Prevalence and factors associated with carbapenem-resistant Enterobacterales (CRE) infection among hematological malignancies patients with CRE intestinal colonization.

BACKGROUND: Knowledge about the prevalence, factors and mortality associated with subsequent carbapenem-resistant Enterobacterales (CRE) infection among hematological malignancies (HM) patients colonized with CRE is limited. METHODS: HM patients were screened for rectal CRE. A retrospective case-control study of subsequent CRE infection among HM patients colonized with CRE was conducted between January 1st, 2020 and January 31st, 2022. Cases were defined as CRE colonized patients with subsequent infection and controls were those without infection. Bacterial identification was performed using MALDI Biotyper and antimicrobial susceptibility testing of strains was carried out using the VITEK 2 system or standard broth microdilution method. Logistic analysis was used for analyzing associated factors and Kaplan-Meier method was used for survival estimates. RESULTS: A total of 953 HM patients were screened for rectal CRE and 98 (10.3%, 98/953) patients were colonized with CRE. Among the 98 colonized patients, 18 (18.4%, 18/98) patients developed subsequent infection. Most of the colonizing CRE isolates were Klebsiella pneumoniae (50.0%, 27/54), followed by Escherichia coli (27.8%, 15/54) and Enterobacter cloacae (9.3%, 5/54). As for the subsequent infecting CRE isolates, the dominated species was K. pneumoniae (55.6%, 10/18), followed by E. coli (33.3%, 6/18) and others (11.2%, 2/18). Receiving proton pump inhibitors and admission to ICU (P < 0.05) were the associated factors. Patients with subsequent CRE infection had significant higher mortality (33.3% vs 2.8%, P = 0.001) and shock was an associated factor (P = 0.008). CONCLUSIONS: Klebsiella pneumoniae was the dominate colonizing species and subsequent infecting species among HM patients with CRE colonization. Receiving proton pump inhibitors and admission to ICU increased the risk of subsequent CRE infection among CRE colonized HM patients. Implementing strict infection control measures targeting those high- risk patients may prevent subsequent CRE infection.

Effects of Trough Concentration and Solute Carrier Polymorphisms on Imatinib Efficacy in Chinese Patients with Chronic Myeloid Leukemia.

PURPOSE: We investigated the relationship between imatinib trough concentrations and genetic polymorphisms with efficacy of imatinib in Chinese patients with chronic myeloid leukemia (CML). METHODS: There were 171 eligible patients. Peripheral blood samples were collected from 171 eligible patients between 21 and 27 hours after the last imatinib administration. Complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR) were used as metrics for efficacy. Nine single nucleotide polymorphisms in 5 genes, SLC22A4 (917 T>C, -248 C>G and -538 C>G), SLC22A5 (-945 T>G and -1889 T>C), SLCO1A2 (-361 G>A), SLCO1B3 (334 T>G and 699 G>A) and ABCG2 (421C>A) were selected for genotyping. RESULTS: Patients with CCyR achieve higher trough concentrations than those without CCyR (1478.18±659.83 vs 984.89±454.06 ng mL-1, p<0.001). Patients with MMR and CMR achieve higher trough concentrations than those without MMR and CMR, respectively (1486.40±703.38 vs 1121.17±527.14 ng mL-1, p=0.007; 1528.00±709.98 vs 1112.67±518.35 ng mL-1, p=0.003, respectively). Carriers of A allele in SLCO1A2 -361G>A achieve higher CCyR and MMR rates (p=0.047, OR=4.320, 95% CI: 0.924-20.206; p=0.042, OR=2.825, 95% CI: 1.016-7.853, respectively). Both trough concentrations and SLCO1A2 -361G>A genotypes are independent factors affecting imatinib efficacy. The positive and negative predictive values for CCyR are 71.01% and 68.75%, respectively. The positive and negative predictive values for MMR are 62.86% and 69.70%, respectively. CONCLUSION: Imatinib trough concentrations and SLCO1A2 -361G>A genotypes are associated with imatinib efficacy in Chinese patients with CML.

Effects of phosphatidylcholine membrane fluidity on the conformation and aggregation of N-terminally acetylated α-synuclein.

