Tracing of Acyl Carrier Protein-channeled Mitomycin Intermediates in Streptomyces caespitosus Facilitates Characterization of the Biosynthetic Steps for AHBA-GlcN Formation and Processing.

Mitomycins are a family of naturally occurring, potent alkylating agents in which the C member has been clinically used for cancer chemotherapy for over 5 decades. In Streptomyces caespitosus, mitomycins are derived from an N-glycoside composed of a 3-amino-5-hydroxybenzoic acid (AHBA) unit and a d-glucosamine (GlcN) unit; however, how this N-glycoside is formed and rearranged to a mitosane, for example, the compact polycyclic ring system of mitomycin C, remains elusive. Benefiting from the development of a method used to trace the mitomycin intermediates that accumulate on an acyl carrier protein (ACP), we here dissect the enzymatic steps for AHBA-GlcN formation and processing to underlie the mitosane structure. Following the N-glycosylation of AHBA with activated N-acetyl-GlcN, deacetylation occurs on ACP to provide AHBA-GlcN. Then, the sugar portion of this N-glycoside is transformed into a linear aminodiol that terminates with an epoxyethane, yielding an ACP-channeled intermediate that is ready for mitosane formation through crosslinking between the AHBA and linearized sugar units. This transformation is unusual and relies on the functional association of a dihydronicotinamide adenine dinucleotide (phosphate)-dependent protein with a radical S-adenosyl-l-methionine protein. Characterization of these ACP-based enzymatic steps for AHBA-GlcN formation and processing sheds light on the poorly understood biosynthetic pathway of mitomycins.

Underground Microseismic Event Monitoring and Localization within Sensor Networks.

Locating underground microseismic events is important for monitoring subsurface activity and understanding the planetary subsurface evolution. Due to bandwidth limitations, especially in applications involving planetarily-distributed sensor networks, networks should be designed to perform the localization algorithm in-situ, so that only the source location information needs to be sent out, not the raw data. In this paper, we propose a decentralized Gaussian beam time-reverse imaging (GB-TRI) algorithm that can be incorporated to the distributed sensors to detect and locate underground microseismic events with reduced usage of computational resources and communication bandwidth of the network. After the in-situ distributed computation, the final real-time location result is generated and delivered. We used a real-time simulation platform to test the performance of the system. We also evaluated the stability and accuracy of our proposed GB-TRI localization algorithm using extensive experiments and tests.

Highly Sensitive Minimal Residual Disease Detection by Biomimetic Multivalent Aptamer Nanoclimber Functionalized Microfluidic Chip.

Minimal residual disease (MRD) offers a highly independent prognostic factor for leukemia patients. However, challenges confronting conventional MRD assays are high invasiveness, as well as limited detection sensitivity and clinical applicability. Inspired by the self-adaptive skeleton and multiple suckers or tendrils of climbing plants, a biomimetic Multivalent Aptamer Nanoclimber (MANC)-functionalized microfluidic chip (MANC-Chip) is reported for minimally invasive, highly sensitive and clinically applicable MRD detection in the peripheral blood of T-cell acute lymphoblastic leukemia patients. The MANCs are synthesized by a simple co-polymerization reaction. Due to their flexible structure and cooperative multivalent effect, MANCs dramatically enhance the binding affinity of aptamers targeting leukemia cells. A deterministic lateral displacement-patterned microfluidic chip is designed to further increase the collision probability between MANCs and leukemia cells. Benefiting from the synergistic effect of multivalent binding and enhanced collision, a high capture efficiency of 92.2% for leukemia cells is achieved. Moreover, the captured leukemia cells can be released with high efficiency of 88.9% and high viability of 93.8% via nuclease treatment prior to downstream analysis. Overall, the excellent features of MANC-Chip make it very useful for precise detection of MRD and better understanding of leukemia.

Ixazomib-based frontline therapy in patients with newly diagnosed multiple myeloma in real-life practice showed comparable efficacy and safety profile with those reported in clinical trial: a multi-center study.

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.

Silencing long non-coding RNA HOTAIR exerts anti-oncogenic effect on human acute myeloid leukemia via demethylation of HOXA5 by inhibiting Dnmt3b.

