Umbilical cord blood stem cells as third-party adjuvant infusions in human leukocyte antigen antibody-positive patients undergoing haploidentical hematopoietic stem cell transplantation.

Introduction: Graft failure (GF) or poor graft function (PGF) remain critical obstacles in haploidentical hematopoietic stem cell transplantation (haplo-HSCT), especially in recipients with HLA antibodies. Here, we performed a retrospective cohort study to investigate the efficacy and safety of the use of unrelated umbilical cord blood stem cells (UCBs) as a third-party adjuvant infusion in patients with HLA-antibodies undergoing haplo-HSCT. Methods: A total of 90 patients were divided into three groups: 17 patients in Group A (with positive HLA antibodies and who received UCB infusion), 36 patients in Group B (with positive HLA antibodies without UCB infusion), and 37 patients in Group C (without HLA antibody or UCB infusion). Results: The median age of patients included in Groups A, B, and C was 43 (IQR, 27 - 49.5), 33 (IQR, 20 - 48.75), and 30 (IQR, 18 - 46.5) years, respectively. All but one patient in Group B achieved granulocyte recovery within 28 days after transplantation. The median time to granulocyte engraftment were all 12 days for patients in Groups A, B, and C, respectively. All the patients in Group A achieved 100% donor chimerism without UCB engraftment. There were no significant differences in granulocyte or platelet engraftment time between the three groups. There were 1, 5, and 0 patients in Groups A, B, and C, respectively, who developed PGF. The cumulative incidence rates for any grade of acute graft-versus-host disease (aGVHD) were comparable among the three groups. Patients in Group B presented a greater incidence of cGVHD than did those in Group A (P = 0.002) and Group C (P = 0.006). Patients in Group A presented more limited and milder cGVHD than those in Group C (P < 0.0001). The 1-year relapse-free survival (RFS) was 70.6% (95% CI, 0.47 - 0.87), 55.6% (95% CI, 0.40 - 0.70), and 77.9% (95% CI, 0.63 - 0.89) in Groups A, B, and C, respectively. Discussion: Our results indicated that patients who were positive for HLA antibodies were at a greater risk of developing GF/PGF. Co-infusion with UCBs was safe and improved engraftment, cGVHD, and improved the 1-year RFS to some extent.

Atypical BCR-ABL1 transcript in mixed phenotype acute leukemia with bone marrow necrosis.

Mixed phenotype acute leukemia (MPAL) is a type of acute leukemia in which encompasses mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. Philadelphia chromosome-positive (Ph+) MPAL is a rare subgroup with a poor prognosis and accounts for ＜1% of adult acute leukemia. Until now, there is still no consensus on how to best treat Ph+ MPAL. Here, we report a 62-year-old male with Ph+ (atypical e13a2 BCR-ABL1 fusion protein) MPAL. This patient presented with recurrent and intense bone pain due to bone marrow necrosis (BMN). Besides, he did not achieve a complete remission for the first two chemotherapies, until he received flumatinib combined with hyper-CVAD (B) (a dose-intensive regimen include methotrexate and cytarabine). To our knowledge, this is the first report to describe the coexistence of BMN and atypical e13a2 BCR-ABL1 transcripts in patients with MPAL. This finding will bring new understandings in the diagnosis and treatment of Ph+ MPAL.

Eltrombopag can promote platelet implantation after allogeneic hematopoietic stem cell transplantation as safely and similarly to thrombopoietin.

Background: Eltrombopag has demonstrated efficacy in treating low platelet (PLT) levels, but it remains unclear whether eltrombopag can promote PLT engraftment after hematopoietic stem cell transplantation (HSCT). Methods: Forty-one HSCT patients received eltrombopag 50 mg/d from +1 day until PLT >50 × 109/L or 1 month after HSCT. Fifty-one patients in the same period received thrombopoietin (TPO) to promote PLT graft after HSCT and served as a control group. Results: A total of 51 patients who applied TPO during the same period were treated as a control. In the eltrombopag group, the median time to white blood cells (WBC) graft was 12 days (range, 10-17 days) and the PLT graft was 15 days (range, 10-30 days), whereas for the patients in the TPO group, the median time to WBC and PLT graft was 12 days (range, 9-23 days) and 15.5 days (range, 9-41 days), respectively. In the first month after HSCT, the median WBC count in the eltrombopag group was 4.41 × 109/L (range, 0.87-40.01 × 109/L) and the median PLT was 89x109/L (range, 30-401 × 109/L); the median WBC and PLT \counts in the TPO group were 4.65 × 109/L (range, 0.99-23.63 × 109/L) and 86 × 109/L (range, 5-512 × 109/L), respectively. Patients in the TPO or eltrombopag group did not experience serious side effects after drug administration, and the difference in side effects on liver and kidney function between the two groups was not statistically significant. Conclusion: Eltrombopag is safe and similarly promotes platelet engraftment to thrombopoietin after allogeneic HSCT.

