-497-5p inhibition in PTX-resistant PCa cells. In conclusion, TRPM2-AS knockdown suppressed cell progression and PTX resistance in PTX-resistant PCa cells by miR-497-5p/FOXK1 axis.

Acute pancreatitis (AP) is an acute inflammatory disorder characterized by acinar cell death and inflammation. Multiple factors cause hyperglycemia after AP. Macrophage polarization is involved in tissue injury and repair, and is regulated by Notch signaling during certain inflammatory diseases. The present study explores the relationship among hyperglycemia, macrophage polarization, and Notch signaling during AP and the related mechanisms. A cerulein-induced AP model was established in FVB/N mice, and AP with hyperglycemia was initiated by injection of 50% concentration glucose. Tissue damage, Notch activity, and macrophage polarization were assessed in pancreatic tissues. The role of Notch signaling in macrophage polarization during AP was also assessed in vitro by co-culturing primary macrophages and pancreatic acinar cells, and establishing a lipopolysaccharide (LPS)-induced inflammatory model in RAW264.7 cells. Pancreatic acinar cells were damaged and proinflammatory factor levels were increased in pancreatic tissues during AP. The hyperglycemic conditions aggravated pancreatic injury, increased macrophage infiltration, promoted macrophage polarization towards an M1 phenotype, and led to excessive up-regulation of Notch activity. Inhibition of Notch signaling by DAPT or Notch1 knockdown decreased the proportion of M1 macrophages and reduced the production of proinflammatory factors, thus mitigating pancreatic injury. These findings suggest that hyperglycemia induces excessive Notch signaling after AP and further aggravates AP by promoting pancreatic macrophage polarization towards the M1 phenotype. The Notch signaling pathway is a potential target for the prevention and treatment of AP.

MORF4-related gene-binding protein (MRGBP) is the subunit of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. Much of the research indicated an oncogenic role of MRGBP in the development of cancers. However, it is still unknown the role MRGBP plays in human cancers, which deserves further exploration. In this research, the expression profile, prognostic value of MRGBP, and the relationship between MRGBP and immune infiltration were explored in 33 types of cancer. The differences in MRGBP expression in tumor and normal tissues were explored using data from The Cancer Genome Atlas, Gene Expression Omnibus and ONCOMINE. Analysis of the association between MRGBP and prognosis using Kaplan-Meier survival curve and COX analysis. The data of Tumor mutational burden (TMB), microsatellite instability (MSI) from TCGA. The relationship Between MRGBP expression and immunity was analyzed using the ESTIMATE algorithm and CIBERSORT. Furthermore, we explored MRGBP expression and the relationship between MRGBP expression and macrophage infiltration using immunohistochemical analysis in lower grade glioma (LGG). Our results revealed that MRGBP was highly expressed in most cancer tissues compared with normal tissues. Tumors with increased MRGBP expression had a high clinicopathologic stage and poor prognosis. The expression of MRGBP was closely related to the TMB, MSI. We also found a significant negative correlation between MRGBP expression and stromal scores and immune scores in various types of cancer. Furthermore, MRGBP expression was associated with a variety of immune cells including B cells, NK cells, T cells, and macrophages. LGG and LIHC was selected as representative cancer types for further study, the results of immunohistochemistry indicated that the protein levels of MRGBP were significantly elevated in tumor tissues. Moreover, our LIHC data analysis showed that patients with high MRGBP expression were associated with short survival rates and MRGBP was a risk factor to determine OS. Immunohistochemistry also confirmed that M0 macrophage infiltration in the MRGBP-high group significantly increased. In conclusion, these results reveal that MRGBP can serve as a potential prognostic biomarker and it plays an important role in tumor immune infiltration in various tumors, especially in LGG and LIHC.