BACKGROUND: As an aggressive hematological malignancy, acute myeloid leukemia (AML) remains a dismal disease with poor prognosis. Long non-coding RNAs (lncRNAs) have been widely reported to be involved in tumorigenesis of AML. Here, we define an important role of lncRNA HOTAIR in AML in relation to HOXA5 methylation. METHODS: Firstly, the expression of HOTAIR was examined in AML samples and cells collected. Next, gain- or loss-of function experiments were conducted in AML cells to explore the effect of HOTAIR on AML. Then, relationship among HOXA5 promoter methylation, HOTAIR and Dnmt3b was measured. Expression of HOXA5 and cell proliferation/apoptosis-related genes was also detected. A last, in vivo assay was performed to assess the tumor formation in nude mice in order to explore the roles of HOTAIR and HOXA5 in cell apoptosis and proliferation. RESULTS: LncRNA HOTAIR was found to be upregulated in AML cells and tissues. With silencing of HOTAIR and overexpression of HOXA5, AML cell proliferation was decreased while the apoptosis was induced. Furthermore, HOTAIR was observed to recruit Dnmt3b and to increase HOXA5 promoter methylation. Moreover, silencing HOTAIR and upregulating HOXA5 were found to induce apoptosis and reduce proliferation of AML cells in vivo. CONCLUSION: Our findings highlight the anti-tumor ability of HOTAIR silencing in AML, suggesting that silencing HOTAIR was able to inhibit AML progression through HOXA5 promoter demethylation by decreasing Dnmt3b.

Frontiers and hotspots of adipose tissue and NAFLD: a bibliometric analysis from 2002 to 2022.

Background: The annual incidence of non-alcoholic fatty liver disease (NAFLD) continues to rise steadily. In recent years, adipose tissue (AT) has gained recognition as a pivotal contributor to the pathogenesis of NAFLD. Employing bibliometric analysis, we examined literature concerning AT and NAFLD. Methods: Relevant literature on AT in NAFLD from 1980 to 2022 was extracted from the Web of Science Core Collection. These records were visualized using CiteSpace and VOSviewer regarding publications, countries/regions, institutions, authors, journals, references, and keywords. Results: Since 2002, a total of 3,330 papers have been included, exhibiting an annual surge in publications. Notably, the quality of publications is superior in the USA and Europe. Kenneth Cusi stands out as the author with the highest number of publications and H-index. Hepatology is the journal boasting the highest citation and H-index. The University of California System holds the highest centrality among institutions. References specifically delve into physiological processes associated with AT in NAFLD. Currently, lipid metabolism and inflammation constitute the principal research mechanisms in the AT-based regulation of NAFLD, with pertinent keywords including microRNA, T cell, hypoxia, sarcopenia, hepatokine, gut microbiota, and autophagy. The Mediterranean diet is among the most widely recommended dietary approaches for potential NAFLD treatment. Conclusion: This paper represents the inaugural bibliometric study on the effects of AT on NAFLD, offering valuable insights and directions for future research.

[KMT2A Activates Akt/mTOR Signaling Pathway Through LncRNA-HOTAIR to Influence the Biological Behavior of AML Cells].

OBJECTIVE: To investigate the expression of lysine methyltransferase 2A (KMT2A) in acute myeloid leukemia (AML) cells and its molecular mechanism affecting the proliferation of AML cells. METHODS: Co-immunoprecipitation assay was used to detect the binding of KMT2A to long non-coding RNA-HOX transcript antisense RNA (lncRNA-HOTAIR). AML cell proliferation was detected by 5-ethynyl-2'-deoxyuridine (EdU) assay. RESULTS: The PCR amplification signal of KMT2A group was significantly stronger than that of the negative control group and IgG group (P<0.01). Compared with the negative control group and KMT2A-OE + lncRNA-HOTAIR-KD group, the ratio of EdU+ cells in both KMT2A-OE group and lncRNA-HOTAIR-OE group significantly increased (P<0.01). Compared with negative control group, the ratio of EDU+ cells in KMT2A-KD group and lncRNA-HOTAIR-KD group significantly decreased (P<0.01), the expression levels of p-Akt and p-mTOR in both KMT2A-OE group and lncRNA-HOTAIR-OE group significantly increased (P<0.01). CONCLUSION: KMT2A can interact with lncRNA-HOTAIR to promote the activation of Akt/mTOR signaling pathway, thus promoting the proliferation of AML cells.

Prognostic significance of CD56 expression in patients with multiple myeloma: a meta-analysis.

