Construction and validation of an 18F-FDG-PET/CT-based prognostic model to predict progression-free survival in newly diagnosed multiple myeloma patients.

OBJECTIVE: To investigate the relationship between 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) related parameters and the prognosis of multiple myeloma and to establish and validate a prediction model regarding the progression-free survival (PFS) of multiple myeloma. METHODS: A retrospective analysis of 126 newly diagnosed multiple myeloma patients who attended Nanjing Drum Tower Hospital from 2014-2021. All patients underwent PET/CT before treatment and were divided into a training cohort (n = 75) and a validation cohort (n = 51). Multivariate Cox proportional hazard regression analysis incorporated PET/CT-related parameters and clinical indicators. A nomogram was established to individually predict PFS in MM patients. The model was evaluated by calculating the C-index and calibration curve. RESULTS: Here, 4.2 was used as the cut-off value of SUVmax to divide patients into high and low groups. PFS significantly differed between patients in the high-SUVmax group and low-SUVmax group, and SUVmax was an independent predictor of PFS in newly diagnosed multiple myeloma (NDMM) patients. Univariate and multivariate cox regression analysis suggested that lactate dehydrogenase (LDH), bone marrow plasma cell (BMPC), and SUVmax affected PFS. These factors were incorporated to construct a nomogram model for predicting PFS at 1 and 2 years in NDMM patients. The C-index and calibration curves of the nomogram exhibited good accuracy and consistency, and the DCA curves suggested that the model had good clinical utility. CONCLUSION: The PET/CT parameter SUVmax is closely related to the prognosis of myeloma patients. The nomogram constructed in this study based on PET/CT-related parameters and clinical indicators individually predicts the PFS rate of NDMM patients and enables further risk stratification of NDMM patients.

Bacillus subtilis JATP-3 Improves Nitrogen Metabolism by Regulating Intestinal Flora and AKG in Weaned Piglets.

Recently, it has been reported that oral probiotics improve the apparent digestibility of nitrogen in weaned piglets; however, the underlying mechanism is unclear. A total of 12 crossbred piglets (Yorkshire × Landrace; 28 days old) were randomly divided into two groups. The control (Con) group was fed with a basic diet + Luria-Bertani (LB; sterile; 10 mL), whereas the subject (Sub) group was fed with a basic diet + B. subtilis JATP-3 (1 × 109 CFU/mL; 10 mL). The results showed that feeding B. subtilis JATP-3 increased the final body weight and nitrogen deposition rate of weaned piglets (P < 0.05); while the daily weight gain showed an upward trend (P < 0.1). The abundance of Pedicoccus, Collinella, Turiciator, Veillonella, Clostridium, and Escherichia were significantly increased in the jejunum (P < 0.05). The abundance of Olsenella and Pediococcus were significantly increased in the ileum (P < 0.05). The metabolomics analysis showed that the levels of l-lactic acid and Alpha-ketoglutaric acid (AKG) in portal vein plasma were significantly increased (P < 0.05). In addition, the content of AKG in muscle and liver increased significantly (P < 0.01). The metagenomics analysis showed that Veillonella encoded the functional genes of 2-oxoglutarate synthase and promoted AKG production. The protein expression of eIF4E-binding protein 1 (4EBP1) phosphorylated in the skeletal muscle increased (P < 0.05). In summary, B. subtilis JATP-3 promotes dietary nitrogen metabolism and skeletal muscle synthesis by modulating the intestinal microbiota and its metabolites, in which AKG may be one of the main mediators of the therapeutic effects of B. subtilis JATP-3.

A novel approach to expedite wound healing with plasma brush of cold flame.