Zhendong Qiu,* Wenhong Deng,* Yupu Hong, Liang Zhao, Man Li, Yongjun Guan, Yingru Su, Chen Chen, Qiao Shi, Jia Yu, Weixing Wang Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weixing Wang; Jia YuDepartment of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, People’s Republic of ChinaEmail sate.llite@163.com; yogaqq116@163.comPurpose: To research the effects of ATP citrate lyase (ACLY) and Sterol-regulatory element binding protein 1 (SREBP1) on the biology and lipid metabolism of colorectal cancer cells.Methods: Colorectal cancer cells Caco-2 and Lovo were transfected with ACLY or SREBP1 gene knockdown lentiviruses. Four groups were set: ACLY knockdown, SREBP1 knockdown group, empty vector-transfected (negative control), and untreated cells (blank control). Cell proliferation was measured using CCK-8, colony formation, and EdU labeling assays. Apoptosis was detected using Annexin V-APC/7- AAD and JC-1 assay. Transwell migration and wound healing assays analyzed cell migration and invasion. A triglyceride test kit and oil red O stain assessed cell lipid production. Key factors related to lipid metabolism were detected.Results: ACLY and SREBP1 promoted cell proliferation at 48 and 120 h, but there was no significant difference in Caco-2 cells at 24 h, at which point the effect of SREBP1 was more important. ACLY’s effect on cell proliferation was more obvious at 120 h. Colony formation assays in Caco-2 showed similar results to the CCK-8 assay at 120 h, but ACLY knockdown had no effect in Lovo cells. EDU assays showed that ACLY or SREBP1 facilitated DNA reproduction in the two cell lines, in which SREBP1 was more significant. Knockdown of the two genes showed significant differences in Lovo cells. However, ALCY knockdown promoted apoptosis to a greater extent than SREBP1 knockdown in Caco-2 cells. In addition, ACLY and SREBP1 enhanced migration, invasion, and lipid production in both cell lines. Knockdown of ACLY or SREBP1 reduced lipid metabolism pathway gene expression in the two cell lines.Conclusion: Knockdown of ACLY and SREBP1 genes inhibit the proliferation, migration, and invasion of colorectal cancer cells, while promoting their apoptosis. Our results identified potential new targets to treat colorectal cancer via lipid synthesis modulation in cancer cells.Keywords: ATP-citrate lyase, colorectal cancer, lipid metabolism, sterol-regulatory element binding protein 1

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease COVID-19 has caused over 275 million cases of illness and over 5 million deaths as of December 2021. The spike glycoproteins expressed on surface of the SARS-CoV-2 particle are the primary target of both vaccination and monoclonal antibody therapies. Widely reported evidence suggests that a subset of both naturally produced and synthetic antibodies (Abs) enhance infection, a phenomenon known as antibody-dependent enhancement (ADE). Recently, it has been demonstrated that the mechanism by which some Abs may elicit ADE is by enhancing the binding affinity of SARS-CoV-2 spike to its ligand - the human ACE2 receptor. Using in vitro spike-ACE2 binding assays, we identified two Abs which demonstrated ADE for spike/human ACE2 binding. Surprisingly, these binding-enhancing antibodies sufficiently neutralized SARS-CoV-2 pseudo-virus infection in human ACE2-knockin 293T cells, as well as live virus infection in Vero-E6 (non-human primate cell line) and Calu-3 (human cell line) cells in vitro. Furthermore, these receptor-binding enhancing antibodies significantly reduce but not enhance signs of SARS-CoV-2 infection in human ACE2-knockin mice, including viral replication and tissue pathology. Taken together, our data suggest a discrepancy between results of in vitro spike/receptor binding assay and virus neutralization assays for SARS-CoV-2 infection. Enhanced spike binding to host receptors is not a reliable measure of screening for ADE antibodies, but may be a mechanism by which virus neutralization is achieved in nature. This work was supported in part by grants from the National Institutes of Health (R01 AI151139, R56 AI146226 and P20 GM130555). W. Huang also received research support from MegaRobo Technologies Corporation.

