Integrating plasma proteomes with genome-wide association data for causal protein identification in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a severely debilitating and fatal B-cell neoplastic disease. The discovery of disease-associated proteins with causal genetic evidence offers a chance to uncover novel therapeutic targets. METHODS: First, we comprehensively investigated the causal association between 2994 proteins and MM through two-sample mendelian randomization (MR) analysis using summary-level data from public genome-wide association studies of plasma proteome (N = 3301 healthy individuals) and MM (598 cases and 180,756 controls). Sensitivity analyses were performed for these identified causal proteins. Furthermore, we pursued the exploration of enriched biological pathways, prioritized the therapeutic proteins, and evaluated their druggability using the KEGG pathway analysis, MR-Bayesian model averaging analysis, and cross-reference with current databases, respectively. RESULTS: We identified 13 proteins causally associated with MM risk (false discovery rate corrected P < 0.05). Six proteins were positively associated with the risk of MM, including nicotinamide phosphoribosyl transferase (NAMPT; OR [95% CI]: 1.35 [1.18, 1.55]), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1; 1.14 [1.06, 1.22]), neutrophil cytosol factor 2 (NCF2; 1.27 [1.12, 1.44]), carbonyl reductase 1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2). Seven proteins were inversely associated with MM, which referred to suppressor of cytokine signaling 3 (SOCS3; 0.90 [0.86, 0.94]), Fc-gamma receptor III-B (FCGR3B; 0.75 [0.65,0.86]), glypican-1 (GPC1; 0.69 [0.58,0.83]), follistatin-related protein 1, protein tyrosine phosphatase non-receptor type 4 (PTPN4), granzyme B, complement C1q subcomponent subunit C (C1QC). Three of the causal proteins, SOCS3, FCGR3B, and NCF2, were enriched in the osteoclast differentiation pathway in KEGG enrichment analyses while GPC1 (marginal inclusion probability (MIP):0.993; model averaged causal effects (MACE): - 0.349), NAMPT (MIP:0.433; MACE: - 0.113), and NCF2 (MIP:0.324; MACE:0.066) ranked among the top three MM-associated proteins according to MR-BMA analyses. Furthermore, therapeutics targeting four proteins are currently under evaluation, five are druggable and four are future breakthrough points. CONCLUSIONS: Our analysis revealed a set of 13 novel proteins, including six risk and seven protective proteins, causally linked to MM risk. The discovery of these MM-associated proteins opens up the possibility for identifying novel therapeutic targets, further advancing the integration of genome and proteome data for drug development.

Causal relationships between inflammatory factors and multiple myeloma: A bidirectional Mendelian randomization study.

Changes in serum inflammatory factors occur throughout the onset and multiple myeloma (MM) progression, the feedback loops make it harder to distinguish between causes and effects. In the present study, we performed a bidirectional summary-level Mendelian randomization (MR) analysis to elucidate the causal relationships of C-reactive protein (CRP) and inflammatory regulators with MM. Summary-level data of genetic variants associated with inflammation were extracted from two genome-wide association studies (GWASs) on CRP and human cytokines, while data on MM was from large meta-analyses of GWASs among 372 617 UK Biobank participants. The inverse-variance weighted (IVW) method was used as the primary MR analysis and MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were used as the sensitivity analyses. Our results suggested that higher levels of monocyte-specific chemokine-3 (IVW estimate odds ratio [ORIVW ] per SD genetic cytokines change: 1.24; 95% confidence interval [CI]: 1.03-1.49; P = .02), vascular endothelial growth factor (1.14, 1.03-1.27; P = .02), interleukin-10 (1.33, 1.01-1.75; P = .04) and interleukin-7 (1.24, 1.03-1.48; P = .02) were associated with increased risk of MM, while lower levels of tumor necrosis factor-ß (0.84, 0.74-0.92; P < .001) was strongly associated with an increased risk of MM. And conversely, genetically predicted MM was related to increased levels of interleukin-17 (IVW estimate ß: 0.051, 95% CI: 0.018-0.085; P = 2.7 × 10-3 ). Besides, we observed no such significant associations for other inflammatory factors in our study. Overall, our study provides genetic evidence on the relationships of CRP and systemic inflammatory regulators with MM. Targeted interventions of specific inflammatory factors may have implications to alleviate MM cancer risk.