Excessive or persistent infection is a major contributing factor in impeding chronic wound healing. Wound bed preparations using antiseptics do not necessarily target the entire bacterial spectrum, and the highly proliferating granulation tissue may be sensitive to the cytotoxic effects, impairing tissue repair. Non-thermal gas atmospheric pressure plasmas are partially ionized gases that contain highly reactive particles while the gas phase remains near room temperature, thus having the capability of accessing small irregular cavities and fissures and killing bacteria because of the diffusive nature of gas phase plasma species that are chemically reactive, providing an ideal approach to topical wound disinfection. A non-thermal plasma brush device of novel design has been developed that is suitable for clinical application in the disinfection of oral and wound bacteria. In vivo studies have indicated that the plasma brush treatment rendered no harmful effect on healthy skin or tissues, while it could improve wound healing in Pseudomonas aeruginosa biofilm infected wounds exposed to an optimized treatment with argon plus 1% nitrogen (Ar + N2) plasma.

Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers.

Targeting the intrinsic apoptotic pathway regulated by B-cell lymphoma-2 (BCL-2) antiapoptotic proteins can overcome the evasion of apoptosis in cancer cells. BCL-2 inhibitors have evolved into an important means of treating cancers by inducing tumor cell apoptosis. As the most extensively investigated BCL-2 inhibitor, venetoclax is highly selective for BCL-2 and can effectively inhibit tumor survival. Its emergence and development have significantly influenced the therapeutic landscape of hematological malignancies, especially in chronic lymphocytic leukemia and acute myeloid leukemia, in which it has been clearly incorporated into the recommended treatment regimens. In addition, the considerable efficacy of venetoclax in combination with other agents has been demonstrated in relapsed and refractory multiple myeloma and certain lymphomas. Although venetoclax plays a prominent antitumor role in preclinical experiments and clinical trials, large individual differences in treatment outcomes have been characterized in real-world patient populations, and reduced drug sensitivity will lead to disease recurrence or progression. The therapeutic efficacy may vary widely in patients with different molecular characteristics, and key genetic mutations potentially result in differential sensitivities to venetoclax. The identification and validation of more novel biomarkers are required to accurately predict the effectiveness of BCL-2 inhibition therapy. Furthermore, we summarize the recent research progress relating to the use of BCL-2 inhibitors in solid tumor treatment and demonstrate that a wealth of preclinical models have shown promising results through combination therapies. The applications of venetoclax in solid tumors warrant further clinical investigation to define its prospects.

Study on the evolution of green innovation city network and its carbon emission effect in Yellow River Basin cities.

Against the background of increasing urbanization rate and intensifying global warming, conflicts between humans and the natural environment continue to arise, and regionalized forms of spatial organization have become an important research direction. This paper constructs a green innovation city network. It empirically tests the evolution process of the green innovation city network and its carbon emission effect by combining the social network approach and the spatial Durbin model. The conclusions are as follows: (1) the strong ties among green innovation city networks are mainly distributed in and around the provincial capital cities and the middle and lower reaches of the Yellow River Basin; the density of green innovation city networks has been strengthened, and the degree centrality and closeness centrality have been improved. (2) The carbon emissions of cities in the Yellow River Basin are generally increasing. Still, the rate of increase is slowing down. The carbon emissions from liquefied petroleum gas show a decreasing trend yearly, and the energy structure tends to improve. (3) The impact of the green innovation city network on carbon emissions mainly comes from its externality's direct and indirect effects; the increase of degree centrality will reduce the total carbon emissions in the region and the network-associated regions.

The Relationships between Waxes and Storage Quality Indexes of Fruits of Three Plum Cultivars.

In the present study, the cuticular wax morphology, composition and the relationship with storage quality in three plum cultivars of Prunus salicina 'Kongxin' (KXL), Prunus salicina 'Fengtang' (FTL) and Prunus salicina 'Cuihong' (CHL) were investigated during storage at room temperature of 25 ± 1 °C. The results illustrated that the highest cuticular wax concentration was discovered in KXL, followed by FTL and the lowest in CHL. The fruit wax composition of the three plum cultivars was similar and principally composed of alkanes, alcohols, fatty acids, ketones, aldehydes, esters, triterpenes and olefins. Alcohols, alkanes and triterpenes were the dominant fruit wax compounds of the three plum cultivars. After storage for 20 d at room temperature, the variation of cuticular wax crystal structure and composition showed significant cultivar-associated differences. The total wax content decreased for FTL and CHL and increased for KXL, and the wax crystal degraded and melted together over time. The higher contents of the main components in the three plum cultivars were nonacosane, 1-triacontanol, 1-heneicosanol, nonacosan-10-one, octacosanal, ursolic aldehyde and oleic acid. Alcohols, triterpenes, fatty acids and aldehydes were most dramatically correlated with the softening of fruit and storage quality, and alkanes, esters and olefins were most significantly correlated with the water loss. Nonacosane and ursolic aldehyde can enhance the water retention of fruit. Overall, this study will provide a theoretical reference for the further precise development of edible plum fruit wax.

