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Abstract Background Hemodialysis patients require a reasonable dietary intake to manage their disease progression effectively. However, there is limited research on these patients’ overall dietary knowledge, attitude, and practice (KAP) status. This study aimed to investigate the dietary KAP status and latent profiles in hemodialysis patients and identify sociodemographic and disease-related factors associated with these profiles and dietary practice. Methods A multicenter cross-sectional study involving 425 hemodialysis patients was conducted. A dietary KAP questionnaire in hemodialysis patients was used to evaluate the dietary KAP of the patients. A structural equation model was employed to analyze the correlations between dietary knowledge, attitude, and practice. Multiple linear regression analysis was used to identify factors associated with dietary practice scores. Latent profile analysis was conducted to determine the latent profiles of dietary KAP, and binary logistic regression was used to explore the sociodemographic and disease-related characteristics associated with each KAP profile in hemodialysis patients. Results The normalized average scores for dietary knowledge, attitude, and practice in hemodialysis patients were 0.58, 0.82, and 0.58, respectively. The structural equation model revealed significant positive correlations between dietary knowledge and attitude, and attitude and practice. Attitude played an indirect effect between knowledge and practice. Gender, cerebrovascular disease, and dietary attitude scores were identified as independent influencing factors for dietary practice scores. Two dietary KAP profiles were developed: a profile with general knowledge and attitude but low practice (40.2%) and a profile with general knowledge and attitude and high practice (59.8%). Binary logistic regression analysis indicated gender and monthly income per household significantly predicted membership in each KAP profile. Conclusions The dietary practice of hemodialysis patients requires improvement. It is necessary to develop more individualized dietary interventions for these patients. Further exploration is needed to understand the motivation of patients to change their dietary behavior.

IntroductionEndophytic fungi can promote secondary metabolite accumulation in medicinal plants. Previously, we observed that the culture filtrate of Fusarium solani CL105 promoted flavonoid production in Scutellaria baicalensis calli. However, the active ingredients and mechanisms associated with this secondary metabolite accumulation remain unclear.MethodsThis study evaluates the effects of different elicitors from the culture filtrate of F. solani CL105 namely, exopolysaccharide (EPS), exoprotein (EP), and other parts (OP), on the flavonoid production in S. baicalensis calli by HPLC. Subsequently, the underlying mechanism of EPS induced flavonoid production in S. baicalensis calli was revealed by transcriptomics and RT-PCR.Results and discussionThe results indicated a significant increase in flavonoid production in S. baicalensis calli following treatment with EPS. Baicalin (1.40 fold), wogonoside (1.91 fold), and wogonin (2.76 fold) were most significantly up-regulated compared with the control. Transcriptome analysis further revealed up-regulation of key enzyme genes (CHS, CHI, FNS, and F6H) involved in flavonoid synthesis after 5 days of EPS treatment. Moreover, the expression of GA2ox and CYP707A—genes involved in gibberellin acid (GA) and abscisic acid biosynthesis (ABA), respectively—were significantly up-regulated. The expression levels of certain transcription factors, including MYB3, MYB8, and MYB13, were also significantly higher than in controls. Our results indicated that EPS was a main active elicitor involved in promoting flavonoid production in S. baicalensis calli. We postulated that EPS might stimulate the expression of MYB3, MYB8, MYB13, GA2ox, and CYP707A, leading to markedly upregulated CHS, CHI, FNS, and F6H expression levels, ultimately promoting flavonoid synthesis. This study provides a novel avenue for large-scale in vitro production of flavonoids in S. baicalensis.

AbstractBackground Decreased dietary protein intake (DPI) may lead to protein-energy malnutrition and may be associated with increased mortality risk. We hypothesized that longitudinal changes in dietary protein intake have independent associations with survival in peritoneal dialysis (PD) patients.Methods 668 stable PD patients were selected in the study from January 2006 to January 2018 and were followed up until December 2019. Their three-day dietary records were collected at the baseline (the sixth month after PD) and thereafter every 3 months for two and a half years. The latent class mixed models (LCMM) were used to identify subgroups of PD patients with similar longitudinal trajectories of DPI. The relation between DPI (baseline and longitudinal data) and survival was examined using Cox model to estimate death hazard ratios. Meanwhile, different formulae were used to assess nitrogen balance.Results The results showed that baseline DPI ≤ 0.60g/kg/day was associated with the worst outcome in PD patients. Patients with DPI 0.80–0.99g/kg/day and DPI ≥ 1.0g/kg/day both presented positive nitrogen balance; patients with DPI 0.61–0.79g/kg/day presented obviously negative nitrogen balance. Longitudinal association between time-dependent DPI and survival was found in PD patients. The consistently low DPI' (0.61–0.79g/kg/d) group was correlated with increased death risk as compared with the 'consistently median DPI' group (0.80–0.99g/kg/d, HR = 1.59, p = 0.008), whereas there was no difference in survival between 'consistently median DPI' group and 'high-level DPI' group (≥1.0 g/kg/d, p > 0.05).Conclusion Our study revealed that DPI ≥ 0.8 g/kg/day was beneficial to the long-term outcome for the PD population.

Abstract Background The objective of this study was to investigate the relationship between P2Y1 and P2Y12 genotypes and the risk of acute myocardial infarction (AMI) in the Quanzhou population and to determine associations between P2Y1 and P2Y12 genotypes and ADP-induced platelet aggregation in this population. Methods All subjects were screened for P2Y1 (c.1622A > G) and P2Y12 (H1/H2, c.34C > T) polymorphisms by direct DNA sequencing. The maximal platelet aggregation rate (MAR) in AMI patients (n = 61) and healthy control subjects (n = 50) was measured by a PL-12 platelet function analyzer, and adenosine diphosphate (ADP) (5 μmol/L) was used as an agonist. Results The haploid H2 allele in the P2Y12 gene was more frequent in patients with AMI than in control subjects (OR 1.887, P = 0.005). The P2Y12 H2 haplotype was significantly associated with AMI in the codominant (P = 0.008), dominant (OR 2.103, P = 0.003), and overdominant models (OR 2.133, P = 0.003). After adjusting for potential confounders, H2 haplotype carriers had a 2.132-fold increased risk for AMI (OR 2.132, P = 0.012) compared with noncarriers. Moreover, we observed that the ADP-induced MAR in the carriers of the H2 haplotype from the control group was somewhat higher than that in noncarriers of this group (P = 0.020). However, we failed to demonstrate that the P2Y1 H1/H2 polymorphism affected ADP-induced MAR in AMI patients. Additionally, P2Y1 c.1622A > and P2Y12 c.34C > T polymorphisms were not associated with the risk of AMI or ADP-induced MAR in either group. Conclusions Therefore, our results suggest that the P2Y12 H2 haplotype was associated with a higher risk of AMI, while its effect on increased ADP-induced platelet aggregation remains to be investigated. Thus, the P2Y12 H2 haplotype may be a potential marker for AMI.