Serum indicators in functional high-risk multiple myeloma patients undertaking proteasome inhibitors therapy: a retrospective study.

OBJECTIVES: Multiple myeloma (MM) is a class of malignant plasma cell diseases. An increasing application of autologous stem cell transplantation (ASCT) and anti-myeloma agents represented by proteasome inhibitors (PIs) has improved the response rates and survival of MM patients. Patients progressing within 12 months were recently categorized with functional high-risk (FHR), which could not be clarified by existing genetic risk factors, with poor outcomes. Our study aimed to investigate clinical indices related to FHR and seek prognostic roles in transplant-eligible MM patients. METHODS: Demographic and individual baseline clinical characteristics were compared by using the Pearson's chi-square and Mann-Whitney U test. Progression-free survival (PFS) and overall survival (OS) were described by Kaplan-Meier estimates and compared using the log-rank test. Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with FHR status. RESULTS: From 18th January 2010 to 1st December 2022, 216 patients were included and divided into two groups according to the FHR status. There was no difference in baseline data between the two groups. Renal impairment (RI, Scr > 2 mg/dL) was common in MM patients and made sense in FHR status. AST levels were validated as independent predictors for FHR status (p = 0.019). DISCUSSION: Patients with RI or higher AST levels (AST > 40 U/L) tended to have worse outcomes. However, transplants had apparently improved prognoses. CONCLUSION: Therefore, in the PIs era, transplantations are still effective therapies for transplant-eligible MM patients.

Echinacoside, a promising sortase A inhibitor, combined with vancomycin against murine models of MRSA-induced pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogenic bacterium responsible for a range of severe infections, such as skin infections, bacteremia, and pneumonia. Due to its antibiotic-resistant nature, current research focuses on targeting its virulence factors. Sortase A (SrtA) is a transpeptidase that anchors surface proteins to the bacterial cell wall and is involved in adhesion and invasion to host cells. Through fluorescence resonance energy transfer (FRET), we identified echinacoside (ECH), a natural polyphenol, as a potential SrtA inhibitor with an IC50 of 38.42 µM in vitro. It was demonstrated that ECH inhibited SrtA-mediated S. aureus fibrinogen binding, surface protein A anchoring, and biofilm formation. The fluorescence quenching assay determined the binding mode of ECH to SrtA and calculated the KA-binding constant of 3.09 × 105 L/mol, demonstrating the direct interaction between the two molecules. Molecular dynamics simulations revealed that ECH-SrtA interactions occurred primarily at the binding sites of A92G, A104G, V168A, G192A, and R197A. Importantly, the combination of ECH and vancomycin offered protection against murine models of MRSA-induced pneumonia. Therefore, ECH may serve as a potential antivirulence agent against S. aureus infections, either alone or in combination with vancomycin.

The epidemiological patterns of non-Hodgkin lymphoma: global estimates of disease burden, risk factors, and temporal trends.