Integration of clinical features and sociodemographic factors: a simplified prognostic model for patients with multiple myeloma based on a double-center retrospective analysis.

This study aimed to develop and validate a prognostic nomogram that combines clinical and sociodemographic factors of patients with newly diagnosed multiple myeloma (MM). A total of 257 newly diagnosed patients with MM from two independent medical centers in China were included in this retrospective cohort study. Univariate and multivariate Cox regression models were used to identify independent risk factors and to construct the nomogram. The predictive ability of the nomogram was evaluated using the areas under the curve (AUCs) and calibration curves. K-fold cross-validation was employed for internal validation of the nomogram performance. Moreover, a stratification system to determine risk level was generated based on the nomogram. Hemoglobulin, creatinine, rurality, and marital status were significantly associated with overall survival (OS) and were incorporated into the nomogram for OS prediction. The prognostic nomogram showed good discrimination and accuracy, and its predictive capability was superior to the International Staging System. The AUC values predicting the 1-, 3-, and 5-year OS probabilities of the nomogram were 0.775, 0.755, and 0.754, respectively. Subsequently, patients were classified into high- and low-risk subgroups based on the median total points of the nomogram; this risk stratification clearly distinguished between high- and low-risk MM patients with significantly different clinical outcomes (median OS: 27 months vs. 84 months). We established a novel prognostic prediction model by comprehensively incorporating clinical and sociodemographic variables, which can effectively predict the survival outcomes in patients with MM.

Evaluation of Preharvest Melatonin on Soft Rot and Quality of Kiwifruit Based on Principal Component Analysis.

Botryosphaeria dothidea is the source of the deadly kiwifruit disease known as soft rot. In order to explore the role of melatonin in regulating the postharvest quality and disease resistance of kiwifruit at different growth and development stages, in this study, we applied melatonin at different concentrations to kiwifruit at the young fruit, expansion, and late expansion stages to assess its effect on fruit resistance to B. dothidea, minimize soft rot, and maintain postharvest fruit quality. The results showed that melatonin significantly suppressed the mycelial growth of B. dothidea, with 1.0 mmol/L melatonin inhibiting it by up to 50%. However, 0.1-0.3 mmol/L melatonin had the best control over soft rot. Furthermore, spraying MT during kiwifruit growth can successfully increase fruit weight; preserve postharvest fruit firmness; reduce respiration intensity in the early stages of storage; delay the rise in soluble solids, while maintaining a high titratable acid content to ensure suitable solid acid ratio; increase total phenol, flavonoid, chlorophyll, carotenoid, and ascorbic acid contents; and delay the rise in soluble sugar contents in the late stages of storage. These results have a positive effect on maintaining the nutritional composition of kiwifruit. However, the effects on weight loss, dry matter content, and soluble protein content were not significant. In addition, the results of the principal component analysis demonstrated that 0.3 mmol/L MT increased kiwifruit's resistance to soft rot while preserving postharvest fruit quality.

Kinetic and isotherm of competitive adsorption cadmium and lead onto Saccharomyces cerevisiae autoclaved cells.