LncRNA UCA1 protects cardiomyocytes against hypoxia/reoxygenation induced apoptosis through inhibiting miR-143/MDM2/p53 axis.

BACKGROUND: lncUCA1 is abundantly expressed in the heart, indicating it may be important in maintaining normal myocardial function. However, the underlying mechanism of lncUCA1 in heart disease, particularly myocardial infarction (MI), is still in its infancy. METHODS: LncUCA1 and miR-143 expression were measured in hearts of MI models. Overexpression and knockdown of lncUCA1 in neonatal rat cardiomyocytes were performed to confirm the effects of lncUCA1 in hypoxia-induced apoptosis. RESULTS: The expression of lncUCA1 decreased but miR-143 increased inversely in MI heart. Overexpressing lncUCA1 protected cardiomyocytes from H/R induced apoptosis via inhibiting miR-143, which regulates apoptosis by targeting MDM2/p53 pathway. While silencing lncUCA1 caused miR-143 upregulation and H/R-induced apoptosis increase. Moreover, miR-143 was proved to be a competitive target of lncUCA1. CONCLUSIONS: lncUCA1 might protect cardiomyocyte against H/R induced apoptosis by suppressing miR-143 and modulated the following downstream MDM2/p53 signaling pathway, indicating the therapeutic potential of targeting lncUCA1 for MI.

[Safety and efficacy of subcutaneous administration of bortezomib in the treatment of multiple myeloma].

OBJECTIVE: To analyze the efficacy and safety of subcutaneous administration of bortezomib in the treatment of multiple myeloma (MM) patients. METHODS: A total of 26 MM patients were enrolled in this study and treated with BDT (bortezomib-dexamethasone-thalidomide). In the 26 MM patients, 12 patients received subcutaneous administration of Bortezomib while 14 patients received conventional intravenous administration. The outcomes and adverse effects of two groups were retrospectively evaluated and compared. RESULTS: Overall response (OR) rates in the two groups were 75.00% and 71.43% respectively, in which complete remission (CR) plus very good complete remission (VGPR) rates were 50.00% and 47.14%, while CR rates were 16.67% and 28.57%. There were no statistically significant difference (P > 0.05). Time to achieve effectiveness in two groups was similar (P > 0.05). More than half patients in both groups achieved partial remission after the first treatment course and CR after the fourth course. Compared to the intravenous group, peripheral neuropathy rates remained significantly lower in subcutaneous group (16.67% vs. 64.29%, P = 0.021). The intravenous group had 7.14% grade 3 or worse, peripheral neuropathy but none found in the subcutaneous group. Rash occurred only in subcutaneous group (66.67%), but it was local, mild and transitional. No significant differences of other adverse events between the two groups were observed. CONCLUSION: Subcutaneous administration of bortezomib offers similar efficacy to standard intravenous administration in the treatment of multiple myelom, with an improved safety for lower rate of peripheral neuropathy.

Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study.

Background: Increasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses. Methods: We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis. Results: Our results showed that genetically predicted higher stem cell growth factor-ß (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra). Conclusions: Our MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.

