Knockdown of let-7b in leukemia associated macrophages inhibit acute myeloid leukemia progression.

Macrophages, critical components of bone marrow microenvironment, are reported to be remodeled into leukemia-associated macrophages (LAMs) in leukemic microenvironment where they contribute to leukemia development, characterized as M2 macrophages with pro-tumor effects. However, how leukemic microenvironment transforms macrophages into LAMs remains unknown. Here, we analyzed the clinical relevance of LAMs and profiled their RNA-Seq from acute myeloid leukemia (AML) patients with complete remission (CR) after induction treatment and refractory AML patients. Our results showed that the proportion and number of LAMs in refractory AML patients was higher than that in CR patients and LAM was a poor prognostic factor of AML patients. Furthermore, let-7b was a potentially aberrant gene in LAMs contributed to M2-subtype characteristics. Knockdown of let-7b in LAMs could inhibit the development of AML by repolarizing LAMs toward M1-subtype characteristics through the activation of Toll-like receptor and NF-κB pathway. Our study provides insight for future LAM-based immunotherapy strategies for AML.

Flagella-Driven Motility Is Critical to the Virulence of Xanthomonas fragariae in Strawberry.

Xanthomonas fragariae (X. fragariae) is the causal agent of angular leaf spots (ALS) in strawberry plants. Recently, a study in China isolated X. fragariae strain YL19, which was observed to cause both typical ALS symptoms and dry cavity rot in strawberry crown tissue; this was the first X. fragariae strain to have both these effects in strawberry. In this study, from 2020 to 2022, we isolated 39 X. fragariae strains from diseased strawberries in different production areas in China. Multilocus sequence typing (MLST) and phylogenetic analysis showed that X. fragariae strain YLX21 was genetically different from YL19 and other strains. Tests indicated that YLX21 and YL19 had different pathogenicities toward strawberry leaves and stem crowns. YLX21 did not cause ALS symptoms, rarely caused dry cavity rot in strawberry crown after wound inoculation, and never caused dry cavity rot after spray inoculation, but it did cause severe ALS symptoms after spray inoculation. However, YL19 caused more severe symptoms in strawberry crowns under both conditions. Moreover, YL19 had a single polar flagellum, while YLX21 had no flagellum. Motility and chemotaxis assays showed that YLX21 had weaker motility than YL19, which may explain why YLX21 tended to multiply in situ within the strawberry leaf rather than migrate to other tissues, causing more severe ALS symptoms and mild crown rot symptoms. Taken together, the new strain YLX21 helped us reveal critical factors underlying the pathogenicity of X. fragariae and the mechanism by which dry cavity rot in strawberry crowns forms.

Systemic Colonization of Xanthomonas fragariae Strain YL19 Causing Dry Cavity Rot of Strawberry Crown Tissue in China.

Xanthomonas fragariae usually causes angular leaf spot (ALS) of strawberry, a serious bacterial disease in many strawberry-producing regions worldwide. Recently, a new strain of X. fragariae (YL19) was isolated from strawberry in China and has been shown to cause dry cavity rot in strawberry crown. In this study, we constructed a green fluorescent protein (GFP)-labeled Xf YL19 (YL19-GFP) to visualize the infection process and pathogen colonization in strawberries. Foliar inoculation of YL19-GFP resulted in the pathogen migrating from the leaves to the crown, whereas dip inoculation of wounded crowns or roots resulted in the migration of bacteria from the crowns or roots to the leaves. These two invasion types both resulted in the systematic spread of YL19-GFP, but inoculation of a wounded crown was more harmful to the strawberry plant than foliar inoculation. Results increased our understanding of the systemic invasion of X. fragariae, and the resultant crown cavity caused by Xf YL19.

Optimization and Antibacterial Evaluation of Novel 3-(5-Fluoropyridine-3-yl)-2-oxazolidinone Derivatives Containing a Pyrimidine Substituted Piperazine.