Membrane association of α-synuclein (α-syn), a neuronal protein associated with Parkinson's disease (PD), is involved in α-syn function and pathology. Most previous studies on α-syn-membrane interactions have not used the physiologically relevant N-terminally acetylated (N-acetyl) α-syn form nor the most naturally abundant cellular lipid, i.e. phosphatidylcholine (PC). Here, we report on how PC membrane fluidity affects the conformation and aggregation propensity of N-acetyl α-syn. It is well established that upon membrane binding, α-syn adopts an α-helical structure. Using CD spectroscopy, we show that N-acetyl α-syn transitions from α-helical to disordered at the lipid melting temperature (Tm ). We found that this fluidity sensing is a robust characteristic, unaffected by acyl chain length (Tm = 34-55 °C) and preserved in its homologs ß- and γ-syn. Interestingly, both N-acetyl α-syn membrane binding and amyloid formation trended with lipid order (1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) > 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/sphingomyelin/cholesterol (2:2:1) ≥ DOPC), with gel-phase vesicles shortening aggregation kinetics and promoting fibril formation compared to fluid membranes. Furthermore, we found that acetylation enhances binding to PC micelles and small unilamellar vesicles with high curvature (r ∼16-20 nm) and that DPPC binding is reduced in the presence of cholesterol. These results confirmed that the exposure of hydrocarbon chains (i.e. packing defects) is essential for binding to zwitterionic gel membranes. Collectively, our in vitro results suggest that N-acetyl α-syn localizes to highly curved, ordered membranes inside a cell. We propose that age-related changes in membrane fluidity can promote the formation of amyloid fibrils, insoluble materials associated with PD.

Segmental 13 C-Labeling and Raman Microspectroscopy of α-Synuclein Amyloid Formation.

Mapping conformational changes of α-synuclein (α-syn) from soluble, unstructured monomers to ß-sheet- rich aggregates is crucial towards understanding amyloid formation. Raman microspectroscopy is now used to spatially resolve conformational heterogeneity of amyloid aggregates and monitor amyloid formation of segmentally 13 C-labeled α-syn in real-time. As the 13 C-isotope shifts the amide-I stretching frequency to lower energy, the ligated construct, 13 C1-8612 CS87C-140 -α-syn, exhibits two distinct bands allowing for simultaneous detection of secondary structural changes in N-terminal 1-86 and C-terminal 87-140 residues. The disordered-to-ß-sheet conformational change is first observed for the N-terminal followed by the C-terminal region. Finally, Raman spectroscopic changes occurred prior to Thioflavin T fluorescence enhancement, indicating that the amide-I band is a superior probe of amyloid formation.

Ambient Electrosynthesis of Ammonia: Electrode Porosity and Composition Engineering.

Ammonia, a key precursor for fertilizer production, convenient hydrogen carrier, and emerging clean fuel, plays a pivotal role in sustaining life on Earth. Currently, the main route for NH3 synthesis is by the heterogeneous catalytic Haber-Bosch process (N2 +3 H2 →2 NH3 ), which proceeds under extreme conditions of temperature and pressure with a very large carbon footprint. Herein we report that a pristine nitrogen-doped nanoporous graphitic carbon membrane (NCM) can electrochemically convert N2 into NH3 in an acidic aqueous solution under ambient conditions. The Faradaic efficiency and rate of production of NH3 on the NCM electrode reach 5.2 % and 0.08 g m-2 h-1 , respectively. Functionalization of the NCM with Au nanoparticles dramatically enhances these performance metrics to 22 % and 0.36 g m-2 h-1 , respectively. As this system offers the potential to be scaled to industrial levels it is highly likely that it might displace the century-old Haber-Bosch process.

Gia/Mthl5 is an aorta specific GPCR required for Drosophila heart tube morphology and normal pericardial cell positioning.