Heavy metal pollution has been regarded as a significant public health hazard during the industrialization, which also have exhibited various types of toxicological manifestations. Moreover, due to the high cost and toxic by-products, some conventional remediation methods were limited to heavy metals pollution control. In this work, autoclaved Saccharomyces cerevisiae was used as a biosorbent for the removal of Cd2+ and Pb2+ from single and binary ions aqueous solution system. The kinetics and isotherm of Cd2+ and Pb2+ were studied in different ion systems. The results showed that the competitive adsorption ability of S. cerevisiae to Pb2+ was stronger than that to Cd2+ in binary ions solution. To all the single ion solution of Cd2+ or Pb2+ and binary ions solution of Cd2+-Pb2+, there always existed that the adsorption of metal ions on S. cerevisiae fitted well with pseudo-second-order kinetic model and Langmuir isotherms model. The adsorption quantity qt in different solutions followed the sequence as qt (Cd2+-Pb2+) > qt (Pb2+-single) > qt (Pb2+-binary) > qt (Cd2+-single) > qt (Cd2+-binary). The autoclaved S. cerevisiae used in this research was one kind of rapid and favourable biosorbent for Pb2+ and Cd2+. In Pb2+ and Cd2+-containing solutions, sites competition and jointed toxicity of Pb2+ and Cd2+ on S. cerevisiae cells were the key to the total adsorption effect, and further researches were necessary in the next work. Thus, the current research presented that the autoclaved S. cerevisiae could be applied as an effective biosorbent for heavy metal adsorption from water environment and the design of eco-friendly technologies for the treatment of waste liquor.

Melatonin Treatment Affects Wax Composition and Maintains Storage Quality in 'Kongxin' Plum (Prunus salicina L. cv) during Postharvest.

Cuticular wax is an essential barrier against biological and abiotic stress and is also an important factor affecting fruit storage quality. This paper investigated the effect of melatonin treatment on cuticular wax and the storage quality of plum fruit at low temperature storage of 4 ± 1 °C. 'Kongxin' plum was treated with 150 µmol·L-1 melatonin, dried overnight at room temperature 25 ± 1 °C, and then stored at 4 ± 1 °C for 40 d. The microstructure of the fruit epidermis was examined after 0, 20, and 40 d of storage, and the wax composition and fruit storage quality were measured at 10 d intervals. The results demonstrated that melatonin promoted the disintegration and thickening of rod-shaped waxy crystals of 'Kongxin' plum fruit and inhibited the combination of disintegrated wax and inner wax. Melatonin maintained fruit firmness and decreased the correlation between fruit firmness and other storage quality parameters. The correlation between firmness and wax composition was enhanced. Melatonin promoted long-chain alkanes that were positively correlated with firmness and water retention and strengthened the correlation between the length of the alkane chain and storage quality parameters but reduced the difference between alkane isomers and storage quality parameters.

Application of clinical nomograms to predicting overall survival and event-free survival in multiple myeloma patients: Visualization tools for prognostic stratification.

Background: This study aimed to develop reliable nomogram-based predictive models that could guide prognostic stratification and individualized treatments in patients with multiple myeloma (MM). Methods: Clinical information of 560 patients was extracted from the MM dataset of the MicroArray Quality Control (MAQC)-II project. The patients were divided into a development cohort (n = 350) and an internal validation cohort (n = 210) according to the therapeutic regimens received. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for nomogram construction. Nomogram performance was assessed using concordance indices, the area under the curve, calibration curves, and decision curve analysis. The nomograms were also validated in an external cohort of 56 patients newly diagnosed with MM at Nanjing Drum Tower Hospital from May 2016 to June 2019. Results: Lactate dehydrogenase (LDH), albumin, and cytogenetic abnormalities were incorporated into the nomogram to predict overall survival (OS), whereas LDH, ß2-microglobulin, and cytogenetic abnormalities were incorporated into the nomogram to predict event-free survival (EFS). The nomograms showed good predictive performances in the development, internal validation, and external validation cohorts. Additionally, we observed a superior prognostic predictive ability in nomograms compared to that of the International Staging System. According to the prognostic nomograms, risk stratification was applied to divide the patients into two risk groups. The OS and EFS rates of low-risk patients were significantly better than those of high-risk patients, suggesting a greater function of the nomogram models for risk stratification. Conclusion: Two simple-to-use prognostic models were established and validated. The proposed nomograms have potential clinical applications in predicting OS and EFS for patients with MM.