OBJECTIVE: Diabetes is common in COVID-19 patients and associated with unfavorable outcomes. We aimed to describe the characteristics, outcomes and analyze the risk factors for in-hospital mortality of COVID-19 patients with diabetes.RESEARCH DESIGN AND METHODS: This two-center, retrospective study was performed at two tertiary hospitals in Wuhan, China. Confirmed COVID-19 patients with diabetes (N=153) who were discharged or died from January 1, 2020, to March 8, 2020, were identified. One sex- and age-matched COVID-19 patient without diabetes was randomly selected for each patient with diabetes. Demographic, clinical, and laboratory data were abstracted. Cox proportional hazards regression analyses were performed to identify the risk factors associated with the mortality in these patients.RESULTS: Of 1561 COVID-19 patients, 153 (9.8%) had diabetes, with a median age of 64.0 (IQR, 56.0-72.0) years. A higher proportion of ICU admission (17.6% vs 7.8%, P=0.01) and more fatal cases (20.3% vs 10.5%, P=0.017) were identified in COVID-19 patients with diabetes than in the matched patients. Multivariable Cox regression analyses of these 306 patients showed that hypertension (hazards ratio [HR] 2.50, 95% CI 1.30-4.78), cardiovascular disease (HR 2.24, 95% CI 1.19-4.23) and chronic pulmonary disease (HR 2.51, 95% CI 1.07-5.90) were independently associated with in-hospital death. Diabetes (HR 1.58, 95% CI 0.84-2.99) was not statistically significantly associated with in-hospital death after adjustment. Among patients with diabetes, nonsurvivors were older (76.0 vs 63.0 years), most were male (71.0% vs 29.0%), and were more likely to have underlying hypertension (83.9% vs 50.0%) and cardiovascular disease (45.2% vs 14.8%) (all P-valuesCONCLUSIONS: COVID-19 patients with diabetes had worse outcomes compared with the sex- and age-matched patients without diabetes. Older age and comorbid hypertension independently contributed to in-hospital death of patients with diabetes.

Additional file 12: The ability of microbiota to convert urea into glutamine was stronger in the gut of FMT_MM mice at week 0, without the induction of MM tumorigenesis.

Additional file 7: Figure S5. The differential taxa in HC and MM subjects. (a) The circles in red and in blue represent MM-enriched and HC-enriched taxa, respectively. (b) The abundance of MM-enriched taxa in MM patients with ISS stage-II and ISS stage-III, respectively.

Additional file 2: Figure S2. Boxplot shows the thirty most abundant microbial genera, accounting for about 96% of gut microbiota. The boxes in blue or red denote samples from HC or MM groups, respectively. The significance was determined by P-value from the two-tailed Wilcoxon rank-sum test. Boxes represent the interquartile ranges (IQRs) between the first and third quartiles, and the line inside the box shows the median; whiskers denote the lowest or highest values within 1.5 times of IQR from the first or third quartiles. Circles represent data points beyond the whiskers. ▪ adj. P > 0.05, * adj. P < 0.05, ** adj. P < 0.01, *** adj. P < 0.001.

Additional file 3: Figure S3. Co-occurrence network derived from the Spearman’s correlation (Rho>0.5, P-value

Additional file 6: Figure S4. Graphs show the species without statistical difference in an expanded cohort using qPCR. HC-enriched species are highlighted in the blue frame, while MM-enriched species in the red frame. In HC, the circles in red and white represent the subjects from a new collection of controls and metagenomic sequenced groups, respectively. In MM, the squares in red and white represent the subjects from a new collection of MM patients and metagenomic sequenced groups, respectively. P-value was determined by using two-tailed Mann-Whitney test. Note that some species were undetected in some samples. There are 1, 3, 18, 12, 1, 15, 5, 10, 3, 8, 8, 16, 6, 24, and 6 undetected samples for Streptococcus anginosus, Streptococcus parasanguinis, Intestinmonas butyriciproducens, Prevotella ruminicola, Prevotella melaninogenica, Collinsella aerofaciens, Bifidobacterium dentium, Fusobacterium varium, Bifidobacterium catenulatum, Bifidobacterium kashiwanohense, Bifidobacterium pseudocatenulatum, Lachnoclostridium phytofermentans, Herbinix luporum, Clostridium beijerinckii, and Clostridium difficile, respectively.

Additional file 9: Figure S6. Heatmap shows the Spearman’s correlation between the 36 differential species and 26 differential metabolites. *, +, and # all suggest the significance; * P

The titanium carbides are potential candidates to achieve both high hardness and refractory property. We carried out a structural search for titanium carbides at three pressures of 0 GPa, 30 GPa and 50 GPa. A phase diagram of the Ti-C system at 0 K was obtained by elucidating formation enthalpies as a function of compositions, and their mechanical and metallic properties of titanium carbides were investigated systematically. We also discussed the relation of titanium concentration to the both mechanical and metallic properties of titanium carbides. It has been found that the average valence electron density and tractility improved at higher concentrations of titanium, while the degree of covalent bonding directionality decreased. To this effect, the hardness of titanium carbide decreases as the content of titanium increases. Our results indicated that the titanium content significantly affected the metallic properties of the Ti-C system.