G-protein signaling is known to be required for cell-cell contacts during the development of the Drosophila dorsal vessel. However, the identity of the G protein-coupled receptor (GPCR) that regulates this signaling pathway activity is unknown. Here we describe the identification of a novel cardiac specific GPCR, called Gia, for "GPCR in aorta". Gia is the only heart-specific GPCR identified in Drosophila to date and it is specifically expressed in cardioblasts that fuse at the dorsal midline to become the aorta. Gia is the only Drosophila gene so far identified for which expression is entirely restricted to cells of the aorta. Deletion of Gia led to a broken-hearted phenotype, characterized by pericardial cells dissociated from cardioblasts and abnormal distribution of cell junction proteins. Both phenotypes were similar to those observed in mutants of the heterotrimeric cardiac G proteins. Lack of Gia also led to defects in the alignment and fusion of cardioblasts in the aorta. Gia forms a protein complex with G-αo47A, the alpha subunit of the heterotrimeric cardiac G proteins and interacts genetically with G-αo47A during cardiac morphogenesis. Our study identified Gia as an essential aorta-specific GPCR that functions upstream of cardiac heterotrimeric G proteins and is required for morphological integrity of the aorta during heart tube formation. These studies lead to a redefinition of the bro phenotype, to encompass morphological integrity of the heart tube as well as cardioblast-pericardial cell spatial interactions.

Structural features of membrane-bound glucocerebrosidase and α-synuclein probed by neutron reflectometry and fluorescence spectroscopy.

Mutations in glucocerebrosidase (GCase), the enzyme deficient in Gaucher disease, are a common genetic risk factor for the development of Parkinson disease and related disorders, implicating the role of this lysosomal hydrolase in the disease etiology. A specific physical interaction exists between the Parkinson disease-related protein α-synuclein (α-syn) and GCase both in solution and on the lipid membrane, resulting in efficient enzyme inhibition. Here, neutron reflectometry was employed as a first direct structural characterization of GCase and α-syn·GCase complex on a sparsely-tethered lipid bilayer, revealing the orientation of the membrane-bound GCase. GCase binds to and partially inserts into the bilayer with its active site most likely lying just above the membrane-water interface. The interaction was further characterized by intrinsic Trp fluorescence, circular dichroism, and surface plasmon resonance spectroscopy. Both Trp fluorescence and neutron reflectometry results suggest a rearrangement of loops surrounding the catalytic site, where they extend into the hydrocarbon chain region of the outer leaflet. Taking advantage of contrasting neutron scattering length densities, the use of deuterated α-syn versus protiated GCase showed a large change in the membrane-bound structure of α-syn in the complex. We propose a model of α-syn·GCase on the membrane, providing structural insights into inhibition of GCase by α-syn. The interaction displaces GCase away from the membrane, possibly impeding substrate access and perturbing the active site. GCase greatly alters membrane-bound α-syn, moving helical residues away from the bilayer, which could impact the degradation of α-syn in the lysosome where these two proteins interact.

Dissociation of glucocerebrosidase dimer in solution by its co-factor, saposin C.

Mutations in the gene for the lysosomal enzyme glucocerebrosidase (GCase) cause Gaucher disease and are the most common risk factor for Parkinson disease (PD). Analytical ultracentrifugation of 8 µM GCase shows equilibrium between monomer and dimer forms. However, in the presence of its co-factor saposin C (Sap C), only monomer GCase is seen. Isothermal calorimetry confirms that Sap C associates with GCase in solution in a 1:1 complex (Kd = 2.1 ± 1.1 µM). Saturation cross-transfer NMR determined that the region of Sap C contacting GCase includes residues 63-66 and 74-76, which is distinct from the region known to enhance GCase activity. Because α-synuclein (α-syn), a protein closely associated with PD etiology, competes with Sap C for GCase binding, its interaction with GCase was also measured by ultracentrifugation and saturation cross-transfer. Unlike Sap C, binding of α-syn to GCase does not affect multimerization. However, adding α-syn reduces saturation cross-transfer from Sap C to GCase, confirming displacement. To explore where Sap C might disrupt multimeric GCase, GCase x-ray structures were analyzed using the program PISA, which predicted stable dimer and tetramer forms. For the most frequently predicted multimer interface, the GCase active sites are partially buried, suggesting that Sap C might disrupt the multimer by binding near the active site.