In this study, a series of novel 3-(5-fluoropyridine-3-yl)-2-oxazolidinone derivatives were designed and synthesized based on compounds previously reported, and their antibacterial activity was investigated. Then their antibacterial activity was investigated for the first time. Preliminary screening results showed that all these compounds exhibited antibacterial activity against gram-positive bacteria, including 7 drug-sensitive strains and 4 drug-resistant strains, among which compound 7j exhibited an 8-fold stronger inhibitory effect than linezolid, with a minimum inhibitory concentration (MIC) value of 0.25 µg/mL. Further molecular docking studies predicted the possible binding mode between active compound 7j and the target. Interestingly, these compounds could not only hamper the formation of biofilms, but also have better safety, as confirmed by cytotoxicity experiments. All these results indicate that these 3-(5-fluoropyridine-3-yl)-2-oxazolidinone derivatives have the potential to be developed into novel candidates for the treatment of gram-positive bacterial infections.

Functional-Unit-Based Material Design: Ultralow Thermal Conductivity in Thermoelectrics with Linear Triatomic Resonant Bonds.

We demonstrate the use of functional-unit-based material design for thermoelectrics. This is an efficient approach for identifying high-performance thermoelectric materials, based on the use of combinations of functional fragments relevant to desired properties. Here, we reveal that linear triatomic resonant bonds (LTRBs) found in some Zintl compounds provide strong anisotropy both structurally and electronically, along with strong anharmonic phonon scattering. An LTRB is thus introduced as a functional unit, and compounds are then screened as potential thermoelectric materials. We identify 17 semiconducting candidates from the MatHub-3d database that contain LTRBs. Detailed transport calculations demonstrate that the LTRB-containing compounds not only have considerably lower lattice thermal conductivities than other compounds with similar average atomic masses, but also exhibit remarkable band anisotropy near the valence band maximums due to the LTRB. K5CuSb2 is adopted as an example to elucidate the fundamental correlation between the LTRB and thermoelectric properties. The [Sb-Cu-Sb]5- resonant structures demonstrate the delocalized Sb-Sb interaction within each LTRB, resulting in the softening of TA phonons and leading to large anharmonicity. The low lattice thermal conductivity (0.39 W/m·K at 300 K) combined with the band anisotropy results in a high thermoelectric figure of merit (ZT) for K5CuSb2 of 1.3 at 800 K. This work is a case study of the functional-unit-based material design for the development of novel thermoelectric materials.

Rare left-sided accessory pathway successfully ablated with atrial insertion site at the left-side fossa ovalis.

INTRODUCTION: Left-sided accessory pathway (AP) with atrial insertion away from the annulus is an atypical variation. Conventional mapping and ablation performed along mitral annulus (MA) is usually ineffective. METHODS: A 14-year-old girl without structural heart disease presented with recurrent episodes of sudden onset palpitations and electrocardiogram (ECG) showed a narrow QRS complex tachycardia. RESULTS: Electrophysiology study (EPS) was done and anterograde atrioventricular reentrant tachycardia (AVRT) with AP was diagnosed. Conventional mapping and ablation performed along TA and MA was failed. 3D-activation mapping found the retrograde atrial insertion site of AP on the left atrium fossa ovalis (FO), and AP was successfully abolished by radiofrequency ablation at that site. CONCLUSION: As reported, this patient is the first report of ablating a left-sided AP with retrograde atrial insertion on the left atrium FO.

Clinical features of cancer with unknown primary site (clinical features, treatment, prognosis of cancer with unknown primary site).

Cancer of unknown primary site(CUPs) is a metastatic syndrome with an unidentifiable primary tumor, even after extensive workup to seek the primary site. CUPs accounts for about 3%-5% of the total number of all cancer diagnoses worldwide. The current precision medicine era has reclassified patients with CUPs into the favorable and unfavorable prognostic subset. In this study clinical characteristics and treatment of patients of CUPs were retropactively analysed. Thirty-two patients treated from July 2016 to October 2021 were included in the Affiliated Tumor Hospital of Tianjin Medical University(Tianjin, China).Common symptoms were anemia, fever, enlarged lymph nodes, abdominal pain, edema/multiple serous cavity effusion. Patients with good prognostic factors achieved good outcomes with treatment, conversely, patients with poor prognosis were generally treated empirically and had poorer outcomes. After anti-tumor treatment, the total effective rate was 41 percent(41% was the percentage of patients who achievedtumour respons). To the end of follow-up, after anti-tumor treatment, the median Overall Survival(OS) of patients was 5.4 months.