Changes in the Primary Metabolites of 'Fengtang' Plums during Storage Detected by Widely Targeted Metabolomics.

Plums are one of the most popular stone fruits worldwide owing to their high nutritional value. After harvest, plum fruit quality and flavor change during storage; however, little is known about the changes in metabolites during this period. A comprehensive comparison of primary metabolites in 'Fengtang' plum fruits during storage is performed using widely targeted primary metabolomics. A total of 272 primary metabolites were identified by means of ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS) in the plums at different storage periods. There was a significant increase in the relative amounts of twenty-eight lipids, twenty amino acids and their derivatives, thirteen organic acids, ten saccharides and alcohols, six nucleotides and their derivatives, and two vitamins. A Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differential metabolites revealed that glucosinolate biosynthesis, starch and sucrose metabolism, ascorbate and aldarate metabolism, lysine degradation, and other metabolic pathways were significantly enriched; therefore, changes in these metabolic pathways may be key to the quality and flavor change in 'Fengtang' plum fruits during storage. Our results provide a theoretical foundation and technical support to evaluate 'Fengtang' plum fruit quality.

Socioeconomic status-based survival disparities and nomogram prediction for patients with multiple myeloma: Results from American and Chinese populations.

Objective: This study aimed to comprehensively investigate the relationship between the survival differences and socioeconomic status (SES) in patients with multiple myeloma (MM) and construct a predictive nomogram to assess clinical outcomes of MM patients. Methods: The Surveillance, Epidemiology, and End Results (SEER) census tract-level SES database provides two specialized attributes: SES index and rurality. Using this database, 37,819 patients diagnosed with MM between January 2007 and December 2016 were enrolled. We evaluated the effects of SES index on overall survival (OS) and myeloma-specific survival (MSS) using Kaplan-Meier curves and Cox regression analyses. Thereafter, we included 126 patients with MM from two independent medical centers in China and divided them into training (Center 1) and validation (Center 2) cohorts. Univariate and multivariate Cox analyses were used in the training cohort to construct a nomogram for predicting clinical outcomes. Nomogram performance was assessed using the area under the curve (AUC) and calibration curves. Results: In the SEER cohort, lower SES was significantly associated with worse OS rates and MSS rates (both P < 0.001). Multivariate analysis confirmed SES as an independent predictor of survival. Subgroup analysis indicated an increasing linear trend in survival benefits in non-Hispanic White, married, insured, and urban populations with increasing SES (all P < 0.001). In the training cohort, albumin, creatinine, rurality, and SES were confirmed as independent prognostic indicators. A nomogram for OS prediction was developed using these four factors, and it showed satisfactory discrimination and calibration. The 18- and 36-month AUC values of the nomogram were 0.79 and 0.82, respectively. Based on the total nomogram points, patients were categorized into two risk levels with good separation. Conclusion: SES strongly influences survival disparities in patients with MM. Our nomogram consisting of clinical and sociodemographic characteristics can potentially predict survival outcomes.

Formosanin C induces autophagy-mediated apoptosis in multiple myeloma cells through the PI3K/AKT/mTOR signaling pathway.

OBJECTIVES: Multiple myeloma (MM) is an incurable plasma cell malignancy associated with poor survival. Novel therapeutic drugs are urgently needed to improve MM therapy and patient outcomes. This study aimed to investigate the effect of formosanin C (FC), a Chinese medicine monomer, on MM in vitro and disclose the underlying molecular mechanism. METHODS: The effect of FC on the viability, proliferation, apoptosis, and autophagy of MM cell lines (NCI-H929 and ARP1) was studied through CCK-8, colony formation, flow cytometry, GFP-LC3, and western blotting assays, respectively. A pharmacological approach and network pharmacology technology were implemented to explore the potential mechanisms of the action of FC on MM cells. RESULTS: FC efficiently suppressed the viability and colony-forming capacity, but promoted the number of autophagic vacuoles with GFP-LC3 localization and the percentage of apoptotic cells in MM cells. Additionally, FC significantly increased the levels of the autophagy-related proteins LC3-Ⅱ and Beclin 1, as well as the apoptosis-related proteins Bax and cleaved caspase-3, but blocked the expression of the proapoptotic protein Bcl-2 in the cells; these effects were reversed by an inhibitor of autophagy, 3-methyladenine. What's more, we found that the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was involved in the FC-mediated inhibition of MM. Pharmacological inhibition of this pathway dramatically relieved FC-triggered excessive expression of autophagy-related proteins and rescued MM cells from FC-induced apoptosis. CONCLUSION: Our findings indicate that FC exhibits an anti-MM effect by activating cell autophagy through the PI3K/AKT/mTOR signaling pathway.