Molecular origin of pH-dependent fibril formation of a functional amyloid.

Fibrils derived from Pmel17 are functional amyloids upon which melanin is deposited. Fibrils of the repeat domain (RPT) of Pmel17 form under strict melanosomal pH (4.5-5.5) and completely dissolve at pH≥6. To determine which Glu residue is responsible for this reversibility, aggregation of single, double, and quadruple Ala and Gln mutants were examined by intrinsic Trp fluorescence, circular dichroism spectroscopy, and transmission electron microscopy. Charge neutralization of E404, E422, E425, or E430, which are located in the putative amyloid-forming region, modulated aggregation kinetics. Remarkably, the removal of a single negative charge at E422, one of 16 carboxylic acids, shifted the pH dependence by a full pH unit. Mutation at E404, E425, or E430 had little to no effect. We suggest that protonation at E422 is essential for initiating amyloid formation and that the other Glu residues play an allosteric role in fibril stability.

Prevalence of and risk factors for intestinal colonisation by multidrug-resistant Gram-negative bacteria in patients with haematological malignancies: A systematic review and meta-analysis.

BACKGROUND: Patients with haematological malignancies (HM patients) are at high risk of infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB). MDR-GNB intestinal colonisation is associated with MDR-GNB infections. The aim of this systematic review and meta-analysis on HM patients was to pool the prevalence of and risk factors for intestinal colonisation by MDR-GNB, including carbapenem-resistant Enterobacterales (CRE) and extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales, reported in previous studies. METHODS: This study was conducted according to the protocol registered in PROSPERO (CRD42022374425). PubMed, Embase, Web of Science, Ovid MEDLINE(R) ALL and Cochrane Library were searched from inception to 25 October 2022. Observational studies reporting CRE and/or ESBL intestinal colonisation in HM patients were included. Subgroup analyses were conducted by study region. RESULTS: A total of 21 402 HM patients from 32 studies were analysed. The pooled CRE and ESBL colonisation rates were 21.7% [95% confidence interval (95%CI) 18.7-24.8] and 19.2% (95%CI 13.9-24.5), respectively. Prior exposure to tigecycline [odds ratio (OR) 3.99, 95%CI 2.08-7.68], carbapenem (OR 1.84, 95%CI 1.13-2.97) or penicillin (OR 1.72, 95%CI 1.05-2.83), as well as chemotherapy (OR 2.45, 95%CI 1.05-5.73), neutropenia (OR 1.88, 95%CI 1.08-3.26) and acute myeloid leukaemia (AML; OR 1.86, 95%CI 1.33-2.61), were risk factors for CRE colonisation in HM patients. Prior antibiotic exposure was a risk factor for ESBL colonisation in HM patients (OR 4.90, 95%CI 2.76-8.70). CONCLUSIONS: This study shows the high prevalence of MDR-GNB (CRE and ESBL) colonisation in HM patients and explains associated factors for the colonisation. The results provide evidence for MDR-GNB infection control in HM management.

Study on the material basis and immunological enhancement activity of dangdi oral liquid.

Studies have shown that a lot of traditional Chinese medicines could improve the immunity of the body. Dangdi oral liquid (DDO) was mainly composed of Angelica sinensis (Oliv.) Diels (Danggui), Rehmannia glutinosa Libosch. (Dihuang), Achyranthes bidentata Bl. (Niuxi), Glycyrrhiza uralensis Fisch. (Gancao). In this study, the rapid ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method was used to identify the potentially effective compounds of DDO. Then the immune activity of DDO was measured by lymphocyte proliferation, macrophage phagocytic function, NK cell activity, delayed type hypersensitivity reaction, hemolytic plaque number, sIgA content and immune organ index. The results showed that a total of 51 compounds were identified. In addition, DDO could significantly promote the lymphocyte proliferation, improve macrophage phagocytic ability, NK cell activity, hemolytic plaque number, sIgA content and immune organ index compared with control group, and the medium dose possessed the best efficacy (P＜0.05). These results indicated that DDO could enhance the immunity of mice.

