Plasma metabolomics signatures of developmental dysplasia of the hip in Tibet plateau.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common childhood health complaint, whose etiology is multifactorial. The incidence of DDH is variable and higher in Tibet plateau. Here, we collected plasma samples and studied the metabolomics signatures of DDH. METHODS: Fifty babies were enrolled: 25 with DDH and 25 age-matched non-DDH healthy controls (HC group). We collected plasma samples, laboratory parameters and conducted untargeted metabolomics profiling. RESULTS: There are many differential metabolites among patients with DDH, including 4-ß-hydroxymethyl-4-α-methyl-5-α-cholest-7-en-3-beta-ol, ß-cryptoxanthin, α-tocopherol, taurocholic acid, glycocholic acid, 2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate, arabinosylhypoxanthine, leucyl-hydroxyproline, hypoxanthine. The main differential metabolic pathways focused on primary bile acid biosynthesis, arginine and proline metabolism, phenylalanine metabolism, histidine metabolism, purine metabolism. CONCLUSIONS: To our knowledge, this is the first report of metabolomics profile in babies with DHH. By combining the α-tocopherol and taurocholic acid, we could achieve the differential diagnosis of DDH.

Dynamic Single-Cell RNA-Seq reveals mechanism of Selinexor-Resistance in Chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a type of hematologic malignancies caused by BCR-ABL chimeric oncogene. Resistance to tyrosine kinase inhibitors (TKIs) leads to the progression of CML into advanced stages. Selinexor is a small molecule inhibitor that targets a nuclear transporter called Exportin 1. Combined with imatinib, selinexor has been shown to disrupt nuclear-cytoplasmic transport signal of leukemia stem cells, resulting in cell death. The objective of this study was to investigate the mechanism of drug resistance to selinexor in CML. We established K562 cell line resistant to selinexor and conducted single cell dynamic transcriptome sequencing to analyze the heterogeneity within the parental and selinexor resistant cell populations. We identified specific gene expression changes associated with resistance to selinexor. Our results revealed differential expression patterns in genes such as MT2A, TFPI, MTND3, and HMGCS1 in the total RNA, as well as MT-TW, DNAJB1, and HSPB1 in the newly synthesized RNA, between the parental and drug-resistant groups. By applying pseudo-time analysis, we discovered that a specific cluster of cells exhibited characteristics of tumor stem cells. Furthermore, we observed a gradual decrease in the expression of ferroptosis-related molecules as drug resistance developed. In vitro experiments confirmed that the combination of a ferroptosis inducer called RSL3 effectively overcame drug resistance. In conclusion, this study revealed the resistance mechanism of selinexor in CML. In conclusion, we identified a subgroup of CML cells with tumor stem cell properties and demonstrated that ferroptosis inducer improved the efficacy of selinexor in overcoming drug resistance.

Liquid extramedullary disease in multiple myeloma strongly predicts a poor prognosis and is associated with bortezomib resistance gene upregulation.

BACKGROUND-AIM: Patients with multiple myeloma (MM) relapse with extramedullary disease (EMD) exhibits an aggressive disease course and poor prognostic features. Myelomatous effusion (ME) is a rare subtype of EMD. METHODS: In this retrospective study, we analyzed the baseline characteristics and therapies of 14 EMD patients relapse with ME and 21 EMD patients relapse without ME. RESULTS: Patients with ME relapse demonstrated higher concentrations of serum lactate dehydrogenase, a higher fraction in the International Staging System stage III, and poorer event-free survival (EFS) (9.3 vs. 36.57 months; P = 0.0013) and overall survival (OS) (12.06 vs. 42.64 months; P < 0.001). The multivariate analysis showed that the presence of ME (hazard ratio [HR] 12.57; P = 0.003) and lack of autologous hematopoietic stem cell transplantation therapy (HR 4.382; P = 0.014) were predictive factors for poor OS. Using single-cell RNA sequencing, we discovered several bortezomib resistance genes were highly expressed in extramedullary malignant plasma cells. CONCLUSIONS: The presence of ME strongly predicts a poor prognosis in patients with MM relapse with EMD, and bortezomib resistance genes are highly expressed in extramedullary malignant plasma cells.