A Bispecific Antibody Targeting RBD and S2 Potently Neutralizes SARS-CoV-2 Omicron and Other Variants of Concern.

Emerging severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) variants, especially the Omicron variant, have impaired the efficacy of existing vaccines and most therapeutic antibodies, highlighting the need for additional antibody-based tools that can efficiently neutralize emerging SARS-CoV-2 variants. The use of a "single" agent to simultaneously target multiple distinct epitopes on the spike is desirable in overcoming the neutralizing escape of SARS-CoV-2 variants. Herein, we generated a human-derived IgG-like bispecific antibody (bsAb), Bi-Nab35B5-47D10, which successfully retained parental specificity and simultaneously bound to the two distinct epitopes on receptor-binding domain (RBD) and S2. Bi-Nab35B5-47D10 showed improved spike binding breadth among wild-type (WT) SARS-CoV-2, variants of concern (VOCs), and variants being monitored (VBMs) compared with its parental monoclonal antibodies (MAbs). Furthermore, pseudotyped virus neutralization demonstrated that Bi-Nab35B5-47D10 can efficiently neutralize VBMs, including Alpha (B.1.1.7), Beta (B.1.351), and Kappa (B.1.617.1), as well as VOCs, including Delta (B.1.617.2), Omicron BA.1, and Omicron BA.2. Crucially, Bi-Nab35B5-47D10 substantially improved neutralizing activity against Omicron BA.1 (IC50 = 0.15 nM) and Omicron BA.2 (IC50 = 0.67 nM) compared with its parental MAbs. Therefore, Bi-Nab35B5-47D10 represents a potential effective countermeasure against SARS-CoV-2 Omicron and other variants of concern. IMPORTANCE The new, highly contagious SARS-CoV-2 Omicron variant caused substantial breakthrough infections and has become the dominant strain in countries across the world. Omicron variants usually bear high mutations in the spike protein and exhibit considerable escape of most potent neutralization monoclonal antibodies and reduced efficacy of current COVID-19 vaccines. The development of neutralizing antibodies with potent efficacy against the Omicron variant is still an urgent priority. Here, we generated a bsAb, Bi-Nab35B5-47D10, which simultaneously targets SARS-CoV-2 RBD and S2 and improves the neutralizing potency and breadth against SARS-CoV-2 WT and the tested variants compared with their parental antibodies. Notably, Bi-Nab35B5-47D10 has more potent neutralizing activity against the VOC Omicron pseudotyped virus. Therefore, Bi-Nab35B5-47D10 is a feasible and potentially effective strategy by which to treat and prevent COVID-19.

Resveratrol induces autophagy impeding BAFF-stimulated B-cell proliferation and survival by inhibiting the Akt/mTOR pathway.