Downregulation of FAPP2 gene induces cell autophagy and inhibits PI3K/AKT/mTOR pathway in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Most patients with T-ALL are treated with high-dose multi-agent chemotherapy due to limited targeted therapeutic options. To further investigate its pathogenesis and establish new therapeutic targets, we studied the role of FAPP2, a Golgi protein, that is, highly expressed in T-ALL, in the growth and function of T-ALL. We found that T-ALL cells underwent reduced cell proliferation and sub-G1 accumulation after knocking down of FAPP2 gene using shRNA systems. Instead, FAPP2 downregulation promoted cell autophagy. The level of autophagy markers, LC3Ⅱ/Ⅰ, Beclin1, and ATG5, was markedly increased, whereas that of P62 decreased after FAPP2 knocking down in T-ALL cells. FAPP2 knocking down led to the accumulation of LC3 in the cytoplasm of T-ALL cells as shown by fluorescence microscopy. In addition, the level of PI(4)P and PI(3,4,5)P decreased and phosphorylation of P-AKT and P-mTOR were downregulated in FAPP2 knock-down cells. In summary, our results show that decreased expression of FAPP2 inhibited cell proliferation, resulted in the sub-G1 phase accumulation of T-ALL cells, and enhanced autophagy of T-ALL cells, likely mediated by PI(4)P, PI(3,4,5)P, and PI3K/AKT/mTOR pathway. Our results provide a new insight into the pathogenesis and development of potential targeted therapy of T-ALL.

Synthesis, Antibacterial and Anthelmintic Activity of Novel 3-(3-Pyridyl)-oxazolidinone-5-methyl Ester Derivatives.

In this study, a series of 3-(3-pyridyl)-oxazolidone-5-methyl ester derivatives was synthesized and characterized by 1H NMR, 13C NMR, and LC-MS. The conducted screening antibacterial studies of the new 3-(3-pyridyl)-oxazolidone-5-methyl ester derivatives established that the methyl sulfonic acid esters have broad activity spectrum towards Staphylococcus aureus, Streptococcus pneumoniae, Bacillus subtilis and Staphylococcus epidermidis. Among them, compound 12e has the most potent activity, with an MIC of 16 µg/mL against B.subtilis, and could reduce the instantaneous growth rate of bacteria. Furthermore, molecular docking studies were also simulated for compound 12e to predict the specific binding mode of this compound. In addition, anthelmintic activity of these compounds was also evaluated against adult Indian earthworms (Pheretima posthuman). The results showed that compound 11b had the best effect. These results above can provide experimental reference for the development of novel antibacterial and anthelmintic drugs.

Multiplex ligation-dependent probe amplification identifies copy number changes in normal and undetectable karyotype MDS patients.

Chromosomal abnormalities play an important role in classification and prognostication of myelodysplastic syndrome (MDS) patients. However, more than 50% of low-risk MDS patients harbor a normal karyotype. Recently, multiplex ligation-dependent probe amplification (MLPA) has emerged as an effective and robust method for the detection of cytogenetic aberrations in MDS patients. To characterize the subset of MDS with normal karyotype or failed chromosome banding analysis, we analyzed 144 patient samples with normal karyotype or undetectable through regular chromosome banding analysis, which were subjected to parallel comparison via fluorescence in situ hybridization (FISH) and MLPA. MLPA identifies copy number changes in 16.7% of 144 MDS patients, and we observed a significant difference in overall survival (OS) (median OS: undefined vs 27 months, p=0.0071) in patients with normal karyotype proved by MLPA versus aberrant karyotype cohort as determined by MLPA. Interestingly, patients with undetectable karyotype via regular chromosome banding indicated inferior outcome. Collectively, MDS patients with normal or undetectable karyotype via chromosome banding analysis can be further clarified by MLPA, providing more prognostic information that benefit for individualized therapy.