Resistance to radiotherapy and chemotherapy currently represents one of the major reasons for therapeutic failure in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying resistance to chemotherapy in NPC remain unclear. In this study, cell counting assay, cell cycle assay and senescence associated β-galactosidase activity were performed to evaluate cell growth, proliferation and senescence, respectively. We found that the aberrant expression of cyclooxygenase-2 (COX-2) was associated with a poor outcome and recurrance in patients with NPC. In NPC cells, COX-2 overexpression increased cell proliferation, inhibited cellular senescence and resulted in chemoresistance, while the knockdown of COX-2 reduced cell proliferation, promoted cellular senescence and overcame chemoresistance. Furthermore, fibroblasts from COX-2 knockout mice exhibited cellular senescence, particularly when treated with chemotherapeutic agents. Mechanistically, COX-2 interacted with p53 protein and inhibited cellular senescence, which resulted in chemotherapeutic resistance. On the whole, these findings indicate that COX-2 may play a critical role in chemotherapeutic resistance in NPC via the inhibition of chemotherapy-induced senescence via the inactivation of p53. This study provides experimental evidence for the preclinical value of increasing chemotherapy-induced senescence by targeting COX-2 as an effective antitumor treatment in patients with recurrent NPC.

A special processing method integrating the hot isostatic pressing and heat treatment was developed to produce TiAl alloy. As compared with the traditional two-step method, which consists of separate hot isostatic pressing and subsequent heat treatment in vacuum, the integrated approach will introduce an isostatic pressure throughout the whole process from the consolidation of powder to the heat treatment of coupon. Two types of microstructure, i.e., lamellar and duplex, have been generated by integrated and separate methods. Tensile test at room temperature indicates that the yield strength and tensile elongation of lamellar microstructure generated by integrated method are 650±30 MPa and 2.1±0.2% respectively, which are improved simultaneously as compared with 550±28 MPa and 0.6±0.1% for sample generated by separate approach. Moreover, such simultaneous enhancement of yield strength and ductility is also observed in duplex microstructure, where the yield strength and tensile elongation increase from 420±18 MPa and 2.4±0.4% in samples with separate method, to 540±25 MPa and 3±0.3% in those generated by integrated approach. Additionally, the microstructural examination also revealed the influence of microstructure to the mechanical performance. The results show that the simultaneous improvement of yield strength and tensile elongation is mainly attributed to the suppression of cracking, which is prone to happen during heat treatment without atmospheric pressure. Using the integrated method, the isostatic pressure could sustain the equilibrium pores during heat treatment, and provides an exterior force to balance the potential internal stresses due to phase transformation.

Nb–C compounds are potential candidates to achieve high hardness and refractory nature. We performed a crystal structure search for the Nb–C system using an ab initio evolutionary algorithm implemented in the USPEX code. By comparing the formation enthalpy, a P–x phase diagram was calculated, and an orthorhombic Pnnm structure of Nb2C was predicted and denoted as Nb2C-I, which was both mechanically and dynamically stable. In this Pnnm phase, there are four-sided rings continuously along the c-axis, which probably contributes to the relatively high incompressibility of Nb2C-I along the crystallographic c-axis. Moreover, the hardness and Young's modulus were calculated to be 28.5 GPa and 448.9 GPa, respectively; hence, the Nb2C-I is considered as a potential ultra-stiff and hard material.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy. Although the use of bortezomib (BTZ) significantly improves MM therapy, intrinsic and acquired drug resistance to BTZ remains a major clinical problem. In this study, we find that Cdc37, a key co-chaperone of Hsp90, is downregulated in relapsed MM patients, especially after BTZ treatment, suggesting a link between Cdc37 and BTZ resistance. Suppression of Cdc37 or inhibition of Cdc37/Hsp90 association induces plasma cell dedifferentiation, quiescence of MM cells, and BTZ resistance in MM. Furthermore, we discover that Cdc37 expression correlates positively with Xbp1s, a critical transcription factor for plasma cell differentiation in MM samples. Depletion/inhibition of Cdc37 downregulates Xbp1s, while overexpression of Xbp1s in MM cell lines partially rescues plasma immaturation and BTZ resistance. It is suggested that Xbp1s may act as a key downstream effector of Cdc37. Experiments with a mouse model also demonstrate that Cdc37 inhibition promotes plasma cell immaturation, confers BTZ resistance, and increases MM progression in vivo. Together, we identify a critical factor and a new signaling mechanism that regulate plasma cell immaturation and BTZ resistance in MM cells. Our findings may constitute a novel strategy that overcomes BTZ resistance in MM therapy.