STAT5a and SH2B3 novel mutations display malignancy roles in a triple-negative primary myelofibrosis patient.

Primary myelofibrosis (PMF) patients frequently have JAK2 (V617F), CALR (exon 9), or MPL (W515 or exon 10) strong driver gene mutation, which triggers abnormal activation of the JAK2-STATs signaling pathway that plays a complex role in the occurrence of PMF. However, about 10-15% of PMF patients have no above typical mutations in these strong driver genes, known as being "triple-negative", which are associated with poor prognosis. In this paper, we reported a unique secondary acute myeloid leukemia (sAML) case transformed from triple-negative PMF combined with lung cancer and erythroderma occurrence at the same time, which has not been reported so far. Through whole blood exome sequencing, four novel noncanonical mutations were detected in key regulatory genes SH2B3 (Q748 and S710) and STAT5a (C350 and K354). Meanwhile, STAT5a-S710 and SH2B3-K354 noncanonical mutations gained strong malignant biofunction on promoting cell growth and tumorigenesis by accelerating the G1/S transition. In the mechanistic study, these pernicious phenotypes driven by noncanonical mutations might be initial PMF by activating p-STAT5a/c-Myc/CyclinD1 and p-STAT3/p-AKT/p-ERK1/2 signaling axes. Therefore, our study explored the deleterious roles of novel noncanonical mutations in STAT5a and SH2B3, which may serve as susceptibility genes and display the oncogenic biofunction in the progression of PMF to acute myeloid leukemia-M2a (AML-M2a).

Analytical validation of the DropXpert S6 system for diagnosis of chronic myelocytic leukemia.

Digital PCR is a powerful method for absolute nucleic acid quantification and is widely used in the absolute quantification of viral copy numbers, tumor marker detection, and prenatal diagnosis. However, for most of the existing droplet-based dPCR systems, the droplet generation, PCR reaction, and droplet detection are performed separately using different instruments. Making digital PCR both easy to use and practical by integrating the qPCR workflow into a superior all-in-one walkaway solution is one of the core ideas. A new innovative and integrated digital droplet PCR platform was developed that utilizes cutting-edge microfluidics to integrate dPCR workflows onto a single consumable chip. This makes previously complex workflows fast and simple; the whole process of droplet generation, PCR amplification, and droplet detection is completed on one chip, which meets the clinical requirement of "sample in, result out". It provides high multiplexing capabilities and strong sensitivity while all measurements were within the 95% confidence interval. This study is the first validation of the DropXpert S6 system and focuses primarily on verifying its reliability, repeatability, and consistency. In addition, the accuracy, detection limit, linearity, and precision of the system were evaluated after sample collection. Among them, the accuracy assessment by calculating the absolute bias of each target gene yielded a range from -0.1 to 0.08, all within ±0.5 logarithmic orders of magnitude; the LOB for the assay was set at 0, and the LoD value calculated using probit curves is MR4.7 (0.002%); the linearity evaluation showed that the R2 value of the BCR-ABL was 0.9996, and the R2 value of the ABL metrics calculated using the ERM standard was 0.9999; and the precision evaluation showed that all samples had a CV of less than 4% for intra-day, inter-day, and inter-instrument variation. The CV of inter-batch variation was less than 7%. The total CV was less than 5%. The results of the study demonstrate that dd-PCR can be applied to molecular detection and the clinical evaluation of CML patients and provide more precise personal treatment guidance, and its reproducibility predicts the future development of a wide range of clinical applications.

Biophysics of α-synuclein membrane interactions.

Membrane proteins participate in nearly all cellular processes; however, because of experimental limitations, their characterization lags far behind that of soluble proteins. Peripheral membrane proteins are particularly challenging to study because of their inherent propensity to adopt multiple and/or transient conformations in solution and upon membrane association. In this review, we summarize useful biophysical techniques for the study of peripheral membrane proteins and their application in the characterization of the membrane interactions of the natively unfolded and Parkinson's disease (PD) related protein, α-synuclein (α-syn). We give particular focus to studies that have led to the current understanding of membrane-bound α-syn structure and the elucidation of specific membrane properties that affect α-syn-membrane binding. Finally, we discuss biophysical evidence supporting a key role for membranes and α-syn in PD pathogenesis. This article is part of a Special Issue entitled: Membrane protein structure and function.