Recombinant human p53 adenovirus injection combined with Bortezomib inhibits proliferation and promotes apoptosis in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a B-cell malignancy characterized by abnormal proliferation of clonal plasma cells in the bone marrow, the incidence of which has further increased in recent years. In multiple myeloma, wild-type functional p53 is often inactivated or dysregulated. Therefore, this study aimed to investigate the role of p53 knockdown or overexpression in multiple myeloma and the therapeutic effect of recombinant adenovirus-p53 (rAd-p53) in combination with Bortezomib. METHODS: SiRNA p53 and rAd-p53 were used to knock down and overexpress p53. RT-qPCR was used to detect gene expression, and western blotting (WB) was used to detect protein expression levels. We also constructed wild-type multiple myeloma cell line-MM1S cell xenograft tumor models and explored the effects of siRNA-p53, rAd-p53, and Bortezomib on multiple myeloma in vivo and in vitro. H&E staining and KI67 immunohistochemical staining were used to assess the anti-myeloma effects of recombinant adenovirus and Bortezomib in vivo. RESULTS: The designed siRNA p53 effectively led to the knockdown of the p53 gene, while rAd-p53 could significantly achieve p53 overexpression. p53 gene inhibited MM1S cell proliferation and promoted apoptosis of wild-type multiple myeloma cell line MM1S. P53 gene inhibited tumor proliferation in vitro by promoting p21 expression and reducing cell cycle protein B1 expression of MM1S. P53 gene overexpression could inhibit tumor growth in vivo. Injection of rAd-p53 in tumor models inhibited tumor development through p21- and cyclin B1-mediated cell proliferation and apoptosis regulation. CONCLUSIONS: We found that overexpression of p53 inhibits MM tumor cell survival and proliferation in vivo and in vitro. Furthermore, the combination of rAd-p53 and Bortezomib significantly improved the efficacy, which provides a new possibility for more effective treatment of MM.

A proteomic approach to analyze nitrogen- and cytokinin-responsive proteins in rice roots.

Nitrogen plays a central role in rice growth and development because it modulates a wide variety of processes, including cytokinin (CK) metabolism. CK-mediated signaling is also related to nitrogen metabolism. The functional relation between nitrogen and CK are extremely complex and unclear. In this study, a comparative proteomic analysis was carried out to analyze proteins regulated by nitrogen and CK in rice roots. Proteins extracted from rice roots are separated by two-dimensional polyacrylamide gel electrophoresis. Thirty-two protein spots that expressed similarly by nitrogen and CK treatments are selected for identification by mass spectrometry. Of these spots, 28 are successfully identified. These proteins were categorized into classes related to energy, metabolism, disease/defense, protein degradation, signal transduction, transposons, and unclear classification. Energy gives the largest functional category, suggesting that the glycolysis (two enzymes detected) and tricarboxylic acid cycle (six enzymes detected) are accurately regulated by nitrogen and CK, thus promoting the synthesis of amino acid. The identification of novel proteins provides new insights into the coordination of nitrogen and CK in rice. The possible role of these proteins is discussed.

Identification of Immune-Related Genes for Risk Stratification in Multiple Myeloma Based on Whole Bone Marrow Gene Expression Profiling.

Background: Multiple myeloma (MM) is characterized by abnormal proliferation of bone marrow clonal plasma cells. Tumor immunotherapy, a new therapy that has emerged in recent years, offers hope to patients, and studying the expression characteristics of immune-related genes (IRGs) based on whole bone marrow gene expression profiling (GEP) in MM patients can help guide personalized immunotherapy. Methods: In this study, we explored the potential prognostic value of IRGs in MM by combining GEP and clinical data from the GEO database. We identified hub IRGs and transcription factors (TFs) associated with disease progression by Weighted Gene Co-expression Network Analysis (WGCNA), and modeled immune-related prognostic signature by univariate and multivariate Cox and least absolute shrinkage and selection operator (LASSO) regression analysis. Subsequently, the prognostic ability of signature was verified by multiple statistical methods. Moreover, ssGSEA and GSEA algorithm reveled different immunological characteristics and biological function variation in different risk groups. We mapped the hub IRGs by protein-protein interaction network (PPI) and extracted the top 10 ranked genes. Finally, we conducted vitro assays on two alternative IRGs. Results: Our study identified a total of 14 TFs and 88 IRGs associated with International Staging System (ISS). Ten IRGs were identified by Cox -LASSO regression analysis, and used to develop optimal prognostic signature for overall survival (OS) in MM patients. The 10-IRGs were BDNF, CETP, CD70, LMBR, LTBP1, NENF, NR1D1, NR1H2, PTK2B and SEMA4. In different groups, risk signatures showed excellent survival prediction ability, and MM patients also could be stratified at survival risk. In addition, IRF7 and SHC1 were hub IRGs in PPI network, and the vitro assays proved that they could promote tumor progression. Notably, ssGSEA and GSEA results confirmed that different risk groups could accurately indicate the status of tumor microenvironment (TME) and activation of biological pathways. Conclusion: Our study suggested that immune-related signature could be used as prognostic markers in MM patients.