Identification of evolutionary mechanisms of myelomatous effusion by single-cell RNA sequencing.

Myelomatous effusion (ME) is a rare manifestation of extramedullary multiple myeloma (MM) with limited therapeutic options and poor outcomes. The molecular mechanisms underlying ME are incompletely understood. We profiled transcriptomes of bone marrow, peripheral blood (PB), and pleural effusion/ascites from 3 patients with ME using single-cell RNA sequencing analysis. We found that ME contained a higher percentage of cytotoxic T cells, whereas PB contained a higher proportion of naive T cells. Malignant cells varied within and between sites and patients in their expression of signatures. We identified a gene module highly expressed in intramedullary and extramedullary plasma cell clusters and defined cell clusters expressing this gene set as extramedullary-initiating cells (EMICs). This gene set was associated with increased cellular proliferation, involved in p53 signaling, and related to poor prognosis in MM. The transcriptional regulators E2F1, YY1, and SMAD1 were activated in EMICs. Leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) was upregulated in extramedullary EMICs. We confirmed that LILRB4 promoted MM cell migration in vitro. This study provided insight into the evolutionary mechanisms of ME and defined EMICs and LILRB4 associated with extramedullary development.

Identification of long noncoding RNA NEAT1 as a key gene involved in the extramedullary disease of multiple myeloma by bioinformatics analysis.

OBJECTIVE: Long non-coding RNAs (lncRNAs) are involved in tumorigenesis and play a key role in cancer progression. To determine whether lncRNAs are involved in extramedullary disease of multiple myeloma (EMD), we analyzed the expression profile of lncRNAs in EMD. METHODS: Three pairs of EMD patients and their intramedullary MM cells were screened by microarray first. We extracted data from gene chips and made an identification of lncRNAs and mRNAs with significant differences between EMD group and non EMD group. WGCNA confirmed the EMD related gene module and drew a heat map to further determine the key gene lncRNA-NEAT1. In the meantime, bone marrow and extramedullary samples (hydrothorax and ascites) were collected from 2 MM patients and subjected to single-cell RNA-seq. Single cell Transcriptome analysis was conducted to verify the gene expression difference of malignant plasma cells derived from intramedullary and extramedullary. Then we verified high expression level of lncRNA-NEAT1 in EMD patients by using quantitative real-time PCR (qRT-PCR) and analyzed the correlation between expression patterns and survival and molecular genetics analysis of the LncRNA (NEAT1) involved in MM patients. At last, cell experiments were conducted to observe the effects of down-regulation of NEAT1on the proliferation, cell cycle and PTEN pathway related proteins of multiple myeloma cell lines U266 and RPMI8226. RESULTS: We identified one of the EMD related key gene is lncRNA-NEAT1. Compared with patients without extramedullary lesions, intramedullary MM cells in EMD patients expressed NEAT1 highly. The outcome of parallel single-cell RNA sequencing (RNA-seq) revealed NEAT1 level of plasma cells came from pleural effusion /ascites increased significantly compared with myeloma-stricken bone marrow. By survival and molecular genetic analysis, NEAT1 gene expression was not associated with OS and PFS in MM patients. However, the expression of NEAT1 is related to adverse therapeutic reactions and the progression of MM. We found that the expressions of NEAT1 were negatively associated with albumin levels and were positively associated with gain of chromosome 1q, IGH-CCND1, IGH@-FGFR3/WHSC1,and IGH-MAF gene fusion, respectively. At the level of cell experiment, CCK-8, soft agar clone formation experiment and CFSE staining showed that down regulating NEAT1 could inhibit the proliferation of U266 and RPMI8226 cells; Cell cycle detection showed that down-regulation of NEAT1 would interfere with the cell cycle process, and RPMI 8226 cells were blocked in G1 phase. Western blot analysis showed that when the expression of NEAT1 was down regulated in U266 and RPMI 8226 cells, the expression of PTEN and p-PTEN (phosphorylated phosphatase and tensin homologue) was up-regulated, and the expression of PI3K, p-PI3K (human phosphorylated inositol 3 kinase), Akt, p-Akt (phosphorylated protein kinase B). DISCUCCION AND CONCLUSION: This study provides novel insights into the lncRNA-NEAT1 and reveals that NEAT1 maybe a potential lncRNA biomarkers in EMD.