Background: The incidence of non-Hodgkin's lymphoma (NHL) has increased steadily over the past few decades. Elucidating its global burden will facilitate more effective disease management and improve patient outcomes. We explored the disease burden, risk factors, and trends in incidence and mortality in NHL globally. Methods: The up-to-date data on age-standardized incidence and mortality rates of NHL were retrieved from the GLOBOCAN 2020, CI5 volumes I-XI, WHO mortality database, and Global Burden of Disease (GBD) 2019, focusing on geographic disparities worldwide. We reported incidence and mortality by sex and age, along with corresponding age-standardized rates (ASRs), the average annual percentage change (AAPC), and future burden estimates to 2040. Results: In 2020, there were an estimated 545,000 new cases and 260,000 deaths of NHL globally. In addition, NHL resulted in 8,650,352 age-standardized DALYs in 2019 worldwide. The age-specific incidence rates varied drastically across world areas, at least 10-fold in both sexes, with the most pronounced increase trend found in Australia and New Zealand. By contrast, North African countries faced a more significant mortality burden (ASR, 3.7 per 100,000) than highly developed countries. In the past decades, the pace of increase in incidence and mortality accelerated, with the highest AAPC of 4.9 (95%CI: 3.6-6.2) and 6.8 (95%CI: 4.3-9.2) in the elderly population, respectively. Considering risk factors, obesity was positively correlated with age-standardized incidence rates (P< 0.001). And North America was the high-risk region for DALYs due to the high body mass index in 2019. Regarding demographic change, NHL incident cases are projected to rise to approximately 778,000 by 2040. Conclusion: In this pooled analysis, we provided evidence for the growing incidence trends in NHL, particularly among women, older adults, obese populations, and HIV-infected people. And the marked increase in the older population is still a public health issue that requires more attention. Future efforts should be directed at cultivating health awareness and formulating effective and locally tailored cancer prevention strategies, especially in most developing countries.

Dietary Effects on Monocyte Phenotypes in Subjects With Hypertriglyceridemia and Metabolic Syndrome.

In patients with hypertriglyceridemia, a short-term low-saturated fat vs high-saturated fat diet induced lower plasma lipids and improved monocyte phenotypes. These findings highlight the role of diet fat content and composition for monocyte phenotypes and possibly cardiovascular disease risk in these patients. (Effects of Dietary Interventions on Monocytes in Metabolic Syndrome; NCT03591588).

Identification of ORM1, vWF, SPARC, and PPBP as immune-related proteins involved in immune thrombocytopenia by quantitative LC-MS/MS.

BACKGROUND: Immune thrombocytopenia (ITP) is a common autoimmune disease characterized by loss of immune tolerance to platelet autoantigens leading to excessive destruction and insufficient production of platelets. METHOD: Quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to detect the differentially expressed proteins in bone marrow samples from active ITP patients and normal controls. RESULT: Our bioinformatic analysis identified two upregulated proteins (ORM1 and vWF) and two downregulated proteins (PPBP and SPARC) related to immune function. The four proteins were all found to be related to the tumor necrosis factor (TNF) -α signalling pathway and involved in the pathogenesis of ITP in KEGG pathway analysis. CONCLUSION: Bioinformatics analysis identified differentially expressed proteins in bone marrow that are involved in the TNF-α signalling pathway and are related to the activation of immune function in ITP patients. These findings could provide new ideas for research on the loss of immune tolerance in ITP patients.

Dyslipidemia in the First 100 days and the Association with Acute Graft-versus-host Disease after Allogeneic Stem Cell Transplantation: A Single-center Retrospective Study in China.

Dyslipidemia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The interaction between post-transplant hyperlipidemia and acute graft-versus-host disease (aGVHD) is uncertain. In this study, we performed a retrospective study to explore the relationship between dyslipidemia and aGVHD and the potential mechanism of aGVHD on dyslipidemia in 147 recipients who underwent allo-HSCT. The lipid profiles, transplantation details, and other laboratory data of the subjects were collected in the first 100 days post-transplantation. Our results indicated 63 patients with new-onset hypertriglyceridemia and 39 patients with new-onset hypercholesterolemia. A total of 57 (38.8%) patients developed aGVHD after transplantation. In a multifactorial analysis, aGVHD was an independent factor in the development of dyslipidemia in recipients (P < 0.05). After transplantation, the median LDL-C level of patients with aGVHD was 3.04 mmol/L (standard deviation value (SD): 1.36 mmol/L, 95% confidence interval (CI): 2.62, 3.45 mmol/L), and the LDL-C level in patients without aGVHD was 2.51 mmol/L (SD: 1.38 mmol/L, CI: 2.67, 3.40 mmol/L) (P < 0.05). Female recipients had higher lipid levels than males (P < 0.05). LDL levels (≥ 3.4 mmol/L) post-transplant were an independent risk factor for the development of aGVHD (OR = 0.311, P < 0.05). In conclusion, larger sample studies are anticipated to confirm our preliminary result, and an accurate mechanism between lipid metabolism and aGVHD needs to be determined in the future.