Objective The protein equivalent of total nitrogen appearance (PNA) formula, based on the urea nitrogen appearance (UNA), is popularly used by stable continuous ambulatory peritoneal dialysis (CAPD) patients to estimate dietary daily protein intake (DPI). However, we found that the estimated DPI was higher than that directly evaluated from the dietary records of most of our CAPD patients. Therefore, in the present study, we tried to determine possible bias in PNA estimation by UNA with a nitrogen balance study of our CAPD patients. Methods Thirty-one CAPD patients with stable clinical conditions were included. Their 3-day dietary records were reviewed by a dedicated dietitian to calculate their energy, protein, and nitrogen intake (NI). The nitrogen removal (NR) from urine and dialysate was measured by the Kjeldahl technique. Then, we calculated the proportion of urea nitrogen appearance (UNA) in total nitrogen appearance (TNA) and analyzed the possible factors that could affect this proportion. Results Among these patients, 17 males and 14 females, the mean age was 64.19 ± 12.42, and the dialysate drainage volume was 6700 (2540) ml/day. The percentage of UNA in TNA was 63.22 ± 6.66%. Compared with the other classic nitrogen balance studies in the CAPD population, the protein nitrogen and other nonurea nitrogen losses in this study were all lower. Based on these 31 nitrogen balance studies, we proposed a pair of new equations to estimate PNA by UNA. (1) PNA = 9.3 + 7.73 UNA; (2) PNA = PNPNA + TPL = 6.7 + 7.28 UNA + TPL. Conclusion Our study suggested that the PNA formula generated from previous European studies overestimated DPI in our CAPD patients.

Abstract Chikungunya virus (CHIKV), a highly infectious and rapidly spread viral pathogen, is classified as a pathogenic agent at the biosafety level 3. Operation of live authentic CHIKV needs a specific laboratory with the P3 or above containment, which greatly confines the CHIKV-associated studies. To establish an evaluation system of CHIKV that can be utilized in a BSL2 laboratory, we constructed a pseudovirus (PsV) system of CHIKV containing double reporter genes (ZsGreen1 and luciferase). The fluorescent ZsGreen1 is a convenient and cheap reporter for monitoring the efficiency of transfection and titration of PsV. The enzyme luciferase is a sensitive reporter for the application of PsV to neutralization assay or drug screening. The CHIKV PsV produced in this study, with a titer of up to 3.16 × 106 TU/ml, was confirmed by Western blotting and transmission electronic microscopy (TEM). Finally, we developed a microneutralization assay with the CHIKV PsV produced in this study, which was successfully applied to evaluate neutralizing activities of convalescent sera from CHIKV-infected patients. In summary, we have established a convenient and sensitive double-reporter CHIKV pseudovirus system, which provides a safe and effective platform for screening anti-CHIKV drugs and evaluating vaccines against CHIKV.

Abstract The purpose of this study was to assess the feasibility of machine learning (ML) in predicting the risk of end-stage kidney disease (ESKD) from patients with chronic kidney disease (CKD). Data were obtained from a longitudinal CKD cohort. Predictor variables included patients’ baseline characteristics and routine blood test results. The outcome of interest was the presence or absence of ESKD by the end of 5 years. Missing data were imputed using multiple imputation. Five ML algorithms, including logistic regression, naïve Bayes, random forest, decision tree, and K-nearest neighbors were trained and tested using fivefold cross-validation. The performance of each model was compared to that of the Kidney Failure Risk Equation (KFRE). The dataset contained 748 CKD patients recruited between April 2006 and March 2008, with the follow-up time of 6.3 ± 2.3 years. ESKD was observed in 70 patients (9.4%). Three ML models, including the logistic regression, naïve Bayes and random forest, showed equivalent predictability and greater sensitivity compared to the KFRE. The KFRE had the highest accuracy, specificity, and precision. This study showed the feasibility of ML in evaluating the prognosis of CKD based on easily accessible features. Three ML models with adequate performance and sensitivity scores suggest a potential use for patient screenings. Future studies include external validation and improving the models with additional predictor variables.

Friedreich's ataxia is a rare disorder resulting from deficiency of frataxin, a mitochondrial protein implicated in the synthesis of iron-sulfur clusters. Preclinical studies in mice have shown that gene therapy is a promising approach to treat individuals with Friedreich's ataxia. However, a recent report provided evidence that AAVrh10-mediated overexpression of frataxin could lead to cardiotoxicity associated with mitochondrial dysfunction. While evaluating an AAV9-based frataxin gene therapy using a chicken β-actin promoter, we showed that toxic overexpression of frataxin could be reached in mouse liver and heart with doses between 1 × 1013 and 1 × 1014 vg/kg. In a mouse model of cardiac disease, these doses only corrected cardiac dysfunction partially and transiently and led to adverse findings associated with iron-sulfur cluster deficiency in liver. We demonstrated that toxicity required frataxin's primary function by using a frataxin construct bearing the N146K mutation, which impairs binding to the iron-sulfur cluster core complex. At the lowest tested dose, we observed moderate liver toxicity that was accompanied by progressive loss of transgene expression and liver regeneration. Together, our data provide insights into the toxicity of frataxin overexpression that should be considered in the development of a gene therapy approach for Friedreich's ataxia.

Abstract Trimethylamine-N-oxide (TMAO), a gut-microbiota-dependent metabolite generated from its dietary precursors such as choline, has been identified as an independent risk factor for atherosclerosis. Metformin is the most widely used drug for the treatment of type 2 diabetes (T2D), which has therapeutic effects on hyperglycemia accelerated atherosclerosis. A growing body of evidence suggest that metformin plays a therapeutic role by regulating the structure and metabolic function of gut microbiota. However, whether metformin has an impact on gut-microbiota-mediated TMAO production from choline remains obscure. In this study, the oral administration of metformin significantly reduced choline diet-increased serum TMAO in choline diet-fed C57BL/6J mice. The diversity analysis based on 16S rRNA gene sequencing of C57BL/6J mice fecal samples indicated that metformin markedly changed the gut-microbiota composition. Metformin was positively correlated with the enrichment of different intestinal bacteria such as Bifidobacterium and Akkermansia and a lower cutC (a choline utilization gene) abundance. Furthermore, the ex vivo and in vitro inhibitory effects of metformin on choline metabolism of TMA-producing bacteria were confirmed under anaerobic condition. The results suggested that metformin suppresses serum TMAO level by remodeling gut microbiota involved in TMA generation from choline.

Abstract Trimethylamine-N-oxide (TMAO), a derivative from the gut microbiota metabolite trimethylamine (TMA), has been identified to be an independent risk factor for promoting atherosclerosis. Evidences suggest that berberine (BBR) could be used to treat obesity, diabetes and atherosclerosis, however, its mechanism is not clear mainly because of its poor oral bioavailability. Here, we show that BBR attenuated TMA/TMAO production in the C57BL/6J and ApoE KO mice fed with choline-supplemented chow diet, and mitigated atherosclerotic lesion areas in ApoE KO mice. Inhibition of TMA/TMAO production by BBR-modulated gut microbiota was proved by a single-dose administration of d9-choline in vivo. Metagenomic analysis of cecal contents demonstrated that BBR altered gut microbiota composition, microbiome functionality, and cutC/cntA gene abundance. Furthermore, BBR was shown to inhibit choline-to-TMA conversion in TMA-producing bacteria in vitro and in gut microbial consortium from fecal samples of choline-fed mice and human volunteers, and the result was confirmed by transplantation of TMA-producing bacteria in mice. These results offer new insights into the mechanisms responsible for the anti-atherosclerosis effects of BBR, which inhibits commensal microbial TMA production via gut microbiota remodeling.