The targeting imaging and treatment capacity of gelsolin-targeted and paclitaxel-loaded PLGA nanoparticles in vitro and in vivo.

As a vital sign of carcinomas, lymph node metastasis is closely related to poor prognosis due to a lack of identification and effective treatment in the early stage. Nanoscale contrast agents targeting specific tumor antigens are expected to identify tumor metastasis in the early stage and achieve precise treatment. As a biomarker in the early stage of tumor invasion and metastasis, gelsolin (GSN) might be a promising molecular target to identify and screen tumor metastasis through the lymphatic system. Therefore, GSN-targeted paclitaxel-loaded poly(lactic-co-glycolic acid) nanoparticles (GSN-PTX-PLGA NPs) were prepared, and their physicochemical properties, encapsulation efficiency, drug loading, and dissolution were determined. Besides, uptake experiments and the fluorescent imaging system were used to evaluate their targeting capability. The targeting imaging and treatment capacity were also assessed by experiments in vitro and in vivo. The diameter of the GSN-PTX-PLGA NPs was 328.59 ± 3.82 nm. Hca-F cells with GSN-PLGA NPs showed stronger green fluorescence than Hca-P cells. DiI-labeled GSN-PLGA NPs in tumor-bearing mice and isolated organs exhibited more prominent fluorescence aggregation. The imaging of GSN-PLGA NPs was satisfactory in vitro, and the echo intensity gradually increased with increasing concentrations of GSN-PLGA NPs. After treatment with GSN-PTX-PLGA NPs, there was an obvious decrease in tumor volume and lymph node metastasis rate compared to the other groups (p < 0.05). In conclusion, GSN-PTX-PLGA NPs have a remarkable targeting capacity in vivo and in vitro, and they effectively inhibit tumor growth and lymph node metastasis in vivo.

[Clinical Characteristics of Multiple Myeloma Patients with Early Relapse].

OBJECTIVE: To analyze the clinical characteristics of multiple myeloma(MM) patients with early relapse. METHODS: A total of 50 MM patients with early relapse (≤12 months) and 50 matched controls with late relapse (>12 months) were selected. The time from diagnosis to relapse and related clinical data of the 100 patients were retrospectively analyzed, and the factors associated with early relapse were identified. Kaplan-Meier curve was used to analyze the overall survival (OS) time of the whole cohort. Area under the curve (AUC) was used to evaluate the effect of circulating plasma cells on early recurrence of the patients. RESULTS: The results showed that high-risk cytogenetics (FISH) (P=0.005), and ISS stage III (P=0.008) were associated with early recurrence of the patients. For patients with early relapse, high-risk FISH showed poor survival. Compared with the patients with late relapse, most of the chromosome karyotype of patients with early relapse showed quantitative and structural abnormalities. The expression of circulating plasma cells was significantly increased in patients with early recurrence group (P=0.0318). The response to initial treatment was poor in the early recurrence group (P=0.001), and the prognosis was significantly worse than those in the late recurrence group (median OS: 38 vs 81 months, P=0.002). CONCLUSION: Early relapse is a marker poor prognostic in MM patients, and such patients should be focused on the improving their prognosis.

Blood hormones and suicidal behaviour: A systematic review and meta-analysis.

This study was to evaluate the relationship between blood hormone levels and suicidal behaviour. We reviewed Web of Science, PubMed and Embase for literature published up to 10 April 2022. Studies were restricted to English-language articles. Studies measuring blood hormone levels in suicidal and non-suicidal subjects were eligible. Standardized mean differences (SMDs) were applied to evaluate group differences. Overall, 57 studies were eligible, of which 51 evaluated suicide attempts, and 9 assessed suicidal ideation. Random-effects meta-analysis indicated that levels of thyrotropin stimulating hormone (TSH) (SMD = 0.50; 95% CI, 0.27-0.72), leptin (SMD = -1.16; 95% CI, -1.94 to -0.38) and dehydroepiandrosterone sulfate (DHEAS) (SMD = -0.67; 95% CI, -1.13 to -0.21) were related to suicide attempts, whereas progesterone levels (SMD = 0.22; 95% CI, 0.03-0.41) were related to suicidal ideation. This analysis offers evidence linking abnormalities of blood hormones with suicidal behaviour, which may be essential for identifying individuals with suicide attempts and suicidal ideation. Large prospective studies are needed for further clarification of roles of hormones in suicidal behaviour.