Prognosis and complications of patients with primary gastrointestinal diffuse large B-cell lymphoma: Development and validation of the systemic inflammation response index-covered score.

BACKGROUND: This study aimed to evaluate the predictive value of systemic inflammation response index (SIRI) in primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) patients and establish a highly discriminating risk prediction model. METHODS: This retrospective analysis included 153 PGI-DCBCL patients diagnosed between 2011 and 2021. These patients were divided into a training set (n = 102) and a validation set (n = 51). Univariate and multivariate Cox regression analyses were conducted to examine the significance of variables on overall survival (OS) and progression-free survival (PFS). An inflammation-covered score system was established according to the multivariate results. RESULTS: The presence of high pretreatment SIRI (≥1.34, p < 0.001) was significantly associated with poorer survival and identified as an independent prognostic factor. Compared with NCCN-IPI, the prognostic and discriminatory capability of the novel model SIRI-PI showed a more precise high-risk assessment with a higher area under the curve (AUC) (0.916 vs 0.835) and C-index (0.912 vs 0.836) for OS in the training cohort, and similar results were obtained in the validation cohort. Moreover, SIRI-PI also showed good discriminative power for efficacy assessment. This new model identified patients at risk of developing severe gastrointestinal complications following chemotherapy. CONCLUSIONS: The results of this analysis suggested that the pretreatment SIRI may be a potential candidate for identifying patients with a poor prognosis. And we established and validated a better-performing clinical model, which facilitated the prognostic stratification of PGI-DLBCL patients and can serve as a reference for clinical decision-making.

Gene mutations in the PI3K/Akt signaling pathway were related to immune thrombocytopenia pathogenesis.

BACKGROUND: Immune thrombocytopenic (ITP) is an autoimmune bleeding disease with genetic susceptibility. Twenty newly diagnosed active primary ITP patients who had not been treated with glucocorticosteroids, immune globulin or immunosuppressants prior to sampling were enrolled in this study. Bone marrow blood mononuclear cells were used for whole exome sequencing to further elucidation the variant genes of ITP. METHODS: High-molecular-weight genomic DNA was extracted from freshly frozen bone marrow blood mononuclear cells from 20 active ITP patients. Next, the samples were subjected to molecular genetic analysis by whole-exome sequencing, and the results were confirmed by Sanger sequencing. The signaling pathways and cellular processes associated with the mutated genes were identified with gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. RESULTS: The results showed that there were 3998 missense mutations involving 2269 genes in more than 10 individuals. Unique genetic variants including phosphatase and tensin homolog, insulin receptor, and coagulation factor C homology were the most associated with the pathogenesis of ITP. Functional analysis revealed these mutation genes mainly affect Phosphatidylinositol 3 kinase/serine/threonine kinase B signaling pathways (signal transduction) and platelet activation (immune system). CONCLUSION: Our finding further demonstrates the functional connections between these variant genes and ITP. Although the substantial mechanism and the impact of genetic variation are required further investigation, the application of next generation sequencing in ITP in this paper is a valuable method to reveal the genetic susceptibility.

High-throughput DNA methylation analysis in ITP confirms NOTCH1 hypermethylation through the Th1 and Th2 cell differentiation pathways.

BACKGROUND: Immune thrombocytopenia (ITP) is a prevalent autoimmune disease with a complex aetiology where DNA methylation changes are becoming triggers. METHOD: To investigate novel abnormally methylated genes in the pathogenesis of ITP, we performed a high-throughput methylation analysis on 21 ITP patients and 9 normal control samples. We analysed the extent of key methylated genes and their downstream cytokines through Luminex assay or qRT-PCR. Then, bone marrow mononuclear cells were extracted from ITP patients, and decitabine (demethylation drug) was added to the culture medium of cultured cells. qRT-PCR and ELISA were used to detect whether decitabine could effectively affect target genes and related cytokines. RESULTS: Through the STRING and Metascape databases, hypermethylated NOTCH1 can be identified and can influence ITP by regulating many downstream cytokines through Th1 and Th2 cell differentiation pathways. Compared with those in the normal control group, the expression levels of NOTCH1 and its downstream Th2 cytokines (IL-4, IL-10, and GATA3) were significantly decreased and those of Th1 cytokines (IFN-γ, IL-12, and TNF-α) were significantly increased in the ITP group. Decitabine exerts its demethylation effect, so the expression of NOTCH1 and its related cytokines in the ITP group treated with 100 nM decitabine were significantly reversed. CONCLUSIONS: Our results suggest that the pathogenesis of ITP may exert its influence on epigenetics through alteration of DNA methylation at regulatory regions of the target NOTCH1 gene in the Th1 and Th2 cell differentiation pathways. At the same time, decitabine may achieve a therapeutic effect on ITP by demethylation.