Clinical features & treatment of early-stage gastric mucosa-associated lymphoid tissue lymphoma.

Background & objectives: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a common marginal zone lymphoma. The stomach is the relatively common origin of the MALT lymphoma, now termed as extranodal marginal zone B-cell lymphoma. Gastric MALT lymphoma has good prognosis due to clinical response to treatment and favourable overall survival. In this study, clinical characteristics and treatment of patients of early gastric MALT lymphoma were retrospectively analysed. Methods: Seventy patients with stages I-II MALT-lymphoma treated from April 2003 to August 2015 were included. The most common symptoms were abdominal discomfort, nausea, vomiting and other digestive symptoms. Helicobacter pylori eradication was done in patients with proven H. pylori infection. Patients in whom H. pylori eradication therapy was not effective, alternative treatments options including chemotherapy, radiotherapy and surgery, were given. Results: Fifty two patients with H. pylori infection underwent anti-H. pylori therapy, the total effective rate of anti-H. pylori treatment was 92.3 per cent (48/52). Thirty two patients were given anti-tumour treatment, including chemotherapy, radiotherapy and surgery. The total effective rate was 90.6 per cent (29/32). The five-year overall survival rate and five-year progression-free survival rate were 93.4 and 84.2 per cent, respectively. Interpretation & conclusions: For patients with early gastric MALT lymphoma, anti-H. pylori treatment may be effective. Patients with poor results of anti-H. pylori treatment need to be treated with anti-tumour therapy.

Extracellular vesicles derived from T-cell acute lymphoblastic leukemia inhibit osteogenic differentiation of bone marrow mesenchymal stem cells via miR-34a-5p.

Reduced bone formation in patients with T-cell acute lymphoblastic leukemia (T-ALL) may be related to the interaction between tumour cells and bone marrow stromal cells (BMSCs). The miRNAs in extracellular vesicles derived from leukemia cells play an essential role in regulating the function of BMSCs; however, the regulatory mechanisms remain unclear. The expression of miR-34a-5p in T-ALL patients and cells was measured by quantitative real-time PCR. BMSCs were co-cultured with extracellular vesicles isolated from T-ALL cells in mineralization medium. The osteogenic differentiation of BMSCs was evaluated by Alizarin Red S staining, alkaline phosphatase (ALP) staining, and detection of osteogenic differentiation markers. A dual-luciferase reporter assay was performed to confirm the targeting relationship between miR-34a-5p and Wnt family member 1 (WNT1). MiR-34a-5p expression was upregulated in T-ALL patients and Jurkat cells. After BMSCs were co-cultured with extracellular vesicles derived from T-ALL cells, osteogenic differentiation of BMSCs was inhibited, and bone mineralization and ALP activity were decreased compared to those of control cells. MiR-34a-5p knockdown in T-ALL cells restored osteogenic differentiation of BMSCs co-cultured with extracellular vesicles. In addition, miR-34a-5p targets and negatively regulates WNT1 expression. In conclusion, our results demonstrated that knockdown of miR-34a-5p in extracellular vesicles derived from T-ALL cells promoted osteogenic differentiation of BMSCs by regulating WNT1.

Revisiting right anterior oblique projections for the triangle of Koch: implications from computed tomography.

BACKGROUND: Variability in the anatomy and orientation of the triangle of Koch (TK) complicates ablation procedures involving the atrioventricular (AV) node. We used CT angiography (CTA) to assess the anatomical TK orientation, the CS ostium direction, and the relationship between the two, and we validated an individualized CS-guided projection during ablation procedures. METHODS: In 104 patients without structural heart disease undergoing computed tomography (CT) angiography, TK orientations were determined in relation to the coronary sinus ostium (CSo) as well as two standard right anterior oblique (RAO) projection angles (30o and 45o) commonly used in ablation procedures. RESULTS: A CS-guided RAO projection (RAOCS) was shown to best track the orientation of the TK compared to RAO30° and 45°, with TK orientation strongly correlating with the CSo direction (r = 0.86, P < 0.001). In addition, the mean relative difference between the angle of the CSo and TK orientation was 5.54 ± 0.48°, consistent with a reduction in the degree of image shortening compared to traditional RAOs. Moreover, in vivo validation following ablation revealed that using a CS-guided projection limited the degree of on-screen image shortening compared to both the RAO30° and 45° in 25 patients with catheter ablation procedures. CONCLUSION: In hearts with a normal structure, the CSo direction offers a reliable predictor of the TK orientation which can be used to guide the projection of the TK during ablation procedures.