OBJECTIVES: Several studies have demonstrated the expression status of CD56 was associated with prognosis in multiple myeloma (MM) patients, the prognostic significance remains controversial. Here, the prognostic value of CD56 is further investigated in MM patients. METHODS: We systematically searched the databases including PubMed, EMBASE, Web of Science and the Cochrane Library. The hazard ratios (HRs) with their 95% confidence intervals (CIs) were pooled to evaluate the relationship between CD56 and overall survival (OS) and progress-free survival (PFS). RESULTS: A total of 14 studies covering 1365 patients were included in this meta-analysis. The results revealed that CD56 negativity in MM was associated with poorer OS (HR = 1.83, 95% CI = 1.29-2.60, P = 0.001) and PFS (HR = 1.57, 95% CI = 1.27-1.95, P = 0.000). Subgroup analysis further demonstrated that there was an effect of treatment regimen, detection method, survival analysis, study region and the cut-off value of CD56 on CD56 expression. DISCUSSION AND CONCLUSION: The meta-analysis suggested that CD56 negative patients had a poor prognosis for OS in Asian patients and for PFS in non-Asian patients. Novel drugs didn't show a significant improvement or overcome on the adverse prognosis brought by CD56 negativity. For patients undergone autologous stem-cell transplantation (ASCT), the poor prognosis was overcome by the treatment, which shed a light on the prognostic judgment and individualized treatment.

Enrichment and single-cell analysis of circulating tumor cells.

Up to 90% of cancer-related deaths are caused by metastatic cancer. Circulating tumor cells (CTCs), a type of cancer cell that spreads through the blood after detaching from a solid tumor, are essential for the establishment of distant metastasis for a given cancer. As a new type of liquid biopsy, analysis of CTCs offers the possibility to avoid invasive tissue biopsy procedures with practical implications for diagnostics. The fundamental challenges of analyzing and profiling CTCs are the extremely low abundances of CTCs in the blood and the intrinsic heterogeneity of CTCs. Various technologies have been proposed for the enrichment and single-cell analysis of CTCs. This review aims to provide in-depth insights into CTC analysis, including various techniques for isolation of CTCs with capture methods based on physical and biochemical principles, and single-cell analysis of CTCs at the genomic, proteomic and phenotypic level, as well as current developmental trends and promising research directions.

Cyclin D1 gene polymorphism and susceptibility to childhood acute lymphoblastic leukemia in a Chinese population.

Cyclin D1 is a key protein involved in cell cycle regulation. A common A870G single nucleotide polymorphism in exon 4 of the cyclin D1 gene (CCND1) has an effect on the transcription of 2 different cyclin D1 messenger RNAs. Correlation between genetic polymorphism of A870G of CCND1 and clinical outcome among patients with acute lymphoblastic leukemia (ALL) has been reported. However, the effect on ALL occurrence remains unclear. To examine the genotypic frequency of CCND1 polymorphism, we performed a case-control study in a Chinese population of 183 children with ALL and 190 healthy controls. The genetic frequency of CCND1 had a significant overall correlation in patients and controls. The AA genotype of CCND1 showed a tendency to increase ALL risk 3.2898-fold compared with the AG + GG genotype (P = .0207). Stratification of patients according to cell type, risk level, and chemotherapeutic response showed significance for the AA genotype in T-cell ALL, ALL with high risk, and no complete remission (P = .047, P = .011, and P = .007, respectively). No gene dosage effect was observed in this study. The results of the present study suggested that CCND1 genetic polymorphism may be related to the occurrence of ALL in a population of Chinese children.

[Clinical features and risk factors for infections in adult acute leukemia after chemotherapy].

OBJECTIVE: To observe the clinical characteristics of infections in adult acute leukemia （AL）patients during chemotherapy in hospital, and identify the risk factors for infections. METHODS: A retrospective study of patients with AL who underwent chemotherapy between July 2010 and Dec 2014 in the First Affiliated Hospital of Xiamen University was conducted. Clinical features and risk factors for infections were analyzed. RESULTS: 191 patients with AL received a total of 728 courses of chemotherapies. During these admissions, 385（52.9%) infections episodes occurred. The common infections sites were lower respiratory tract infection（36.3%，153/374）, bloodstream infection（17.1%, 64/374）, oral infection（13.6%，51/374）, and perianal infection（13.4%, 50/374）. 164 strains of pathogenic bacteria were detected. Gram- negative bacteria were recorded in 59.1% of documented pathogens, and Gram- positive bacteria were responsible for 32.9% of infections. Multivariate unconditioned logistic analysis of factors identified consistent independent risk factors for no completely remission（OR=0.142, P< 0.001）, duration of neutropenia longer than 7 days（OR=12.764, P<0.001）, general wards（OR=1.821, P< 0.001）, and hospitalization interval longer than 10 days（OR=0.720, P=0.039）. CONCLUSION: Infections after chemotherapy for AL continues to be common. AL patients with induction chemotherapy or severe neutropenia faced an increased risk of infections by multivariate analysis. And patients with short-term stay or laminar flow wards seem to be less susceptible to infections.