Membrane remodeling by α-synuclein and effects on amyloid formation.

α-Synuclein (α-Syn), an intrinsically disordered protein, is associated with Parkinson's disease. Though molecular pathogenic mechanisms are ill-defined, mounting evidence connects its amyloid forming and membrane binding propensities to disease etiology. Contrary to recent data suggesting that membrane remodeling by α-syn involves anionic phospholipids and helical structure, we discovered that the protein deforms vesicles with no net surface charge (phosphatidylcholine, PC) into tubules (average diameter ∼20 nm). No discernible secondary structural changes were detected by circular dichroism spectroscopy upon the addition of vesicles. Notably, membrane remodeling inhibits α-syn amyloid formation affecting both lag and growth phases. Using five single tryptophan variants and time-resolved fluorescence anisotropy measurements, we determined that α-syn influences bilayer structure with surprisingly weak interaction and no site specificity (partition constant, Kp ∼ 300 M(-1)). Vesicle deformation by α-syn under a variety of different lipid/protein conditions is characterized via transmission electron microscopy. As cellular membranes are enriched in PC lipids, these results support possible biological consequences for α-syn induced membrane remodeling related to both function and pathogenesis.

Ambra1 modulates the sensitivity of mantle cell lymphoma to palbociclib by regulating cyclin D1.

Mantle cell lymphoma (MCL) is a rare B-cell malignancy with a predominantly aggressive clinical course and poor prognosis. Abnormal expression of Ambra1 is closely related to the occurrence and development of various tumors. However, the role of Ambra1 in MCL remains unknown. Here, we performed both in vitro and in vivo experiments to investigate how Ambra1 regulates MCL progression and whether Ambra1 modulates the sensitivity of MCL cells to the CDK4/6 inhibitor palbociclib. We discovered that MCL cells had decreased levels of Ambra1 expression relative to normal B cells. Overexpression of Ambra1 in MCL cells inhibited autophagy, reduced cell proliferation, migration, and invasion, and decreased cyclin D1 level. While knockdown of Ambra1 reduced MCL cell sensitivity to CDK4/6 inhibitor palbociclib. Furthermore, overexpression of cyclin D1 lowered the sensitivity of MCL cells to palbociclib, enhanced cell proliferation, migration, invasion, and autophagy, and inhibited cell apoptosis. When Ambra1 expression was inhibited, the in vivo antitumor effects of palbociclib on MCL were reversed. Ambra1 expression was downregulated but cyclin D1 expression was upregulated in MCL samples, demonstrating a negative correlation between Ambra1 and cyclin D1. Our findings suggest a unique tumor suppressor function for Ambra1 in the development of MCL.

Prognostic value of ASXL1 mutations in patients with myelodysplastic syndromes and acute myeloid leukemia: A meta-analysis.

Additional sex combs-like 1 (ASXL1) mutations, a hotspot in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), have been frequently reported for their potential prognostic value, but the results are controversial. Therefore, a meta-analysis was performed. Databases, including PubMed, Embase, and Cochrane Library, were searched for relevant studies published up to January 13, 2022. STATA v16.0 software was used to calculate the combined hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and AML transformation. Subgroup analysis was used to explore the effects of the grouping factors on heterogeneity.Ten studies on ASXL1 mutations and the prognosis of MDS were selected. Our results indicate that ASXL1 mutations have an adverse prognostic impact on OS (HR = 1.68,95%CI:1.45-1.94, p < .0001) and AML transformation (HR = 2.20,95% CI:1.68-2.87, p < .0001). The results for different age groups were not significantly different (HR = 1.87,95% CI: 1.31-2.67; HR = 1.62,95% CI:1.35-2.07). Ten studies covering 5816 patients with AML were included. The pooled HR for OS was 1.37 (95% CI:1.20-1.56, p < .0001). ASXL1 mutations were especially associated with a poorer OS in the subgroup aged ≥60 years (HR = 2.86, 95% CI:1.34-6.08, p = .006); when considering cytogenetically normal AML (CN-AML), the HR was 1.78(95% CI:1.27-2.49, p = .001). This meta-analysis indicates an independent, adverse prognostic impact of ASXL1 mutations in patients with MDS and AML, which also applies to patients with CN-AML. Age was a risk factor for patients with AML and ASXL1 mutations but not for patients with MDS.