High prevalence of hepatitis B virus infection in patients with aggressive B cell non-Hodgkin's lymphoma in China.

We retrospectively analyzed a large study to investigate the association of hepatitis B virus (HBV) with aggressive B cell non-Hodgkin's lymphoma (aggressive B-NHL) in China, where HBV is endemic. HBV was present in 39 aggressive B-NHL patients (10.46%), 13 indolent B-NHL patients (5.09%), 12 multiple myeloma (MM) patients (3.67%), and 5 solitary plasmacytoma (SP) patients (6.67%). HBV infection was significantly associated with increased risks for aggressive B-NHL (P < 0.01). HBV seems to have a very important role in the pathogenesis of aggressive B-NHL in China.

Atorvastatin Attenuates Metabolic Remodeling in Ischemic Myocardium through the Downregulation of UCP2 Expression.

Uncoupling protein 2 (UCP2) is primarily expressed in the myocardium and is closely related to myocardial ischemia/reperfusion injury and myocardial metabolism. To explore the effects and the mechanisms of UCP2 on atorvastatin-mediated myocardium protection, the rat model of myocardial ischemia was established by ligation of the left anterior descending coronary arteries (LADs). The rats were divided into the sham operation (SO) group, myocardial infarction (MI) group and MI-atorvastatin group. The study that atorvastatin reduced myocardial remodeling and improved the disturbed myocardial energy metabolism after MI. Furthermore, the mechanisms of myocardial metabolic remodeling affected by atorvastatin were explored. The atorvastatin group showed a significantly decreased expression of UCP2 mRNA and protein. Furthermore, the primary rat cardiomyocytes were cultured and treated with angiotensin II (Ang II) to induce cardiomyocyte hypertrophy. The results showed that in the atorvastatin group, the surface area of the cardiomyocytes, the total protein content per unit of cells, and the expression of the UCP2 protein were significantly decreased. These data suggested that atorvastatin significantly attenuated the myocardial remodeling by downregulating the expression of UCP2 that was found to improve the myocardial energy metabolism, inhibit myocardial hypertrophy, and eventually reduce myocardial remodeling.

Unique Ventricular Tachycardia Originating from the Right Bundle Branch.

Ventricular tachycardia (VT), a common arrhythmia, frequently originates from in the right ventricular outflow tract, left ventricular outflow tract, aortic sinus, and left ventricular papillary muscle but infrequently from the His-Purkinje system, whereas the VT stemming from the right bundle branch has rarely been reported. Here we reported a case with of VT originating from the right bundle branch which was subsequently successfully treated with radiofrequency ablation and demonstrated the electrocardiac features of VT using an electrophysiological examination.

Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation.

Autophagy is a cell biological pathway affecting immune responses. In vitro, autophagy acts as a cell-autonomous defense against Mycobacterium tuberculosis, but its role in vivo is unknown. Here we show that autophagy plays a dual role against tuberculosis: antibacterial and anti-inflammatory. M. tuberculosis infection of Atg5(fl/fl) LysM-Cre(+) mice relative to autophagy-proficient littermates resulted in increased bacillary burden and excessive pulmonary inflammation characterized by neutrophil infiltration and IL-17 response with increased IL-1α levels. Macrophages from uninfected Atg5(fl/fl) LysM-Cre(+) mice displayed a cell-autonomous IL-1α hypersecretion phenotype, whereas T cells showed propensity toward IL-17 polarization during nonspecific activation or upon restimulation with mycobacterial antigens. Thus, autophagy acts in vivo by suppressing both M. tuberculosis growth and damaging inflammation.