Nasopharyngeal carcinoma (NPC) has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. We have previously shown that high cyclooxygenase‐2 (COX‐2) expression is associated with a poor prognosis of patients with NPC and inhibits chemotherapy‐induced senescence in NPC cells. In this study, we found that COX‐2 was upregulated in cancer‐associated fibroblasts (CAFs) derived from NPC by RNA‐Seq. Furthermore, elevated COX‐2 expression in CAF was detected in NPC patients with poor survival and distant metastasis by using immunohistochemistry. Then, we identified that COX‐2 is highly expressed in CAF at the distant metastasis site in seven paired NPC patients. High expression of COX‐2 and secretion of prostaglandin E2, a major product catalyzed by COX‐2 in fibroblasts, promotes migration and invasiveness of NPC cells in vitro. On the contrary, inhibition of COX‐2 has the opposite effect in vitro as well as in the COX‐2−/− mouse with the lung metastasis model in vivo. Mechanistically, we discovered that COX‐2 elevates tumor necrosis factor‐α expression in CAF to promote NPC cell migration and invasiveness. Overall, our results identified a novel target in CAF promoting NPC metastasis. Our findings suggested that high expression of COX‐2 in CAF may serve as a new prognostic indicator for NPC metastasis and provide the possibility of targeting CAF for treating advanced NPC.

Objective: Prostate cancer is one of the most diagnosed malignancies in men worldwide. Novel (nua) kinase family 1 (NUAK1) is a member of adenosine monophosphate (AMP)-related kinase which participates in varying cancers progression. However, the role of NUAK1 in prostate tumorigenesis has not been fully characterized. The aim of this study was to elucidate the potential biological role of NUAK1 in prostate cancer. Methods: Quantitative real-time PCR (qRT-PCR) was performed to determine the expression levels of NUAK1 and microRNA-30b-5p (miRNA-30b-5p) in prostate cancer cell lines and samples. Western blot was conducted to explore the related protein levels of epithelial-mesenchymal transition (EMT) and NUAK1 expression in prostate cancer cells. Trans-well test was used to assay prostate cancer cell migration and invasion. Luciferase assays were employed to probe the interaction between NUAK1 and miR-30b-5p. Results: NUAK1 abundance was enhanced in prostate cancer tissues and cell lines. The knockdown of NUAK1 may inhibit prostate cancer cells EMT, migration and invasion. Luciferase assays suggested NUAK1 was a target gene of miR-30b-5p. Furthermore, miR-30b-5p suppressed EMT, migration, and invasion in prostate cancer cells and introduction of NUAK1 abated the inhibitory effect. Conclusions: Both of NUAK1 and miR-30b-5p were required for prostate cancer progression. NUAK1 interference limited prostate cancer cell EMT, migration and invasion by miRNA-30b-5p modulating, providing a promising therapeutic approach for prostate cancer.

Background: Renal cell carcinoma (RCC) is one of the most common types of cancer. miR-572 has been proposed to be implicated in a number of human cancers, including RCC. Nevertheless, the detailed functions and molecular mechanisms of miR-572 in RCC have not been well illustrated. Methods: qRT-PCR assay was used to assess the expression of miR-572 in RCC specimens and cell lines. Loss-of-function experiments were carried out to explore the effect of miR-572 on proliferation and apoptosis in 786-O cells. Predicted by TargetScan, the interaction between miR-572 and neurofibromin 2 (NF2) was explored by dual-luciferase reporter assay and western blot analysis. To investigate whether the regulatory effect of miR-572 was mediated by NF2, 786-O cells were transfected with anti-miR-572 alone, or together with si-NF2. After that, western blot assay was used to validate whethermiR-572 regulated proliferation and apoptosis of the RCC cell line through NF2/Hippo signaling. Results: miR-572 expression was upregulated in RCC specimens and cell lines, and miR-572 knockdown suppressed proliferation and enhanced apoptosis in 786-O cells. miR-572 repressed NF2 expression by binding to NF2 mRNA 3’-UTR. Moreover, the anti-miR-572-mediated regulatory effect on proliferation and apoptosis was abated by the restoration of NF2 expression in RCC cells. Furthermore, miR-572 knockdown activated NF2/Hippo signaling pathway in RCC cells. Conclusions: The regulatory effect of miR-572 on proliferation and apoptosis is mediated through modulating NF2/Hippo signaling in RCC cell lines, providing a novel potential strategy for RCC.