Co-infection of chikungunya virus (CHIKV) has been recently reported during dengue fever epidemics. However, the infection of CHIKV is often neglected due to its misdiagnosis as dengue virus (DENV) infection. In the summer of 2019 when dengue fever was epidemic, we collected 697 serum samples from febrile dengue fever–like patients in Xishuangbanna, southwestern part of China. DENV RNA was detectable in 99.42% of these patients. Notably, 88 patients (12.62%) showed the presence of CHIKV RNA, among which 86 patients were co-infected with DENV and CHIKV. We sequenced and analyzed the full genome of CHIKV virus in four out of 88 samples (two CHIKV infected and two co-infected). The results suggested that the four strains were all Asian genotype and had the highest homology (99.4%) with the SZ1239 strain (accession number MG664851) isolated in 2012 and possibly introduced from Indonesia. Further comparison with the conserved sequences in the whole genome of 47 strains of CHIKV showed that there were 13 and 15 amino acid mutants in structural proteins and non-structural proteins, respectively. The previously reported adaptive mutations of E2-W64R, E2-I211T, E2-K233E, E1-A98T, and E1-K211E occurred in the four strains of this study. In conclusion, this study reports a co-infection of CHIKV during the DENV epidemic in the city Xishuangbanna, 2019. Molecular epidemiology revealed that CHIKV identified in this study was indigenous and belongs to Asian lineage with lineage-specific mutations and some reported adaptive mutations, which is distinct from the recently reported CHIKV (East/Central/South African) in Ruili, the city next to Xishuangbanna.

To analyze pesticide residues, GC coupled with quadrupole-Orbitrap MS (GC-Orbitrap-MS) has become a powerful tool because of its unique characteristics of accurate mass full-spectrum acquisition, high resolution, fast acquisition rates, and overcoming matrix interference. This paper presents an efficiency evaluation of GC-Orbitrap-MS for identification and quantitation in the 352 pesticide residues analysis of chrysanthemum flowers in full-scan mode. A streamlined pretreatment approach using one-step extraction and dilution was used, which provided high-throughput processing and excellent recovery. The samples were extracted using acetonitrile. The extracted solution was purified by a Sin-QuEChERS Nano column to suppress the matrix in chrysanthemum flowers and determined by GC-Orbitrap-MS. The calibration curves for the 352 pesticides obtained by GC-Orbitrap-MS were linear in the range of 0.5–200 μg·kg−1, with the correlation coefficients higher than 0.99. The limits of detection (LODs) and the limits of quantification (LOQs) for the 352 pesticide residues were 0.3–3.0 μg·kg−1 and 1.0–10.0 μg·kg−1, respectively. The average recoveries in chrysanthemum flower at three levels were 95.2%, 88.6%, and 95.7%, respectively, with relative standard deviations (RSDs) of 7.1%, 7.5%, and 7.2%, respectively. Lastly, the validated method and retrospective analysis was applied to a total of 200 chrysanthemum flower samples bought in local pharmacies. The proposed method can simultaneously detect multipesticide residues with a good performance in qualitative and quantitative detection.

Background: Though many literatures documented burnout and occupational hazard among healthcare workers and frontliners during pandemic, not many adopted a systemic approach to look at the resilience among this population. Another under-studied population was the large numbers of global healthcare workers who have been deployed to tackle the crisis of COVID-19 pandemic in the less resourceful regions. We investigated both the mental wellbeing risk and protective factors of a deployed healthcare workers (DHWs) team in Wuhan, the epicenter of the virus outbreak during 2020.Method: A consensual qualitative research approach was adopted with 25 DHWs from H province through semi-structured interviews after 3 months of deployment period.Results: Inductive-Deductive thematic coding with self-reflexivity revealed multi-layered risk and protective factors for DHWs at the COVID-19 frontline. Intensive working schedule and high-risk environment, compounded by unfamiliar work setting and colleagues; local culture adaptation; isolation from usual social circle, strained the DHWs. Meanwhile, reciprocal relationships and “familial relatedness” with patients and colleagues; organizational support to the DHWs and their immediate families back home, formed crucial wellbeing resources in sustaining the DHWs. The dynamic and dialectical relationships between risk and protective factors embedded in multiple layers of relational contexts could be mapped into a socio-ecological framework.Conclusion: Our multidisciplinary study highlights the unique social connectedness between patient-DHWs; within DHWs team; between deploying hospital and DHWs; and between DHWs and the local partners. We recommend five organizational strategies as mental health promotion and capacity building for DHWs to build a resilient network and prevent burnout at the disaster frontline.

Objective To explore the roles of human mesenchymal stem cell (hMSC) death-associated protein kinase 1 (DAPK1) in modulating CD4+ T lymphocyte proliferation. Methods Human MSCs and peripheral blood mononuclear cells were isolated and cocultured in vitro for 3 days. Lentiviral-mediated RNA interference (LV-sh-DAPK1) was used to silence DAPK1 expression in hMSCs. Expression of DAPK1 was assessed by western blotting. Transcriptional levels of DAPK1, transforming growth factor-β1, indoleamine 2,3-dioxygenase, inducible nitric oxide synthase, interleukin (IL)-6, suppressor of cytokine signaling 1, IL-10 and cyclooxygenase-2 were investigated by quantitative PCR. Levels of IL-10 were assessed by ELISA. Proliferation of CD4+ T cells was assessed by flow cytometry. Results DAPK1 was abundantly expressed in ex vivo -expanded hMSCs and expression was positively correlated with hMSC suppression of CD4+ T cell proliferation. Silencing of DAPK1 in hMSCs reduced the ability of these cells to inhibit CD4+ T cell proliferation and resulted in decreased IL-10 levels compared with untreated controls. Exogenous supplementation with recombinant human IL-10 in DAPK1-silenced hMSCs restored immunosuppression of CD4+ T cells. Conclusions The DAPK1-IL-10 axis mediates a novel immunoregulatory function of hMSCs toward CD4+ T cells.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that down-regulates hepatic low-density lipoprotein receptor (LDLR) by binding and shuttling LDLR to lysosomes for degradation. The development of therapy that inhibits PCSK9 has attracted considerable attention for the management of cardiovascular disease risk. However, only monoclonal antibodies of PCSK9 have reached the clinic use. Oral administration of small-molecule transcriptional inhibitors has the potential to become a therapeutic option. Methods: Here, we developed a cell-based small molecule screening platform to identify transcriptional inhibitors of PCSK9. Through high-throughput screening and a series of evaluation, we found several active compounds. After detailed investigation on the pharmacological effect and molecular mechanistic characterization, 7030B-C5 was identified as a potential small-molecule PCSK9 inhibitor. Findings: Our data showed that 7030B-C5 down-regulated PCSK9 expression and increased the total cellular LDLR protein and its mediated LDL-C uptake by HepG2 cells. In both C57BL/6 J and ApoE KO mice, oral administration of 7030B-C5 reduced hepatic and plasma PCSK9 level and increased hepatic LDLR expression. Most importantly, 7030B-C5 inhibited lesions in en face aortas and aortic root in ApoE KO mice with a slight amelioration of lipid profiles. We further provide evidences suggesting that transcriptional regulation of PCSK9 by 7030B-C5 mostly depend on the transcriptional factor HNF1α and FoxO3. Furthermore, FoxO1 was found to play an important role in 7030B-C5 mediated integration of hepatic glucose and lipid metabolism. Interpretation: 7030B-C5 with potential suppressive effect of PCSK9 expression may serve as a promising lead compound for drug development of cholesterol/glucose homeostasis and cardiovascular disease therapy. Fund: This work was supported by grants from the National Natural Science Foundation of China (81473214, 81402929, and 81621064), the Drug Innovation Major Project of China (2018ZX09711001-003-006, 2018ZX09711001-007 and 2018ZX09735001-002), CAMS Innovation Fund for Medical Sciences (2016-I2M-2-002, 2016-I2M-1-011 and 2017-I2M-1-008), Beijing Natural Science Foundation (7162129). Keywords: PCSK9, Small-molecule inhibitor, FoxO1/3, HNF1α, Lipid and glucose metabolism, Atherosclerosis