Relationship between depressive symptoms and internet usage time among adolescents: Results from a nationwide survey.

Adolescent depression is becoming a public health problem. In this study the association between depressive symptoms and internet usage time in adolescents was examined, with data collected from the China Education Tracking Survey (CEPS). The survey is publicly available and carried out nationwide. A logistic regression analysis was conducted with odds ratios (OR) and 95% confidence intervals (CI), the subgroup analysis examined the relationships between internet usage time and depressive symptoms. A total of 10,705 adolescents were involved, where 46.4% of them are caught by the internet for more than two hours per day. Adolescents keeping on the internet for 6-8 h per day were reported to have higher odds of depressive symptoms than adolescents who were free from it with the confounders of individual, family, and school adjusted, which were observed among groups with a medium family economic status without living with their father and with a sleep time less than nine hours. The results revealed that adolescents spending more time online had a higher risk of experiencing depression symptoms. This study suggested that it is helpful for mental health professionals to evaluate and develop prevention interventions for depressive symptoms in adolescents promptly through monitoring and managing online time.

Pomalidomide-based therapy for extramedullary multiple myeloma.

OBJECTIVES: Extramedullary disease (EMD) is characterized by plasma cells outside of bone marrow in multiple myeloma (MM) patients, which results in an adverse prognosis. EMD treatment is yet challenging even in the era of novel drugs. Only limited data are available on pomalidomide-based therapy for EMD patients. The purpose of the current study was to assess the efficacy of pomalidomide-based therapy in EMD. METHODS: The current retrospective analysis of six patients assessed the utility of pomalidomide-based therapy in the treatment of EMD. RESULTS: The median age at diagnosis was 55 (47-70) years. A serological response was observed: 16% (n = 1) complete response (CR), 67% (n = 4) partial response (PR), and 16% (n = 1) progressive disease (PD). Extramedullary overall response rate (ORR) was 83% (n = 5), with 50% (n = 3) CR, 33% (n = 2) PR, and extramedullary progression in one patient. The median progression-free survival (PFS) was 5 months and the median overall survival (OS) was 8 months from diagnosis of EMD. DISCUSSION AND CONCLUSION: Pomalidomide-based therapy showed efficacy in these previously treated patients with EMD.

Evaluation of Ascending Aortic Longitudinal Strain Via Two-Dimensional Speckle Tracking Echocardiography in Hypertensive Patients Complicated by Type A Aortic Dissection.

OBJECTIVE: To explore the value of ascending aortic longitudinal strain (LS) in identification of hypertensive (HP) patients with a high risk of type A aortic dissection (AAD). METHODS: Total 40 primary HP patients with AAD (group C), 80 selected age- and sex-matched primary HP patients (group A, normal-sized ascending aorta (AA), n = 40; group B, dilated AA, n = 40) and 40 healthy volunteers were enrolled in this study. Brachial blood pressures were measured, and the aortic stiffness index (ß) determined by M-mode analysis was calculated as a conventional parameter of arterial stiffness. The LS of the anterior and posterior ascending aortic wall (AW-LS and PW-LS) were determined. RESULTS: Compared to the control group (34.21 ± 5.25%), the mean LS of AA in HP patients (group A 28.6 ± 5.95%; group B 23.64 ± 4.98%; group C 17.93 ± 3.96%; P < .001) were significantly reduced. Multivariate logistic regression analysis showed that the mean LS (OR 0.719, 95% CI 0.615-0.839, P < .001) and pulse pressure (PP) (OR 1.055, 95% CI 1.006-1.106, P = .028) were identified as independent predictors of AAD in HP patients. The AUC of mean LS combined with PP reached 0.926 (sensitivity, 95.0%; specificity, 82.5%), which was higher than the mean LS, PP, stiffness index, and ascending aortic diameter (AAd) separately. Besides, the AW-LS and PW-LS were negatively correlated with the AAd, stiffness index, stroke volume, systolic blood pressure, and PP, respectively (P < .001). CONCLUSION: The LS of AA evaluated by two-dimensional speckle tracking echocardiography decreased significantly along with the expansion of aortic lumen and the occurrence of AAD in HP patients. It is also an independent predictor of AAD in HP patients.