Effects of Insect-Proof Net Cultivation, Rice-Duck Farming, and Organic Matter Return on Rice Dry Matter Accumulation and Nitrogen Utilization.

Insect-proof net cultivation (IPN), rice-duck farming (RD), and organic matter return (OM) are important methods to realize sustainable development of rice production. A split-plot field experiment was performed to study the effects of IPN, RD, and OM on the rice yield, dry matter accumulation and N utilization. Results showed that compared to inorganic N fertilizer (IN), wheat straw return, and biogas residue return increased the rice yield by 2.11-4.28 and 4.78-7.67%, respectively, and also improved dry matter and N accumulation after the elongation stage (EG), dry matter and N translocation, and N recovery efficiency (NRE). These results attributed to an increase in leaf SPAD values and net photosynthetic rate (Pn) after the EG. Compared to conventional rice farming (CR), RD promoted the rice yield by 1.52-3.74%, and contributed to higher the leaf photosynthesis, dry matter and N accumulation, dry matter and N translocation, and NRE. IPN decreased the intensity of sun radiation in the nets due to the coverage of the insect-proof nets, which declined the leaf Pn, dry matter accumulation and translocation, N absorption and translocation, and NRE compared to open field cultivation (OFC). The rice yield of IPN were 2.48-4.98% lower than that of OFC. Compared to the interaction between CR and IN, the interaction between RD and OM improved the rice yield by 5.26-9.33%, and increased dry matter and N accumulation after the EG, dry matter and N translocation, and NRE. These results indicated that OM, RD and the interaction between RD and OM could promote dry matter accumulation and N utilization, which was beneficial to improve the rice yield.

Effects of screenhouse cultivation and organic materials incorporation on global warming potential in rice fields.

Global rice production will be increasingly challenged by providing healthy food for a growing population at minimal environmental cost. In this study, a 2-year field experiment was conducted to investigate the effects of a novel rice cultivation mode (screenhouse cultivation, SHC) and organic material (OM) incorporation (wheat straw and wheat straw-based biogas residue) on methane (CH4) and nitrous oxide (N2O) emissions and rice yields. In addition, the environmental factors and soil properties were also determined. Relative to the traditional open-field cultivation (OFC), SHC decreased the CH4 and N2O emissions by 6.58-18.73 and 2.51-21.35%, respectively, and the global warming potential (GWP) was reduced by 6.49-18.65%. This trend was mainly because of lower soil temperature and higher soil redox potential in SHC. Although the rice grain yield for SHC were reduced by 2.51-4.98% compared to the OFC, the CH4 emissions and GWP per unit of grain yield (yield-scaled CH4 emissions and GWP) under SHC were declined. Compared to use of inorganic fertilizer only (IN), combining inorganic fertilizer with wheat straw (WS) or wheat straw-based biogas residue (BR) improved rice grain yield by 2.12-4.10 and 4.68-5.89%, respectively. However, OM incorporation enhanced CH4 emissions and GWP, leading to higher yield-scaled CH4 emissions and GWP in WS treatment. Due to rice yield that is relatively high, there was no obvious effect of BR treatment on them. These findings suggest that apparent environmental benefit can be realized by applying SHC and fermenting straw aerobically before its incorporation.