Myeloperoxidase (MPO) is a highly abundant protein within the neutrophil that is associated with lipoprotein oxidation, and increased plasma MPO levels are correlated with poor prognosis after myocardial infarct. Thus, MPO inhibitors have been developed for the treatment of heart failure and acute coronary syndrome in humans. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide PF-06282999 is a recently described selective small molecule mechanism-based inactivator of MPO. Here, utilizing PF-06282999, we investigated the role of MPO to regulate atherosclerotic lesion formation and composition in the Ldlr-/- mouse model of atherosclerosis. Though MPO inhibition did not affect lesion area in Ldlr-/- mice fed a Western diet, reduced necrotic core area was observed in aortic root sections after MPO inhibitor treatment. MPO inhibition did not alter macrophage content in and leukocyte homing to atherosclerotic plaques. To assess non-invasive monitoring of plaque inflammation, [18F]-Fluoro-deoxy-glucose (FDG) was administered to Ldlr-/- mice with established atherosclerosis that had been treated with clinically relevant doses of PF-06282999, and reduced FDG signal was observed in animals treated with a dose of PF-06282999 that corresponded with reduced necrotic core area. These data suggest that MPO inhibition does not alter atherosclerotic plaque area or leukocyte homing, but rather alters the inflammatory tone of atherosclerotic lesions; thus, MPO inhibition could have utility to promote atherosclerotic lesion stabilization and prevent atherosclerotic plaque rupture.

BackgroundPeritoneal dialysis (PD) is increasingly used for long-term management of Cardiorenal Syndrome (CRS). We compared outcomes in incident PD patients according to their baseline heart failure status.MethodsThis retrospective cohort study evaluated all-cause and cardiovascular mortality in incident PD patients with different heart failure status (non-CRS, acute heart failure [AHF], type II CRS, type IV CRS) who started PD between 2006 and 2016 in the Peking University Third Hospital.ResultsOf 748 patients included in the study, there were 466 (62.3%), 214 (28.6%), 27 (3.6%), and 41 (5.5%) patients in the non-CRS, AHF, type II CRS and type IV CRS groups, respectively. Patients with CRS were older (pConclusionIncident PD patients with different types of CRS had higher rates of both all-cause and cardiovascular mortality compared with patients without CRS. However, these observed adverse outcomes may be related to associated older age and higher prevalence of comorbidities, rather than CRS per se, except for type IV CRS, treatment strategies to reduce high cardiovascular CVD mortality may needed.

Extracellular vesicles (Evs) contain diverse functional proteins, mRNAs, miRNAs, and DNA fragments, are secreted by various types of cells, and play important roles in cellular communication. Here, we show for the first time that plasma Evs inhibited the osteogenic differentiation of mesenchymal stromal cells (MSCs) in vitro and the level of inhibition was positively correlated with the plasma Evs concentration. Plasma Evs downregulated the expression of markers such as osteocalcin (OCN), Runt-related transcription factor 2 (Runx2), and Osterix at mRNA levels required for osteogenic differentiation and reduced pSmad1/5/8 levels in MSCs. Furthermore, pSmad1/5/8 levels increased and MSCs underwent normal osteogenic differentiation after Evs-derived α2-HS glycoprotein (AHSG) function was inhibited with an anti-AHSG neutralizing antibody. However, the levels of pERK1/2, active β-catenin, and HES1 were not significantly altered. Therefore, we propose that as essential components of the extracellular microenvironment of MSCs, plasma Evs are taken up by MSCs and subsequently repress osteogenic differentiation through an AHSG-mediated decrease in pSmad1/5/8 levels. Our work identifies plasma Evs as novel regulators of MSC osteogenic differentiation.

In this work, magnetic In _2 S _3 /ZnFe _2 O _4 nanocomposites were fabricated via a two-step solvothermal process, which In _2 S _3 loading amount on ZnFe _2 O _4 support medium could be controlled by changing reaction mass. Investigation revealed that the photocatalytic activity of In _2 S _3 /ZnFe _2 O _4 nanocomposites was uperior to pure In _2 S _3 and ZnFe _2 O _4 for the degradation of MB driven by visible light. The improved photocatalytic activity may be stemming from the synergy effect of In _2 S _3 and ZnFe _2 O _4 , resulting in the enhanced visible light absorbance and higher separation efficiency of the photo-generated charge carriers. Significantly, this sort of nanocomposites could rapidly be separated through an external magnetic field, and five successive cycle experiments have proved that it was stable and recyclable. Finally, a possible mechanism related to the separation of charge and photocatalytic decomposition of MB was also provided.

AbstractBackground Circulating plasma cells (CPCs) are defined by the presence of peripheral blood clonal plasma cells, which would contribute to the progression and dissemination of multiple myeloma (MM). An increasing number of studies have demonstrated the predictive potential of CPCs in the past few years. Therefore, there is a growing need for an updated meta-analysis to identify the specific relationship between CPCs and the prognosis of MM based on the current research status.Methods The PubMed, Embase, and Cochrane Library databases were screened to determine eligible studies from inception to November 5, 2023. Publications that reported the prognostic value of CPCs in MM patients were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and progression-free survival (PFS) were extracted to pool the results. Subgroup analyses were performed based on region, sample size, cut-off value, detection time, initial treatment, and data type. The association between CPCs level and clinicopathological characteristics, including the International Staging System (ISS), Revised-ISS (R-ISS), and cytogenetic abnormalities were also evaluated. Statistical analyses were conducted using STATA 17.0 software.Results Twenty-two studies with a total of 5637 myeloma patients were enrolled in the current meta-analysis. The results indicated that myeloma patients with elevated CPCs were expected to have a poor OS (HR = 2.19, 95% CI: 1.81–2.66, p

Abstract Hematological malignancies (HMs) encompass a diverse group of blood neoplasms with significant morbidity and mortality. Immunotherapy has emerged as a validated and crucial treatment modality for patients with HMs. Despite notable advancements having been made in understanding and implementing immunotherapy for HMs over the past decade, several challenges persist. These challenges include immune-related adverse effects, the precise biodistribution and elimination of therapeutic antigens in vivo, immune tolerance of tumors, and immune evasion by tumor cells within the tumor microenvironment (TME). Nanotechnology, with its capacity to manipulate material properties at the nanometer scale, has the potential to tackle these obstacles and revolutionize treatment outcomes by improving various aspects such as drug targeting and stability. The convergence of nanotechnology and immunotherapy has given rise to nano-immunotherapy, a specialized branch of anti-tumor therapy. Nanotechnology has found applications in chimeric antigen receptor T cell (CAR-T) therapy, cancer vaccines, immune checkpoint inhibitors, and other immunotherapeutic strategies for HMs. In this review, we delineate recent developments and discuss current challenges in the field of nano-immunotherapy for HMs, offering novel insights into the potential of nanotechnology-based therapeutic approaches for these diseases.