Therapeutically targeting B cells has received great attention in the treatment of B-cell malignancies and autoimmune diseases. The B-cell activating factor (BAFF) is critical to the survival of normal and neoplastic B cells, and excess production of BAFF contributes to autoimmune diseases. Resveratrol, a natural polyphenolic compound, has a positive effect on the treatment of autoimmune diseases. However, how resveratrol affects BAFF-stimulated B-cell proliferation and survival is poorly understood. Here, we show that resveratrol increased autophagosome formation and ATG5/LC3-II levels and decreased p62 level, promoting autophagic flux/autophagy and thereby suppressing the basal or human soluble BAFF (hsBAFF)-stimulated proliferation and survival of normal and B-lymphoid (Raji) cells. This is supported by the findings that inhibition of autophagy with 3-methyladenine (3-MA, an inhibitor of Vps34) or ATG5 shRNA attenuates resveratrol-induced autophagy and -reduced proliferation/viability in B-cells. Inhibition of mTOR with rapamycin or knockdown of mTOR potentiated resveratrol-induced autophagy and inhibition of hsBAFF-stimulated B-cell proliferation/viability, while overexpression of wild-type mTOR conferred resistance to the actions of resveratrol. Similarly, inhibition of Akt with Akt inhibitor X or ectopic expression of dominant negative Akt reinforced resveratrol-induced autophagy and inhibition of hsBAFF-stimulated B-cell proliferation/viability, whereas expression of constitutively active Akt conferred resistance to the actions of resveratrol. Taken together, these results indicate that resveratrol induces autophagy impeding BAFF-stimulated proliferation and survival via blocking the Akt/mTOR signaling pathway in normal and neoplastic B cells. Our findings highlight that resveratrol has a great potential for prevention and treatment of excessive BAFF-elicited aggressive B-cell disorders and autoimmune diseases.

Associations of Education Level With Survival Outcomes and Treatment Receipt in Patients With Gastric Adenocarcinoma.

Background: It remains largely unclear how education level, an important socioeconomic factor, affects prognoses for patients with gastric adenocarcinoma (GAC). We aimed to demonstrate the associations between education level and clinical outcomes in patients with GAC. Methods: We included a total of 30,409 patients diagnosed with GAC from the Surveillance, Epidemiology, and End Results 18 registry database. Education level, household income, unemployment rate, poverty rate, insurance status, and marital status were selected as sociodemographic variables for the comprehensive analysis. Cox and logistic regression models, Kaplan-Meier curves, and subgroup analyses were the primary statistical methods employed. Results: A low level of education was correlated with less income, higher unemployment rates, and higher poverty rates (all p < 0.001). The multivariate Cox analysis indicated that a high education level was significantly associated with superior overall survival rates and cancer-specific survival rates in patients with GAC (both p < 0.001). We also corroborated favorable survival outcomes by high education level within almost every clinical and demographic subgroup. Furthermore, chemotherapy combined with surgery could markedly prolong the survival for all patients, including patients of stage IV cancer (both p < 0.001). By using multivariable logistic models, patients in counties with high education levels had a higher probability of chemotherapy receipt (p < 0.001). Contrarily, those in the counties with low levels of education were less likely to receive chemotherapy or undergo surgery (p < 0.001). Conclusions: Education level was identified and confirmed as an independent predictor of treatment and survival for GAC patients. Efforts are needed to provide effective interventions for those whose educational status is adverse.

Mutations and Phylogenetic Analyses of SARS-CoV-2 Among Imported COVID-19 From Abroad in Nanjing, China.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic and is threatening human health globally. The rapid genome sequencing and bioinformatic analysis of SARS-CoV-2 have become a helpful tool in the battle against the COVID-19. Here, we report the genetic characteristics, variations and phylogenetic analysis of SARS-CoV-2 sequenced from 42 clinical specimens. The complete genomes sequencing of SARS-CoV-2 were performed using Oxford Nanopore sequencing. All genomes accumulated mutations compared to the Wuhan-Hu-1 (GenBank Accession No: MN908947.3). Our data of the 42 whole genomes revealed 16 different lineages. The B.1.1 lineage was the most frequent, and 5, 2, 2, 3, and 1 sequences were classified as lineages of B.1.1.7, B.1.351, P.1, B.1.617.2, and C.37, respectively. A total of 328 nucleotide mutation sites were found in 42 genomes, among which A23403G mutation (D614G amino acid change in the spike protein) was the most common substitution. The phylogenetic trees of 42 SARS-CoV-2 sequences and GISAID-available SARS-CoV-2 sequences were constructed and its taxonomic status was supported. These results will provide scientific basis for tracing the source and prevention and control of SARS-CoV-2 imported from abroad in Nanjing, China.