Solamargine Inhibits the Development of Hypopharyngeal Squamous Cell Carcinoma by Decreasing LncRNA HOXA11-As Expression.

Hypopharyngeal squamous cell carcinoma (HSCC) is one of the high mortality cancers with a poor prognosis, which is driving the development of new chemotherapeutic agents. We identified the anticancer effects of a natural compound, solamargine (SM), on FaDU cells and explored its mechanism in terms of non-coding RNA. It was observed that SM inhibited the proliferation of FaDU cells with an IC50 of 5.17 µM. High-throughput sequencing data revealed that lncRNA HOXA11-AS was significantly downregulated in cells co-incubated with SM. Further assays demonstrated that SM-induced downregulation of lncRNA HOXA11-AS showed important implications for apoptosis. Given the properties of HOXA11-AS as a miR-155 sponge, we further confirmed that SM upregulated the expression of miR-155 in FaDU cells. C-Myc is a transcription factor that regulates cell differentiation and apoptosis, whose mRNA is considered to be targeted by miR-155. We showed that c-Myc expression was downregulated by SM and accompanied by increased apoptosis, which was consistent with the findings of transcriptome sequencing. Furthermore, SM administration suppressed xenograft tumor growth in a xenograft mouse model in vivo. In the light of the aforementioned findings, our results suggested that SM downregulated the expression of HOXA11-AS, which in turn induces apoptosis by downregulating c-Myc in FaDU, providing evidence for the anticancer effect of SM on HSCC and uncovering the effect of SM on non-coding RNAs as, at least partly, a mechanism of action.

Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr-/- Mice.

BACKGROUND: Hypertriglyceridemia (HTG) increases the risk for atherosclerotic cardiovascular disease, but underlying mechanisms are incompletely understood. Circulating monocytes play an important role in atherogenesis by infiltrating arterial walls, where they differentiate into macrophages. We tested the hypothesis that HTG is mechanistically linked to atherogenesis by altering the monocyte phenotype and infiltration into atherosclerotic lesions in a model of diet-induced atherogenesis in Ldlr-/- mice. METHODS: HTG was induced in male Ldlr-/- mice, fed a Western, high-fat high-cholesterol diet, by daily injection of poloxamer 407 (P407), a lipoprotein lipase inhibitor, for seven weeks. Atherosclerosis, monocyte phenotypes, and monocyte migration into atherosclerotic lesions were determined by well-validated methods. RESULTS: Compared with the saline control, P407 injection in Ldlr-/- mice rapidly induced profound and persistent HTG, modestly elevated plasma cholesterol levels, and increased levels of triglyceride and cholesterol carried in very-low-density lipoprotein and low-density lipoprotein. Unexpectedly, mice receiving P407 versus saline control showed less atherosclerosis. Following induction of HTG by P407, CD36+ (also CD11c+), but not CD36- (CD11c-), monocytes showed early increases in lipid accumulation, but the number of CD36+ (not CD36-) monocytes was dramatically decreased afterwards in the circulation until the end of the test. Concurrently, CD36+ (CD11c+) monocyte migration into atherosclerotic lesions was also reduced in mice receiving P407 versus controls. CONCLUSIONS: P407 induced severe HTG, but reduced atherosclerosis, in Ldlr-/- mice, possibly because of profound reductions of circulating CD36+ (CD11c+) monocytes, leading to decreased monocyte migration into atherosclerotic lesions.

An Extended Prognostic Index of the ISSWM Score Based on Thyroid Complications in Waldenström Macroglobulinemia/Lymphoplasmacytoid Lymphoma.