[Objectives] To optimize the water extraction process of Bawei Shangke Huoxue tablets and determine the best drying method of the extract. [Methods] The orthogonal test method was used to select the optimal water extraction process, with the content of total flavonoids and the yield of dry extract as the test indicators, and the soaking time, the amount of water added, the extraction time and the extraction times as the main test factors. The water content of spray powder was taken as the evaluation indicator, the inlet air temperature, the density of liquid phase and the outlet air temperature were selected as the factors, and the spray drying process of water-extracted concentrated liquid was optimized by orthogonal test. [Results] The optimal water extraction process was no immersion, water decoction and extraction twice, adding 10 times of water each time, extraction for lh, in which the amount of water added was the main factor. The liquid density of spray dried extract powder is 1.05 -1.08 (60 °C), the inlet air temperature is 180°C, the outlet air temperature is 80 °C is the most suitable, and the liquid density is the main factor. [Conclusions] The extraction and drying technology of Bawei Huangke Huoxue tablet is feasible, scientific and reasonable, and can be used for industrial production. [ABSTRACT FROM AUTHOR]

Fluorescent aptasensor was developed for acrylamide (AAm) detection by utilizing the adsorption effect of Au nanoparticles (AuNPs) and fluorescence properties of SYBR Green I (SGI) towards double-stranded DNA (dsDNA). Compared to the binding of aptamer with AAm, the higher affinity of aptamer with cDNA may facilitate a structure switching from the aptamer/AAm complex to aptamer/cDNA dsDNA. The free aptamers were adsorbed onto AuNPs and separated by centrifugation. Subsequently, SGI was introduced as a fluorescent reporter for quantitative detection. Compared to conventional AuNPs-based colorimetric detection, the sensitivity of this strategy was improved by 3.18-fold in the range of 0.005–50 mg/L with a low detection limit of 4.68 μg/L. The method has been successfully applied to analyze fried twists and biscuits. Notably, it is a low-cost and general method that provides guidance for the development of rapid screening technology in the field.

Chronic inflammation is critical in the onset and progression of atherosclerosis (AS). The lipopolysaccharide (LPS) level in the circulation system is elevated in AS patients and animal models, which is correlated with the severity of AS. Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype, aggravate inflammation, and ultimately contribute to the exacerbation of AS, LPS in the circulation system was supposed to be the therapeutic target for AS treatment. In the present study, polymyxin (PMB) covalently conjugated to PEGylated liposomes (PLPs) were formulated to adsorb LPS through specific interactions between PMB and LPS. In vitro, the experiments demonstrated that PLPs could adsorb LPS, reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells. In vivo, the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines, decreased the proportion of M1-type macrophages in AS plaque, stabilized AS plaque, and downsized the plaque burdens in arteries, which eventually attenuated the progression of AS. Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.

Multiple myeloma is the second most common malignant hematologic malignancy which evolved different strategies for immune escape from the host immune surveillance and drug resistance, including uncontrolled proliferation of malignant plasma cells in the bone marrow, genetic mutations, or deletion of tumor antigens to escape from special targets and so. Therefore, it is a big challenge to efficiently treat multiple myeloma patients. Despite recent applications of immunomodulatory drugs (IMiDS), protease inhibitors (PI), targeted monoclonal antibodies (mAb), and even hematopoietic stem cell transplantation (HSCT), it remains hardly curable. Summarizing the possible evasion strategies can help design specific drugs for multiple myeloma treatment. This review aims to provide an integrative overview of the intrinsic and extrinsic evasion mechanisms as well as recently discovered microbiota utilized by multiple myeloma for immune evasion and drug resistance, hopefully providing a theoretical basis for the rational design of specific immunotherapies or drug combinations to prevent the uncontrolled proliferation of MM, overcome drug resistance and improve patient survival.

The treatment options for multiple myeloma (MM) have undergone significant transformation with the advent of immunotherapy. Novel therapies that focus on tumor antigens now drive advances in MM research. Bispecific antibodies (bsAbs) leverage revolutionary advances in bioengineering techniques and embody the second generation of antibody-based tumor therapy. Recent studies on bsAbs in relapsed/refractory MM cases have revealed remarkable efficacy and acceptable safety profiles. The approval of elranatamab and teclistamab represents the next step in the development of bsAbs for the treatment of MM. This review article addresses the antigen targeting, efficacy, safety, and strategies in the application of bsAbs against treatment-resistant MM, with a focus on clinical trials and real-world data.

AbstractBackground Venous thromboembolism (VTE) is one of the most common and severe complications of multiple myeloma (MM). The aim of this study was to learn about the current awareness regarding MM-associated VTE among Chinese hematologists.Methods A nationwide, online, questionnaire-based survey was sent to the specialized hematologists in mainland China. The questionnaire investigated respondents’ demographic and occupational characteristics, their ability to identify VTE risk factors, and their thromboprophylaxis decisions for different anti-MM regimens. Six clinical vignettes were used to evaluate hematologists’ awareness of stratified thromboprophylaxis. The data were analyzed using SPSS software.Results A total of 518 valid questionnaires were received. Of the 518 hematologists investigated, only 23.7% of them could identify VTE-related risk factors correctly. Most hematologists could select appropriate thromboprophylaxis for common anti-MM regimens such as VCd (bortezomib, cyclophosphamide, and dexamethasone) and VRd (bortezomib, lenalidomide, and dexamethasone), but not for uncommon ones such as VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) and KRd (carfilzomib, lenalidomide, and dexamethasone). The results from the vignettes suggested that only 19.5% of the hematologists could be defined as the ‘stratified thromboprophylaxis’ group, and the awareness of stratified thromboprophylaxis depended significantly on physicians’ age and working seniority.Conclusion The results of our study showed that a large proportion of Chinese hematologists failed to recognize the VTE risk factors, most of them cannot select appropriate thromboprophylaxis for different MM therapeutic regimens and lack awareness of stratified thromboprophylaxis for MM-associated VTE. A standard VTE prevention guideline is urgently needed for the Chinese myeloma group. Continuous education for new professionals should be encouraged. A VTE collaborative group is supposed to be established in each hospital to enhance the overall medical care for VTE patients.