Validation of the 2020 AHA/ACC Risk Stratification for Sudden Cardiac Death in Chinese Patients With Hypertrophic Cardiomyopathy.

Background: Sudden cardiac death (SCD) is a common cause of death in hypertrophic cardiomyopathy (HCM), but identification of patients at a high risk of SCD is challenging. The study aimed to validate the three SCD risk stratifications recommended by the 2011 ACCF/AHA guideline, the 2014 ESC guideline, and the 2020 AHA/ACC guideline in Chinese HCM patients. Methods: The study population consisted of a consecutive cohort of 511 patients with HCM without a history of SCD event. The endpoint was a composite of SCD or an equivalent event (appropriate implantable cardioverter defibrillator therapy or successful resuscitation after cardiac arrest). Results: During a follow-up of 4.7 ± 1.7 years, 15 patients (2.9%) reached the SCD endpoint and 12 (2.3%) were protected by implantable cardioverter defibrillator for primary prevention. A total of 13 (2.8%) patients experiencing SCD events were misclassified as low-risk patients by the 2011 ACCF/AHA guideline, 12 (2.3%) by the 2014 ESC model, and 7 (1.6%) by the 2020 AHA/ACC guideline. The SCD risk stratification in the 2020 AHA/ACC guideline showed greater area under the curve (0.71; 95% CI 0.56-0.87, p < 0.001) than the one in the 2011 ACCF/AHA guideline (0.52; 95% CI 0.37-0.67, p = 0.76) and 2014 ESC guideline (0.68; 95% CI 0.54-0.81, p = 0.02). Conclusion: The SCD risk stratification recommended by the 2020 AHA/ACC guideline showed a better discrimination than previous stratifications in Chinese patients with HCM. A larger multicenter, independent, and prospective study with long-term follow-up would be warranted to validate our result.

Pure erythroid leukemia subsequent to acute myelomonocytic leukemia: A case report.

RATIONALE: Pure erythroid leukemia is a rare subcategory of acute myeloid leukemia characterized by predominant immature erythroid population. Its occurrence subsequent to acute myelomonocytic leukemia has not been reported before. We reported this rare case to call attention because it may pose a diagnostic challenge. PATIENTS CONCERNS: A 54-year-old female patient presented to our hospital in March 2018 with symptoms of easy fatigability. DIAGNOSIS: Bone marrow aspiration was hypercellular showing 67.2% blasts mainly including moderate myeloblasts and monoblasts. There was mild dysplasia with some cells having round, oval, or bizarre nuclei which containing 1 to 3 nucleolus. Erythroid lineage was hypoplasia and mature erythrocytes were generally normal. Conventional cytogenetics of bone marrow cells revealed complex karyotype (44, XX, del (5) (q14q34) del (5) (q14q34), del (14) t (11;14) (q10; q10), -16, del (17), -18[10]). INTERVENTIONS: The patient was treated with second line chemotherapy but did not respond. QUTCOMES: She died of cardiopulmonary failure 19days after starting of therapy. LESSONS: This unexpected and relatively uncommon occurrence was associated with a universally rapid and fatal clinical course with survival measured in <2 months despite intensive chemotherapy. We call attention to this rare phenomenon because it may pose a diagnostic challenge.

Evaluation of Common Carotid Stiffness via Echo Tracking in Hypertensive Patients Complicated by Acute Aortic Dissection.