Autonomous mobile platform for enhanced situational awareness in Mass Casualty Incidents.

To enhance the efficiency of the search and rescue process of a Mass Casualty Incident, we introduce a low cost autonomous mobile platform. The mobile platform motion is controlled by an Android Smartphone mounted on a robot. The pictures and video captured by the Smartphone camera can significantly enhance the situational awareness of the incident commander leading to a more efficient search and rescue process. Moreover, the active RFID readers mounted on the mobile platform can improve the localization accuracy of victims in the disaster site in areas where the paramedics are not present, reducing the triage and evacuation time.

[Clinical implications of tumor necrosis factor-α in lymphomas].

OBJECTIVE: To investigate the levels of tumor necrosis factor-α (TNF-α) in tissue or plasma and its clinical implications in different types of lymphoma. METHODS: The levels of TNF-α in paraffin tissue or plasma samples were detected by immunohistochemistry or ELISA assay in 88 lymphoma patients and 88 healthy controls. Univariate and multivariate Cox regression analysis were used to identify the correlation between Ann Ardor stage, blood cells count, bone marrow abnormalities, erythrocyte sedimentation rate (ESR), serum ferritin and TNF-α expression. RESULTS: The levels of TNF-α had significant difference in different types of lymphoma (P<0.05). High positive and levels in Hodgkin lymphoma [HL, 72.72% and (43.12±15.28) ng/L], aggressive non-HL [NHL, 67.86% and (40.73±16.65) ng/L], and indolent NHL [57.14% and (53.18±20.47) ng/L]. Cox regression analysis showed that Ann Ardor stage, bone marrow abnormalities, ESR, and the levels of TNF-α were independent risk factors for lymphoma with poor prognosis. CONCLUSION: As an independent factor, TNF-α may play a role in the development of lymphoma and is an important prognostic factor.

Preventive cardioprotection of erythropoietin against doxorubicin-induced cardiomyopathy.

INTRODUCTION: Doxorubicin (DOX) is a highly effective chemotherapeutic agent related to dose-dependent cardiomyopathy. Recent evidence suggests that erythropoietin (EPO) can play a protective role in cardiovascular diseases by non-erythropoietic effects. In the present study, we tested the hypothesis that EPO may protect against DOX-induced cardiomyopathy through anti-apoptotic mechanisms both in vitro and in vivo. MATERIALS AND METHODS: Isolated neonatal Wistar rat cardiomyocytes were treated with vehicle, DOX with or without EPO, or EPO. Twenty-four hours later, the cells were used to determine cardiomyocyte apoptosis (TUNEL assay). Cardiomyopathy was induced in Wistar rats by intraperitoneal injections (IP) of DOX (2.5 mg/kg, six times for 2 weeks). EPO (2,500 U/kg, six times for 2 weeks) was administered simultaneously in the DOX+EPO group and the EPO group. Two weeks after the last administration, cardiac function was evaluated by echocardiography and invasive haemodynamic measurements. Rats were then sacrificed for histological and TUNEL analyses, with immunological detection for cardiac Troponin-T (cTnT), alpha-actinin, Bax and Bcl-2. RESULTS: EPO significantly ameliorated DOX-induced apoptosis of cultured cardiomyocytes as demonstrated by TUNEL assay. In the rat model, cardiac function significantly decreased in the DOX group. In contrast, the DOX+EPO group showed considerable improvement in cardiac function, inhibition of cardiomyocyte apoptosis, reduction of fibrosis, as well as up-regulation of Bcl-2 protein expression. CONCLUSIONS: Our results suggest that EPO exerts preventive cardioprotective effects on DOX-induced cardiomyopathy via anti-apoptotic pathways. The up-regulation of Bcl-2 protein expression may contribute to this.