ABSTRACTObjectives Multiple myeloma (MM) remains an incurable disease despite advances in treatment options. Recently, selinexor has shown promising efficacy for relapsed/refractory multiple myeloma (RRMM), whereas its optimal timing and drug combination remain unclear. In order to assess the various regimens that incorporate selinexor, a systematic review and meta-analysis was conducted.Methods Clinical trials and real-world studies involving MM patients treated with selinexor were included. Pooled risk ratio (RR) was calculated to compare the rates, along with a 95% confidence interval (CI) and concurrent p-value assessment. A random-effects model was employed to provide a more conservative evaluation.Results A total of 16 studies enrolling 817 patients were reviewed. The usage of selinexor as the fifth-line or prior therapy achieved a higher objective response rate (ORR) (65.9% versus 23.4%, p

Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction. Inspired by macrophage membranes harbor the receptors with special high affinity for proinflammation cytokines, lipopolysaccharide (LPS)-stimulated macrophage membrane-coated nanoparticles (LMNP) were developed to show strong sponge ability to both IFN-γ and IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo. Besides, LMNP also efficiently alleviated HLH-related symptoms including cytopenia, hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models. Furthermore, its sponge effect also worked well for five human HLH samples in vitro. Altogether, it's firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation, which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.

Herein, we propose a simple and effective strategy for designing a zeolitic imidazolate frameworks (ZIFs) fluorescent probe with a two-dimensional leaf-like structure. By doping ZIF-L with phosphate, we developed a fluorescent probe for iron (Fe3+) in systems with high salinity. The fluorescence of P-ZIF-L was quenched effectively with the presence of Fe3+. The physicochemical structure, surface morphology, selectivity, stability and composition of the probe were investigated. Under optimized conditions, the fluorescent probe had a detection limit of 0.5 μM. Furthermore, the results that the probe exhibited desirable salt-tolerance and was suitable for determination of Fe3+ in brine water samples with satisfactory results.

Abstract Background Intravenous daratumumab (DARA IV) has been increasingly used in the treatment of amyloid light-chain (AL) amyloidosis. However, the outcomes for patients administered with DARA IV have not been aggregated. The objective of this systematic review and meta-analysis was to investigate the efficacy and safety of DARA IV for AL amyloidosis. Methods We searched Medline, EMBASE, Cochrane Library and Web of Science up to 17 June 2021. Response rates and survival rates, and the corresponding 95% confidence intervals (CIs) were pooled and calculated using a fixed-effects model. Results Thirty studies (5 cohort studies and 25 single-arm studies) with 997 patients were included. In patients receiving DARA IV-based treatments, very good partial response or better response rate, complete response rate, very good partial response rate, partial response rate and overall response rate were 66% (95% CI, 62–69%), 30% (95% CI, 23–36%), 40% (95% CI, 33–46%), 17% (95% CI, 14–21%), and 77% (95% CI, 73–80%), respectively. Cardiac and renal responses were 41% (95% CI, 34–49%) and 43% (95% CI, 32–54%), respectively. 58% (95% CI, 49–66%) of patients achieved PFS one year or longer. 2.5% (range, 1–10.0%) of patients experienced grade 3 or 4 adverse events, of which the most common adverse event was lymphocytopenia (range, 13.6–25.0%). Conclusion This study supports the efficacy and safety of DARA IV for the treatment of patients with AL amyloidosis.

Cell surface molecules PD-L1 and CD47 are potent inhibitors of adaptive and innate anti-cancer immunity. We sought to generate a safe, therapeutic, bispecific antibody specifically targeting, and blocking both PD-L1 and CD47 inhibitory activity. Novel anti-PDL-1 and anti-CD47 antibodies with favorable inhibitory activity, were humanized and constructed into a unique bi-specific antibody intended for clinical use. Previous pre-clinical and clinical studies using anti-CD47 antibodies indicated anemia and thrombocytopenia as potential risks. QL401 is a PD-L1 x CD47 bispecific antibody engineered to reduce effect on red blood cells while retaining potent phagocytic activation of macrophages in vitro and delayed tumor growth in vivo. QL401 comprises three functional components: a PD-L1 binding Fab arm, a CD47 binding scFv arm, and a human IgG4 backbone. The PD-L1 binding arm provides both tumor targeting and blocking of PD-1 for reactivating T cells. The CD47 arm blocks the binding of SIRPα, while the IgG4 Fc retains Fc gamma receptor binding to provide a phagocytic signal. In preclinical efficacy studies, QL401 potently blocked SIRPα to promote phagocytosis of tumor cells with sub-nanomolar potency. In vivo efficacy studies in mouse xenograft tumor models showed QL401 to be comparable or superior to PD-L1 or CD47 monoclonal antibodies alone or in combination. In vitro safety evaluation of QL401 showed significantly reduced binding and phagocytosis of red blood cells, in contrast to CD47 monoclonal antibodies. In addition, QL401 did not induce hemagglutination. In non-human primates, QL401 was well tolerated up to 100 mg/kg without reduction of red blood cells or platelets below the normal range. QL401 is presently in a human phase I safety study.

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This article discusses the Chinese state crackdown on homosexuality during the reform period through the narratives of homosexual men who were arrested and sentenced to re-education through labour at that time. Utilising the work on morality and law by Zygmunt Bauman, it is shown that Deng Xiaoping's proposal in 1979 to advance Chinese socialist spiritual civilisation was operationalised through a wide variety of procedures, including the use of the criminal justice system through the new crime of 'hooliganism'. It was understood that the object infringed upon by hooliganism was the social order itself, through acts that violated the moral principles of Chinese society. Legislated in 1979, hooliganism was an obvious tool for the regulation of sexuality. Those engaged in hooliganism had to be severely punished. Seven men of the 31 men in our study were arrested and six were sentenced to re-education through labour. [ABSTRACT FROM AUTHOR]

Abstract Background BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations. Methods We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial. Results BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10–4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months. Conclusion Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. Trial registration: Chictr.org.cn ChiCTR1800018143.

Herbs derived from roots, leaves, flowers, or fruits of plants are unavoidably contaminated with fungi and mycotoxins during growth, harvest, and storage, thereby posing a health threat to humans. Especially, root herbs (RHs) are more easily contaminated with fungi and mycotoxins because the roots are in direct contact with the soil. Here, we investigated the occurrence of fungi, aflatoxins (AFs), and ochratoxin A (OTA) in eight RHs that are used as medicines, beverages, dietary supplements, and functional foods in China and other countries. Morphological observation and MultiGeneBlast (β-tubulin and calmodulin) were used to identify the potentially toxigenic fungi. Of the 48 samples tested, all were contaminated by fungi, and 1,844 isolates belonging to 25 genera were detected. The genera Aspergillus and Penicillium, which contain potentially toxigenic fungal species, represented a frequency of 10 and 25%, respectively. Thirty-three isolates of Aspergillus flavus, Aspergillus parasiticus, Aspergillus niger, and Penicillium polonicum were arbitrarily selected for analysis of their toxigenic potential. Five of 13 isolates of A. flavus and 1 isolate of A. parasiticus produced AFs, whereas OTA production was not detected for any of the isolates of A. niger and P. polonicum. The occurrence of AFs and OTA in the 48 samples of eight RHs was tested by ultraperformance liquid chromatography–tandem mass spectrometry; 37.50% of samples from six RHs were contaminated with AFs and 16.67% of samples from four RHs were contaminated with OTA. Seven (14.58%) and four (8.33%) samples of ginseng, polygala, and liquorice exceeded the permissible limits of aflatoxin B1 and AFs, respectively. Because ginseng, polygala, and liquorice are widely used as herbs, dietary supplements, and functional foods, the high frequency of AF contamination of these herbs indicated by our current study warrant attention to raise public awareness. [ABSTRACT FROM AUTHOR]