Waldenström macroglobulinemia/lymphoplasmacytoid lymphoma (WM/LPL) is a rare lymphoproliferative neoplasm characterized by clonally related lymphocytes, lymphoplasmacytic cells, and plasma cell proliferation. WM/LPL patients commonly present with elevated immunoglobulin, predominantly immunoglobulin M (IgM). Previous studies reported that thyroid dysfunction was associated with the development and progression of solid tumors. However, only limited information is available on the correlation between thyroid complications and lymphoid malignancies. The aim of our study was to explore the prognostic significance of thyroid complications in WM/LPL. Herein, 13.3% of WM/LPL patients were diagnosed with thyroid complications, which were significantly associated with unfavorable progression-free survival (PFS), overall survival (OS), and adverse treatment response. Co-existing thyroid disease was significantly related to alleviated serum IgM levels, providing an answer to practical problems. Furthermore, the presence of thyroid complications was identified as an independent prognostic indicator for PFS in WM/LPL. Incorporating the ISSWM score with thyroid complications was superior to ISSWM alone in risk stratification and prognostic prediction. Furthermore, subgroup analyses of WM/LPL patients revealed that subclinical hypothyroidism predicted undesirable outcomes at the early stage. These results were also supported by independent microarray dataset analyses. In conclusion, the primary strength of this study is that it provides robust real-world evidence on the prognostic role of thyroid complications, highlighting further clinical concerns in the management of WM/LPL patients.

Mechanism-based ligand design for copper-catalysed enantioconvergent C(sp3)-C(sp) cross-coupling of tertiary electrophiles with alkynes.

In contrast with the well-established enantioconvergent radical C(sp3)-C cross-coupling of racemic secondary alkyl electrophiles, the corresponding coupling of tertiary electrophiles to forge all-carbon quaternary stereocentres remains underexplored. The major challenge arises from the steric hindrance and the difficult enantio-differentiation of three distinct carbon substituents of prochiral tertiary radicals. Here we demonstrate a general copper-catalysed enantioconvergent C(sp3)-C(sp) cross-coupling of diverse racemic tertiary alkyl halides with terminal alkynes (87 examples). Key to the success is the rational design of chiral anionic N,N,N-ligands tailor-made for the computationally predicted outer-sphere radical group transfer pathway. This protocol provides a practical platform for the construction of chiral C(sp3)-C(sp/sp2/sp3) bonds, allowing for expedient access to an array of synthetically challenging quaternary carbon building blocks of interest in organic synthesis and related areas.

Liquiritin Alleviates Depression-Like Behavior in CUMS Mice by Inhibiting Oxidative Stress and NLRP3 Inflammasome in Hippocampus.

OBJECTIVE: Central inflammation is generally accepted to be involved in the pathology of depression. We investigated whether liquiritin exerts antidepressant effects by inhibiting central NLRP3 inflammasomes. RESULTS: The behavioral despair model and chronic unpredictable mild stress (CUMS) model in mice were established to evaluate the antidepressant action of liquiritin. In the despair model study, liquiritin (40 mg/kg) administration reduced immobility time in tail suspension test (TST) and forced swimming test (FST) without affecting locomotion activity. In CUMS model study, liquiritin (40 mg/kg, once daily for 4 weeks) significantly increased sucrose consumption and body weight of CUMS mice. The behavioral experiment results showed that liquiritin reduced the immobile time of CUMS mice in TST and FST, respectively, and increased the time spent and open arm entries in the elevated plus-maze (EPM) test. Further, the hippocampal superoxide dismutase (SOD) activity was increased in liquiritin-treated group, while malonaldehyde (MDA) decreased. Additionally, the hippocampal cytokines interleukin-18 (IL-18) and interleukin-1 beta (IL-1ß) contents were reduced in the liquiritin-treated group. Further, liquiritin downregulated the expression of NLRP3 in the hippocampus of CUMS mice rather than TLR4. Besides, NLRP3 inflammasome-associated proteins caspase-1 and ASC were also downregulated. However, liquiritin did not alter the thermal stability of NLRP3 in the cellular thermal shift assay (CETSA), suggesting that its inhibition of NLPR3 was not by direct targeting of NLRP3 protein. CONCLUSIONS: Liquiritin attenuates depression-like behavior of CUMS mice and inhibited cytokines levels triggered by NLRP3 inflammasome, suggesting the antidepressant action is, at least partially, associated with antioxidant stress and inhibition of NLRP3 inflammasome activation.