Toll-like receptor 4-induced inflammatory responses contribute to the tumor-associated macrophages formation and infiltration in patients with diffuse large B-cell lymphoma.

To evaluate the expression of tumor-associated macrophages (TAMs) and Toll-like receptor 4 (TLR4) in diffuse large B-cell lymphoma (DLBCL) and their correlation with patient clinical characteristics, we detected using immunohistochemistry in 81 specimens of patients with DLBCL. The correlation between protein expression levels and clinical parameters, as well as the association between CD68 and TLR4 were analyzed. The number of CD68 TAMs was closely related to ß2-microglobulin (P = .028 and P < .05), whereas there was no significant correlation between the number of CD68 TAMs and other clinical factors. Toll-like receptor 4 was related to tumor size and peripheral blood lymphocyte to monocyte ratio. The Spearman correlation coefficient indicated a significant positive correlation between CD68 TAMs and TLR4 expression (r = 0.240; P = .038, P = .05). These results, on one hand, indicated that TLR4-induced inflammatory responses may affect TAM infiltration and accumulation, and that TAMs and TLR4 may interact to play important roles in DLBCL microenvironment regulating the tumor growth, but, on the other hand demonstrated that both of TAMs and TLR4 had not only one side on DLBCL growth.

Bcl-2 expression is associated with poor prognosis of solitary plasmacytoma of bone.

Solitary plasmacytoma of bone (SPB) is a rare tumor that represents a minority of patients with plasma cell localized malignancy characterized by a single osteolytic bone lesion. The molecular mechanism underlying the genesis of SPB has remained enigmatic. Signal transducers and activators of transcription-3 (STAT3) is often activated in human cancers and is implicated in tumorigenesis. In the present work, the immunohistochemical expression of pSTAT3 (the active isoform of STAT3) and its potential downstream mediators (Bcl-2, Bcl-xL, c-Myc, cyclin D1, VEGF, cIAP-2, Mcl-1, and survivin) were examined, clinical features were investigated, and relative prognostic factors were analyzed. Positive expression of Bcl-2 was observed in 46.7 % (14/30) of patients, c-Myc in 36.7 % (11/30), and cyclin D1 in 23.3 % (7/30). By univariate analysis, Bcl-2 expression was found to be closely associated with shorter overall survival (OS) and progression-free survival. Bcl-2 and c-Myc positive expression were also found to be a factor that affect time to progression to multiple myeloma. In conclusion, results showed Bcl-2 expression to be a clinically significant prognostic indicator for SPB patients and constitutive activated STAT3 may not be the sole primary regulatory mechanism.

Development and Validation of Computational Fluid Dynamics Model of Ladle Furnace with Electromagnetic Stirring System.

Numerical methods are crucial to supporting the development of new technology in different industries, especially steelmaking, where many phenomena cannot be directly measured or observed under industrial conditions. As a result, further designing and optimizing steelmaking equipment and technology are not easy tasks. At the same time, numerical approaches enable modeling of various phenomena controlling material behavior and, thus, understanding the physics behind the processes occurring in different metallurgical devices. With this, it is possible to design and develop new technological solutions that improve the quality of steel products and minimize the negative impact on the environment. However, the usage of numerical approaches without proper validation can lead to misleading results and conclusions. Therefore, in this paper, the authors focus on the development of the CFD-based (computational fluid dynamics) approach to investigate the liquid steel flow inside one metallurgical device, namely a ladle furnace combined with an EMS (electromagnetic stirring) system. First, a numerical simulation of electromagnetic stirring in a scaled mercury model of a ladle furnace was carried out. The numerical results, such as stirring speed and turbulent kinetic energy, were compared with measurements in the mercury model. It was found that the results of the transient multiphase CFD model achieve good agreement with the measurements, but a free surface should be included in the CFD model to simulate the instability of the flow pattern in the mercury model. Based on the developed model, a full-scale industrial ladle furnace with electromagnetic stirring was also simulated and presented. This research confirms that such a coupled model can be used to design new types of EMS devices that improve molten steel flow in metallurgical equipment.