Nitrogen (N) inhibits soybean (Glycine max L.) nodulation and N2 fixation. Isoflavones secreted by soybean roots can stimulate signal transduction for symbiotic nodules, thus playing a key role in root nodule development and N2 fixation. The relationship between the inhibition of soybean nodulation, N2 fixation and isoflavones by N is still unclear. In this study, dual-root soybean plants were prepared by grafting, and N or isoflavones were supplied to unilateral roots. The number and dry weight of the soybean nodules, nitrogenase activity, isoflavone concentrations and relative changes in the level of expression of nodulation-related genes were measured to study the response relationship between the N systemic regulation the soybean nodule N2 fixation and changes in the concentrations of isoflavones in its roots. The results showed that N supply to one side of the dual-root soybeans systematically affected the N2 fixation of root nodules on both sides, and this effect began in the early stage of nodulation. Moreover, a unilateral supply of N systematically affected the concentrations of daidzein and genistein on both sides of the roots. The concentrations of isoflavones were consistent with the change trend of soybean root nodule and nodulation-related gene expression level. Treatment with unilateral N or isoflavones affected the soybean nodule N2 fixation and its nodulation-related genes, which had the same response to the changes in concentrations of root isoflavones. N regulates soybean nodulation and N2 fixation by systematically affecting the concentrations of isoflavones in the roots.

Background: Qinzhi Zhudan Formula (QZZD), optimized from Angong Niuhuang Wan, consists of Radix Scutellariae, Fructus Gardeniae and Pulvis Fellis Suis. We had investigated the neuroprotective effects of QZZD and its active components, and demonstrated that it could treat cerebral ischemia and dementia through multiple pathways and mechanisms. Nevertheless, toxicological data on this formula still remains limited. In the study, we sought to examine the toxicological effects of QZZD during the treatment and recovery periods.Methods: We investigated potential toxicities of QZZD in Sprague-Dawley (SD) rats via 28-day gavage administration. SD rats were randomly divided into control group and treatment groups of A (0.5 g/kg/d QZZD), B (1.5 g/kg/d QZZD), and C (5.0 g/kg/d QZZD). The 56-day course includes treatment period (administration with water or QZZD once a day for 28 consecutive days) and recovery period (28 days). The rats received daily monitoring of general signs of toxicity and mortality, as well as weekly determination of body weight and food consumption. Moreover, the complete blood cell count, biochemistry, coagulation, and urine indicators, organ weights, and histopathological report were analyzed respectively at the end of the treatment and recovery periods.Results: There was no death related to the active pharmaceutical ingredients of QZZD during the treatment period. The maximum no observed adverse effect level (NOAEL) was 0.5 g/kg/d, which is approximately 16.7 times of the equivalent dose of clinical dose in rats. In group TB (1.5 g/kg/d QZZD) and TC (5.0 g/kg/d QZZD), there were adverse effects of blue coloring of tail skin, weight loss, a significant increase of total bilirubin (TBIL), blackening of liver and kidney in gross examination, hyperplasia of bile duct and karyomegaly of hepatocytes in histopathological examination. Besides, in females rats, the food consumption was reduced, while in male rats, there was decrease in triglycerides (TG) and slight increase in white blood cell (WBC) count and neutrophils. In group TC (5.0 g/kg/d QZZD), the indicators of red blood cell (RBC) count, hemoglobin (HGB) and hematocrit (HCT) were decreased slightly, while the platelet count (PLT) was increased. However, these changes were not considered to be toxicologically significant because they resolved during the recovery period.Conclusion: Overall, QZZD exhibited a good safety profile. The maximum no observed adverse effect level was 0.5 g/kg/d, and no target organs toxicity were identified. The present findings might confirm the safety of QZZD in clinical practices.

TEMPI (telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting) syndrome is a rare and newly defined multisystemic disease, which belongs to “monoclonal gammopathy of clinical significances”. Due to its rarity, the etiology, pathogenesis, and clinical features of this disease remain largely unknown. Owing to its hidden and diverse clinical manifestations, missed diagnosis and misdiagnosis are common. In recent years, as more patients (including three fatal cases) were identified, some special clinical manifestations other than the typical pentad of TEMPI syndrome have been reported. Meanwhile, several studies attempting to identify the pathogenesis of TEMPI syndrome were conducted. In this review, we summarize the reported clinical characteristics of TEMPI syndrome and discuss the current and potential treatment options for patients with TEMPI syndrome, including those with relapsed/refractory disease. Furthermore, we provide an overview of current knowledge on the pathophysiology of TEMPI syndrome.

Introduction: Multiple myeloma (MM) survival has greatly improved in recent decades. MM is usually diagnosed at a median age of 66–70 years. MM patients do not necessarily die from primary cancer, so cardiovascular health may be a key factor threatening long-term survival. This study was designed to explore the cardiovascular disease mortality (CVM) trends in MM patients and compare them with those in the general population. Methods: In total, 88,328 MM patients from the Surveillance, Epidemiology, and End Results (SEER) database (1975–2016) were included. Standardized mortality ratios (SMRs) were used to assess CVM risk. Results: The CVM risk was significantly higher in MM patients than in the general population (SMR, 1.84 (95% CI, 1.78–1.89)). MM patients had the highest CVM SMR, at 2.62 (95% CI, 2.49–2.75), in the first year after diagnosis, and it decreased over the follow-up period. Over the study period, the incidence of CVM continued to decrease in MM patients diagnosed at age 65–74 (APC, −1.2% (95% CI, −1.9% to −0.4%)) and ⩾75 years (APC, −1.9% (95% CI, −2.6% to −1.2%)) but not younger. CVM was the second-most common cause of death in patients ⩾75 years. In only MM case analyses, male sex, Black race, older age at diagnosis, and earlier year of diagnosis were poor prognostic factors for heart-specific mortality. Conclusion: The CVM risk in MM patients was significantly higher than that in the general population. To improve survival, cardiovascular health should receive attention upon diagnosis.