Quantitative LC-MS/MS uncovers the regulatory role of autophagy in immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune haemorrhagic disease whose pathogenesis is associated with bone marrow megakaryocyte maturation disorder and destruction of the haematopoietic stem cell microenvironment. METHODS: In this study, we report the qualitative and quantitative profiles of the ITP proteome. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was conducted to elucidate the protein profiles of clinical bone marrow mononuclear cell (BMMC) samples from ITP patients and healthy donors (controls). Gene Ontology (GO) and Kyoto Encyclopaedia Genes and Genome (KEGG) pathway analyses were performed to annotate the differentially expressed proteins. A protein-protein interaction (PPI) network was constructed with the BLAST online database. Target proteins associated with autophagy were quantitatively identified by parallel reaction monitoring (PRM) analysis. RESULTS: Our approaches showed that the differentially expressed autophagy-related proteins, namely, HSPA8, PARK7, YWHAH, ITGB3 and CSF1R, were changed the most. The protein expression of CSF1R in ITP patients was higher than that in controls, while other autophagy-related proteins were expressed at lower levels in ITP patients than in controls. CONCLUSION: Bioinformatics analysis indicated that disruption of the autophagy pathway is a potential pathological mechanism of ITP. These results can provide a new direction for exploring the molecular mechanism of ITP.

Pegylated Liposomal Doxorubicin in Vindesine-Based and Bortezomib-Based Regimens for Patients With Newly Diagnosed Multiple Myeloma: A Retrospective Study of Efficacy and Safety.

PURPOSE: Although pegylated liposomal doxorubicin (PLD) has been approved in combination with bortezomib for relapsed/refractory multiple myeloma (MM), the antitumor efficacy and tolerability of PLD in different regimens for patients with newly diagnosed MM (NDMM) have not been fully defined. METHODS: A total of 249 NDMM patients diagnosed between January 2008 and October 2019 were included in this retrospective study. Among them, 112 patients received vindesine-based chemotherapy (35 vDD and 77 vAD) and 137 received bortezomib-based chemotherapy (58 VDD and 79 VD). RESULTS: In bortezomib-containing regimens, the complete response rate (48.3 vs. 30.4%, p = 0.033) and very good partial response or better rate (74.1 vs. 57.0%, p = 0.038) of VDD were significantly higher than those of VD subgroup. While no superior survival was found between VDD and VD subgroup. In vindesine-containing regimens, no statistical significance was identified between vDD and vAD in terms of response rate and survival. The occurrence rates of all cardiac AEs were similar between VDD and VD. CONCLUSIONS: The vDD regimen was similar with vAD in the aspect of response rate, survival, and toxicity in NDMM patients. The addition of PLD to VD brought deeper response without increased toxicity, while no superior survival was found.

Diffusion tensor imaging revealed different pathological processes of white matter hyperintensities.

BACKGROUND: Although increasing evidence showed the correlations between white matter hyperintensities (WMHs) and cognitive impairment, the relationship between them is still modest. Many researchers began to focus on the variation caused by the heterogeneity of WMH. We tried to explore the pathological heterogeneity in WMH by using diffusion tensor imaging (DTI), so as to provide a new insight into the future research. METHODS: Diffusion weighted images (DWIs) of the brain were acquired from 73 patients with WMH and 18 healthy controls, which were then modeled by DTI. We measured fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of white matter of the periventricular frontal lobe (pFL), periventricular occipital lobe (pOL), periventricular parietal lobe (pPL) and deep centrum ovales (dCO), and grouped these measures according to the Fazekas scale. Then we compared the DTI metrics of different regions with the same Fazekas scale grade. RESULTS: Significantly lower FA values (all p < 0.001), and higher MD (all p < 0.001) and RD values (all p < 0.001) were associated with WMH observed in the periventricular frontal lobe (pFL) compared to all other regions with the same Fazekas grades. The AD of WMH in the pFL was higher than that of pPL and dCO, but the differences between groups was not as high as of MD and RD, as indicated by the effect size. In the normal control group, DTI metrics between pFL and other regions were not significantly different or less significant different. The difference of DTI metrics of WMH between pPL, pOL and dCO was lower than that of normal white matter, as indicated by the effect size. CONCLUSION: Distinct pathological processes can be revealed by DTI between frontal periventricular WMH and other regions. These processes may represent the effects of severe demyelination within the frontal periventricular WMH.