OBJECTIVES: To evaluate the common carotid stiffness via echo tracking in patients with hypertension and acute aortic dissection (AD) and to investigate the independent predictors for the occurrence of AD in hypertensive (HP) patients. METHODS: Fifty HP patients complicated by acute AD (AD group), 50 HP patients without AD (HP group), and 50 age-matched healthy volunteers (control group) were enrolled to assess the common carotid stiffness index (ß), single-point pulsed wave velocity (PWVß), and arterial compliance (AC) via echo tracking. RESULTS: The intima-media thickness, diameter, ß and PWVß of the common carotid artery (CCA) in the AD group were significantly higher than those in the HP and control groups, whereas AC in the AD group was significantly lower (P < .05). In a multivariate logistic regression analysis, the systolic blood pressure (SBP; odds ratio [OR], 2.316; 95% confidence interval [CI], 2.033-2.563; P < .001), ß (OR, 2.140; 95% CI, 1.931-2.367; P < .001), PWVß (OR, 1.212; 95% CI, 1.004-1.397; P = .023), and AC (OR, 0.565; 95% CI, 0.339-0.654; P < .001) were significantly related to the occurrence of AD in HP patients. The area under the curve values for the AC, SBP, ß, and PWVß were 0.822, 0.806, 0.778, and 0.741, respectively, and the area under the curve was up to 0.943 when these parameters were combined. CONCLUSIONS: The compliance of the CCA decreased, and the stiffness of the CCA increased significantly in HP patients complicated by AD. The AC, ß, and PWVß of the CCA, together with the SBP, were independent predictors of the occurrence of AD in HP patients.

Berberine attenuates XRCC1-mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs.

Berberine (BBR) is a natural isoquinoline alkaloid, which is used in traditional medicine for its anti-microbial, anti-protozoal, anti-diarrhoeal activities. Berberine interacts with DNA and displays anti-cancer activities, yet its effects on cellular DNA repair and on synthetic treatments with chemotherapeutic drugs remain unclear. In this study, we investigated the effects of BBR on DNA repair and on sensitization of breast cancer cells to different types of DNA damage anti-tumoural drugs. We found BBR arrested cells in the cell cycle S phase and induced DNA breaks. Cell growth analysis showed BBR sensitized MDA-MB-231 cells to cisplatin, camptothecin and methyl methanesulfonate; however, BBR had no synergistic effects with hydroxurea and olaparib. These results suggest BBR only affects specific DNA repair pathways. Western blot showed BBR down-regulated XRCC1 expressions, and the rescued XRCC1 recovered the resistance of cancer cells to BBR. Therefore, we conclude that BBR interferes with XRCC1-mediated base excision repair to sensitize cancer cells to chemotherapeutic drugs. These finding can contribute to understanding the effects of BBR on cellular DNA repair and the clinical employment of BBR in treatment of breast cancer.

Triptolide interferes with XRCC1/PARP1-mediated DNA repair and confers sensitization of triple-negative breast cancer cells to cisplatin.

Triptolide is a natural compound isolated from the Tripterygium wilfordii, which possesses anti-inflammatory and anti-tumor activities. Triptolide reportedly inhibits RNA polymerase II-mediated transcription and ATM activities to interfere with DNA repair. However, the roles of triptolide in DNA repair are still largely unknown. Triple negative breast cancer cells (TNBC) are insensitive to targeted anti-tumoral drugs, thus DNA damage chemotherapeutic drugs are the available treatments used in clinic, while the drug resistance of TNBC causes the challenge for successful cure. In this study, we investigated the efficiency of cisplatin in combination with triptolide in treatment of TNBC. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay shows triptolide suppresses the growth of two triple-negative breast cancer cells, BT549 and MDA-MB-231. Triptolide induces DNA breaks and arrests TNBC in the cell cycle S phase, and sensitizes TNBC to cisplatin. Western blot analysis shows triptolide down-regulated the levels of PARP1 and XRCC1, and slightly decreases the levels of RAD51. The results demonstrate triptolide interferes with single strand-break and base excision repair. The over-expressed PARP1/XRCC1 help the TNBC to resist triptolide. Based on these results, we conclude triptolide confers sensitization of TNBC to cisplatin via interference with XRCC1/PARP1-mediated base excision repair.