In this study, we prepared novel fluorescent carbon quantum dots/hydrogel nanocomposite material (CQDsHG) with good adsorption and stable fluorescence detection of Fe3+. The materials were subsequently characterized according to their morphological features, chemical composition, adsorption, and optical properties. The carbon quantum dots (CQDs) were prepared using a microwave-assisted hydrothermal method in no more than 15 min, and the as-prepared CQDs exhibited excellent water solubility, as well as emitted strong bright blue fluorescence with an ultrahigh quantum yield of 93.60%. The CQDs were then loaded into a hydrogel (HG) using the sol-gel method to obtain a functional CQDsHG. The CQDsHG exhibited high adsorption amounts (31.94 mg/g) and a good quenching response for Fe3+, thus, it could be used as a sensor to selectively detect Fe3+ in the linear range of 0–150 μM with a detection limit of 0.24 μM. We observed minimal difference in the fluorescence lifetimes between the CQDsHG with and without a quencher (Fe3+), with values of 5.816 ns and 5.824 ns, respectively, confirming that Fe3+ was statically quenched on CQDsHG. The results indicated that the innovative combination of CQDs and HG can improve the synergistic performance of each component for the adsorption and quantitative detection of heavy metal ions in the aqueous environment.

Nanodelivery systems combining photothermal therapy (PTT) and chemotherapy (CT), have been widely used to improve the efficacy and biosafety of chemotherapeutic agents in cancer. In this work, we constructed a self-assembled nanodelivery system, formed by the assembling of photosensitizer (IR820), rapamycin (RAPA), and curcumin (CUR) into IR820-RAPA/CUR NPs, to realize photothermal therapy and chemotherapy for breast cancer. The IR820-RAPA/CUR NPs displayed a regular sphere, with a narrow particle size distribution, a high drug loading capacity, and good stability and pH response. Compared with free RAPA or free CUR, the nanoparticles showed a superior inhibitory effect on 4T1 cells in vitro. The IR820-RAPA/CUR NP treatment displayed an enhanced inhibitory effect on tumor growth in 4T1 tumor-bearing mice, compared to free drugs in vivo. In addition, PTT could provide mild hyperthermia (46.0 °C) for 4T1 tumor-bearing mice, and basically achieve tumor ablation, which is beneficial to improving the efficacy of chemotherapeutic drugs and avoiding damage to the surrounding normal tissue. The self-assembled nanodelivery system provides a promising strategy for coordinating photothermal therapy and chemotherapy to treat breast cancer.

BackgroundThe International Prognostic Index (IPI) is widely used to discriminate the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). However, there is a significant need to identify novel valuable biomarkers in the context of targeted therapy, such as immune checkpoint blockade (ICB).MethodsGene expression data and clinical DLBCL information were obtained from The Cancer Genome Atlas and Gene Expression Omnibus datasets. A total of 371 immune-related genes in DLBCL patients associated with different IPI risk groups were identified by weighted gene co-expression network analysis, and eight genes were selected to construct an IPI-based immune prognostic model (IPI-IPM). Subsequently, we analyzed the somatic mutation and transcription profiles of the IPI-IPM subgroups as well as the potential clinical response to immune checkpoint blockade (ICB) in IPI-IPM subgroups.ResultsThe IPI-IPM was constructed based on the expression of CMBL, TLCD3B, SYNDIG1, ESM1, EPHA3, HUNK, PTX3, and IL12A, where high-risk patients had worse overall survival than low-risk patients, consistent with the results in the independent validation cohorts. The comprehensive results showed that high IPI-IPM risk scores were correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, and upregulation of inhibitory immune checkpoints, including PD-L1, BTLA, and SIGLEC7, indicating a greater potential response to ICB therapy.ConclusionThe IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms of tumor progression and sheds light on the development of immunotherapy for DLBCL.

Background: Recent studies have reported that diffuse large B-cell lymphoma (DLBCL) involving different primary extranodal sites have distinct clinicopathological characteristics and prognosis. However, the risk of secondary malignant neoplasms (SMNs) in DLBCL survivors with different primary extranodal sites are unknown. Methods: A total of 40,714 patients diagnosed with stage I/II DLBCL were included from the Surveillance, Epidemiology, and End Results (SEER) database from 1983 to 2015.The standardized incidence ratio (SIR) and absolute excess risk (AER) were used to assess the risk of SMNs. Results: The results show that the risk of SMN was significantly higher in extranodal DLBCL than in the US general population (SIR, 1.18; 95% CI, 1.11–1.26), and the risk of developing SMN remains significantly elevated with increased latency. Moreover, there were multiple site-specific risk patterns. There was a 22%, 44%, 66%, 123% and 151% increased risk of SMN 10 years after primary gastrointestinal tract, head/neck, skeletal, lung and liver/pancreas DLBCL diagnosis, respectively. There was a significant decrease risk of SMN with increasing age at diagnosis for primary gastrointestinal tract and skeletal DLBCL. In addition, DLBCL patients with primary sites in the gastrointestinal tract, thyroid and liver/pancreas had the highest incidences of secondary stomach cancer, second thyroid cancer, and second hepatobiliary cancer, respectively, which indicated that the initial site of DLBCL may predict the type of SMN. Conclusions: The strategies for cancer surveillance after extranodal DLBCL diagnosis may need to be individualized according to the subsite of extranodal DLBCL.

Background/Aims: The term monoclonal gammopathy of renal significance (MGRS) was introduced in 2012 to emphasize kidney lesions in monoclonal gammopathy patients. Bortezomib-based chemotherapy has become the first-line treatment for MGRS. Objectives: The objective of this study was to investigate whether the strategy of combining chemotherapy with autologous stem cell transplantation (ASCT) could improve prognosis and decrease functional kidney impairment in patients with MGRS. Methods: We reported the case of a 44-year-old Asian patient who was diagnosed with MGRS and received 5 cycles of Velcade® (a trade name for bortezomib), thalidomide, and dexamethasone therapy (VTD therapy), and subsequently underwent ASCT. In addition, we performed a literature review and summarized the latest advances in the characterization, treatment, and prognosis of MGRS. Results: The patient was diagnosed with light chain deposition disease by renal biopsy. After 5 cycles of VTD therapy, the patient had a very good partial response characterized by the resolution of M-protein (20.2% before treatment vs. 2.5% after treatment), remission of the level of serum free lambda (FLAM; over 80% decline), and normalization of the serum free light chain (sFLC) ratio (κ to λ). He also had a renal response characterized by a decreased serum creatinine level (1.61 vs.1.34 mg/dL) and less severe proteinuria (6.77 g/24 h vs.1.264 g/24 h) after chemotherapy. Importantly, after ASCT, the patient achieved a complete response (CR) characterized by a negative serum immunofixation electrophoresis (IFE) result and a dramatic decrement in FLAM (over 90%). Furthermore, 6 months after ASCT, the patient still remained in stable condition with a negative IFE result, normal sFLC ratio, and low level of serum creatinine (1.31 mg/dL) and proteinuria (0.339 g/24 h). In our retrospective literature analysis, we found that MGRS patient survival time and renal outcome had been markedly improved by current therapies due to the popularization of bortezomib-based chemotherapy and ASCT. Conclusions: The patient successfully achieved CR after VTD therapy followed by ASCT. However, this treatment is controversial, and a standard therapy recommendation for MGRS has not been established. Bortezomib-based chemotherapy combined with ASCT may have prospects for the treatment of MGRS, but the exact effects of ASCT remain unclear and should be thoroughly investigated.

Abstract Background Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood. Methods The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells. Results Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo. Conclusion Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.