Integrated rice-duck farming mitigates the global warming potential in rice season.

Integrated rice-duck farming (IRDF), as a mode of ecological agriculture, is an important way to realize sustainable development of agriculture. A 2-year split-plot field experiment was performed to evaluate the effects of IRDF on methane (CH4) and nitrous oxide (N2O) emissions and its ecological mechanism in rice season. This experiment was conducted with two rice farming systems (FS) of IRDF and conventional farming (CF) under four paddy-upland rotation systems (PUR): rice-fallow (RF), annual straw incorporating in rice-wheat rotation system (RWS), annual straw-based biogas residues incorporating in rice-wheat rotation system (RWB), and rice-green manure (RGM). During the rice growing seasons, IRDF decreased the CH4 emission by 8.80-16.68%, while increased the N2O emission by 4.23-15.20%, when compared to CF. Given that CH4 emission contributed to 85.83-96.22% of global warming potential (GWP), the strong reduction in CH4 emission led to a significantly lower GWP of IRDF as compared to CF. The reason for this trend was because IRDF has significant effect on dissolved oxygen (DO) and soil redox potential (Eh), which were two pivotal factors for CH4 and N2O emissions in this study. The IRDF not only mitigates the GWP, but also increases the rice yield by 0.76-2.43% compared to CF. Moreover, compared to RWS system, RF, RWB and RGM systems significantly reduced CH4 emission by 50.17%, 44.89% and 39.51%, respectively, while increased N2O emission by 10.58%, 14.60% and 23.90%, respectively. And RWS system had the highest GWP. These findings suggest that mitigating GWP and improving rice yield could be simultaneously achieved by the IRDF, and employing suitable PUR would benefit for relieving greenhouse effect.

[Heavy metals content and pollution risk assessment of cropland soils around a pesticide industrial park].

By the method of concentric circle distribution method, a total of 183 topsoil samples were collected from 30-km2 area around a pesticide industrial park in south Jiangsu Province, with the content and pollution index of soil Cd, Cr, Cu, Ni, Pb, Zn, Hg and As analyzed. The average contents of Hg, Cu, Cd, and Pb in the top soils were higher than those of the natural background values, and the contents of Hg and Cu were the highest. Taking the national standard II as the assessment criterion, the average pollution index values of Cd, Cr, Cu, Ni, Pb, Zn, and As in the top soils were all below 1, while those of the Hg and Cu were 1.59 and 1.05, respectively. In the southeast and northwest to the pesticide industrial park, soil heavy metals contamination was more serious, and, with the increasing distance to the park, the contents of soil Cd, Ni, Pb, Cr, As, Hg, Zn, and Cu increased first and then decreased to a stable level. The comprehensive pollution index of test metals indicated that the areas 200-1000 meter around the industrial park were of high risk in soil heavy metals contamination, while the areas 1000 meter beyond were safety. By using geostatistics and GIS, it was found that the pollution index of the eight heavy metals had significant spatial variability. Based on the principal component analysis and correlation analysis, it was speculated that the Zn, Ni, Cr, Pb, and As were mainly from soil parent materials, while the Hg, Cu, and Cd were mainly related to human activities.

[Characteristics of paddy field nitrogen leakage and runoff in rice-duck farming system].