NOX2-derived hydrogen peroxide impedes the AMPK/Akt-mTOR signaling pathway contributing to cell death in neuronal cells.

Oxidative stress is closely related to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. NADPH oxidase 2 (NOX2) is involved in hydrogen peroxide (H2O2) generation. Recently, we have reported that treatment with H2O2 and PD toxins, including 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenylpyridin-1-ium (MPP+) and rotenone, induces neuronal apoptosis by inhibiting the mTOR pathway. Here, we show that treatment with 6-OHDA, MPP+ or rotenone induced H2O2 generation by upregulating the levels of NOX2 and its regulatory proteins (p22phox, p40phox, p47phox, p67phox, and Rac1), leading to apoptotic cell death in PC12 cells and primary neurons. Inhibition of NOX2 with apocynin or diphenyleneiodonium, or knockdown of NOX2 powerfully attenuated PD toxins-evoked NOX2 and H2O2, thereby hindering activation of AMPK, inhibition of Akt/mTOR, and induction of apoptosis in neuronal cells. Pretreatment with catalase, a H2O2-scavenging enzyme, blocked the effects of PD toxins on NOX2-dependent H2O2 production, AMPK/Akt/mTOR signaling and apoptosis in the cells. Similar effects were also seen in the cells pretreated with Mito-TEMPO, a mitochondria-selective superoxide scavenger, implying a mitochondrial H2O2-dependent mechanism involved. Further research revealed that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPK with compound C suppressed PD toxins-induced expression of NOX2 and its regulatory proteins, as well as consequential H2O2 production and apoptosis in the cells. Taken together, these results indicate that certain PD toxins can impede the AMPK/Akt-mTOR signaling pathway leading to neuronal apoptosis by eliciting NOX2-derived H2O2 production. Our findings suggest that neuronal loss in PD may be prevented by regulating the NOX2, AMPK/Akt-mTOR signaling and/or applying antioxidants to ameliorate oxidative stress.

DOK2 Has Prognostic and Immunologic Significance in Adults With Acute Myeloid Leukemia: A Novel Immune-Related Therapeutic Target.

Background: The role of downstream tyrosine kinase 2 (DOK2), a major member of the DOK family, remains poorly defined in acute myeloid leukemia (AML). Herein, we investigated the expression levels, clinical outcomes, and biological functions of DOK2 in patients with AML. Methods: Datasets were obtained from the Cancer Genome Atlas (TCGA) database for transcriptomic and clinical information. Nomogram construction and assessment were conducted using Cox regression analysis, receiver operating characteristic (ROC) curves, and calibration plots. Public databases, including the Gene Expression Omnibus, Cancer Cell Line Encyclopedia, LinkedOmics, GeneMANIA, TISIDB, and Gene Set Cancer Analysis, were employed for relevant bioinformatic studies. Moreover, we utilized the CIBERSORT algorithm to evaluate the level of infiltration of immune cells into the bone marrow microenvironment. Results: We observed that DOK2 transcription levels were markedly upregulated in AML samples (P < 0.001), and its high expression was associated with inferior overall survival (OS) (HR = 2.17, P < 0.001) and disease-free survival (DFS) (HR = 2.50, P < 0.001). ROC curve analysis also showed the reliable diagnostic efficiency of DOK2 in AML. For treatment regimens, patients with high DOK2 expression could significantly prolong OS by receiving hematopoietic stem cell transplantation (HSCT) (P < 0.001), whereas those with low DOK2 expression were more likely to improve DFS by chemotherapy alone rather than HSCT. Nomograms constructed for predicting OS and DFS exhibited satisfactory discrimination and accuracy. Functional enrichment analysis identified that DOK2 was involved in important pathways associated with immune-related activities. Furthermore, CIBERSORT scores reflected negative correlations of DOK2 with activated mast cells and resting CD4+ memory T cells, which indicated its adverse immunomodulatory potential. Conclusion: We suggest that elevated DOK2 expression could be an unfavorable prognostic indicator of survival in patients with AML. Our findings provide new insights into the role of DOK2 in AML, with promising clinical implications.