To clarify the high temperature flow stress behavior and microstructures evolution of the wrought superalloy GH4066, the thermal simulation compression tests were conducted at the temperatures of 800, 900, 1000, 1100 and 1150 °C with the strain rate of 0.0003, 0.001, 0.01, 0.1, 1 and 10 s−1 on Gleeble-3800. The test results were used to construct the constitutive model of the superalloy based on the Arrhenius equation modified with the hyperbolic sine form. According to the test results, the dynamic recrystallization happened during the hot compression deformation process. The influence of temperature and strain rate on the dynamic recrystallization was analyzed in this paper, and the results were verified through the metallographic test. The comparison between the experimental and the predicted flow stress showed that the established constitutive model could well reflect the material properties of the superalloy.

The human papillomavirus pseudovirions (HPV-PsVs) approach is an effective gene-delivery system that can prime or boost an immune response in the vaginal tract of nonhuman primates and mice. Intravaginal vaccination with HPV-PsVs expressing SIV genes, combined with an i.m. gp120 protein injection, induced humoral and cellular SIV-specific responses in macaques. Priming systemic immune responses with i.m. immunization with ALVAC-SIV vaccines, followed by intravaginal HPV-PsV–SIV/gp120 boosting, expanded and/or recruited T cells in the female genital tract. Using a stringent repeated low-dose intravaginal challenge with the highly pathogenic SIVmac251, we show that although these regimens did not demonstrate significant protection from virus acquisition, they provided control of viremia in a number of animals. High-avidity Ab responses to the envelope gp120 V1/V2 region correlated with delayed SIVmac251 acquisition, whereas virus levels in mucosal tissues were inversely correlated with antienvelope CD4+ T cell responses. CD8+ T cell depletion in animals with controlled viremia caused an increase in tissue virus load in some animals, suggesting a role for CD8+ T cells in virus control. This study highlights the importance of CD8+ cells and antienvelope CD4+ T cells in curtailing virus replication and antienvelope V1/V2 Abs in preventing SIVmac251 acquisition.

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that shares a considerable degree of homology with dengue virus (DENV). Here, we examined longitudinal antibody response against ZIKV during natural infection in 2 convalescent individuals. By decomposing the antibody recognition into DI/DII and DIII of the E glycoprotein, we showed their development in humans followed a spatiotemporal hierarchy. Plasma binding to DI/DII appeared to peak and wane during early infection with extensive cross-reactivity with DI/DII of DENV. Binding to DIII, however, peaked early but persisted months into the infection without detectable cross-reactivity with DIII of DENV. A clear trend of increase in DIII-specific neutralizing activity was observed over the course of infection. mAbs isolated during early infection are largely DI/DII specific, weakly neutralizing, and highly cross-reactive with DENV, while those from later infection are more diverse in recognition, potently neutralizing, and ZIKV specific. The most potent neutralizing mAb targeting the DIII provided 100% protection in mice from lethal ZIKV infection and could therefore serve as a promising candidate for antibody-based therapy and prevention. The dynamic features unveiled here will assist us to better understand the pathogenesis of ZIKV infection and inform rational design of vaccines.

Background A desirable HIV vaccine should induce protective long-lasting humoral and cellular immune responses. Methods Macaques were immunized by env DNA, selected from a panel of recently transmitted SIVmac251 Env using intradermal electroporation as vaccine delivery method and magnitude, breadth and longevity of humoral and cellular immune responses. Results The macaques developed high, long-lasting humoral immune responses with neutralizing capacity against homologous and heterologous Env. The avidity of the antibody responses was also preserved over 1-year follow-up. Analysis of cellular immune responses demonstrated induction of Env-specific memory T cells harboring granzyme B, albeit their overall levels were low. Similar to the humoral responses, the cellular immunity was persistent over the ~1-year follow-up. Conclusion These data show that vaccination by this intradermal DNA delivery regimen is able to induce potent and durable immune responses in macaques.