A field experiment was conducted to study the characteristics of paddy field nitrogen (N) leakage and runoff under rice-duck farming (MRD), conventional farming (MR), and conventional farming with flooding (CK). Comparing with that under MR, the paddy field under MRD had a notable decrease of N (especially NO3- -N) concentration in its leaked liquid; but this concentration was tended to be increased, compared with that under CK. After 7-9 days of fertilization, the NH4+ -N and NO3- -N concentrations in paddy field surface water were higher under MRD than under MR. However, owing to the no draining and the higher band, the paddy field under MRD had a notable reduction of drainage, resulting in a marked decrease of N runoff than that under MR. Comparing with MR, the paddy field under MRD had an addition of nitrogen supply from duck dung, a reduction of N leakage and runoff, a lesser application of chemical nitrogen fertilizer, and more nitrogen uptake by rice plant. Both the reduction of N input and that of N output in rice-duck farming system were nearly equal in quantity.

[Strong stem effect and physiological characteristics of rice plant under rice-duck farming].

A field plot comparison experiment was conducted to study the strong stem effect and physiological characteristics of rice plant under rice-duck farming. The results showed that under rice-duck farming, the morphology of rice plant changed obviously, and the carbohydrate content and C/N ratio of the plant as well as the dry matter output from rice stem increased significantly, due to the activities of duck in paddy field. In the meantime, the length of basal internodes decreased by 2. 88%, while the stem diameter, stem mechanical strength, and stem lodging resistant index increased by 64.90%, 11.78%, and 10.95%, respectively. Rice-duck farming increased the root mass and root vitality in deeper soil layers, and decreased the proportion of black roots by 16.63%. It was indicated that rice-duck farming benefited the formation of strong rice stem and increased the stress resistance of rice plant, which would be favorable to the stable and high-yielding of rice.

[Effects of relatively high temperature at grain-filling stage on rice grain's starch viscosity profile and magnesium and potassium contents].

With rice cultivars Yangdao 6 (Indica) and Wuyujing 3 (Japonica) as test materials, the effects of relatively high temperature (RHT, mean temperature 30 degrees C) at grain-filling stage (GFS) on the starch viscosity profile and magnesium (Mg) and potassium (K) contents of rice grain were studied in a phytotron. Four temperature treatments were installed, i.e., RHT at whole GFS, RHT at early GFS and optimum temperature at later GFS, optimum temperature at early GFS and RHT at later GFS, and optimum temperature (CK, mean temperature 23 degrees C) at whole GFS. The results showed that RHT at GFS significantly influenced the characteristic values of rice grain' s starch viscosity profile, e.g., the values of gelatinization temperature, final viscosity, consistency, and setback increased, while those of peak viscosity, hot viscosity, and breakdown decreased, with Yangdao 6 and Wuyujing 3 followed the similar pattern. The RHT increased the contents of Mg, K, and N, especially of K, resulting in a marked decrease of Mg/K and Mg/(N * AC * K) in the grain. The grain's amylase content (AC) of the two cultivars showed contrasting in response to temperature treatments. Wuyujing 3 performed decrease, while Yangdao 6 exhibited increase in AC values. The RHT at whole GFS affected the starch viscosity profile and the Mg and K contents most greatly, followed by the RHT at early GFS, and the RHT at later GFS. The period within 20 days after flowering was the key period during which temperature affected the grain's starch viscosity profile and Mg and K contents. The Mg/K and Mg/ (N * AC * K) in rice grain significant correlated with the characteristic values of starch viscosity profile, which could be used as the reference indices of rice eating quality.

[Effect of rice-duck mutualism on nutrition ecology of paddy field and rice quality].

The production of nuisanceless rice was conducted by the technique of rice-duck mutualism without applying any pesticide and chemical fertilizer. The results showed that compared to the control, the effect of eliminating weeds was over 99.4%, and the cardinal numbers of plant diseases and insect pests reduced obviously. Nutrients and dissolved oxygen in paddy water and rapidly available nutrients in soil increased, but after maturing stage, compared to basal fertility, rapidly available P and K decreased. The N, P, and K absorption amounts of rice plant, rice yield, setting panicles rate, filled grains and ripened rate increased. The milling, appearance, nutritional, cooking and eating quality of rice improved, especially in reducing chalkiness. The comprehensive benefits of paddy field enhanced obviously.