Case Report: First Report of T-Cell Large Granular Lymphocytic Leukemia With NPL-DHX9 Gene Fusion Successfully Treated With Cladribine: Clinical Experience and Literature Review.

Background: T-cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder that starts in T cells and is usually indolent. Long-term use of immunosuppressants, combined with agranulocytosis, is a double-edged sword, as both can lead to serious infections, especially in patients with combined hematologic malignancies and immune defects. Case Presentation: A 30-year-old female patient was admitted to the hospital because of agranulocytosis for five years, with chest tightness, fatigue, and fever for two days. Pathology and metagenomic next-generation sequencing (mNGS) detected Aspergillus. Although she received cyclosporine and methylprednisolone, the patient showed drug intolerance and progression with invasive pulmonary fungal infections. After a bone marrow aspiration biopsy and other related examinations, she was diagnosed with T-LGLL and invasive pulmonary aspergillosis (IPA). T-cell immunophenotype was CD45+CD3dim+CD5-CD4-CD8+CD7+CD57p+CD25-CD30-, TCRγδ+, transducer and activator of transcripton-3 (STAT3) Y640F mutation and fusion gene NPL-DHX9 rearrangement were confirmed, which has never been reported in hematological diseases. After voriconazole regimen adjustment during treatment based on therapeutic drug concentration monitoring (TDM) and improvement in lung infection, the patient finally treated with purine nucleoside analogues (PNA) cladribine as a single agent at 0.14 mg/kg/d for 5 days. Complete response was achieved after four-cycles cladribine treatment (WBC 2.1*109/L, HGB 117 g/L, PLT 196*109/L, ANC 1.6*109/L, and ALC 0.2*109/L). Conclusions: To our knowledge, this is the first case of T-LGLL with a rare γδ type and fusion gene NPL-DHX9 rearrangement. The patient was successfully treated with cladribine, suggesting that this regimen could be a promising therapeutic strategy for patients with aggressive T-LGLL.

Evaluation of Novel Tranexamic Acid/Montmorillonite Intercalation Composite, as a New Type of Hemostatic Material.

Radiation enteritis-clinically manifested as diarrhea, intestinal bleeding, and so on-is frequently caused when the body is exposed to radiation or radiotherapy because the intestine is radiation-sensitive as an abdominal organ. Therefore, strategies to modulate intestinal hemostasis had inspired an important research trend in the process of preventing and treating radiation enteritis. Based on the structural characteristics of montmorillonite (MMT) and the hemostatic drug tranexamic acid (TXA) which was used clinically to treat enteritis, the tranexamic acid-montmorillonite composite material (TXA-MMT) was prepared through intercalation composite technology. According to the analysis of FTIR, XRD, TG-DTG, SEM, and XRF, the prepared TXA-MMT was verified that tranexamic acid could intercalate into layers of montmorillonite. To evaluate the biocompatibility, two experiments were conducted by in vitro hemolysis and in vitro cytotoxicity experiments and results showed that TXA-MMT exhibited good visible biocompatibility. Activated partial thromboplastin time, prothrombin time, and in vitro clotting time were adopted to determine the hemostatic effect of TXA-MMT. Compared with other groups, TXA-MMT revealed a significant decrease in clotting time variations, APTT, and PT. In addition, to investigate the preventive effect of TXA-MMT by the intervention of radiation enteritis mice, inflammatory factors IL-1ß, IL-6, and TNF-α and the content of endotoxin in the serum of mice were detected. It demonstrated that TXA-MMT reduced the levels of these factors. Besides, the expression and the pathological changes of the small intestine tissue of mice were relieved. Our findings suggests that TXA-MMT as a promising intercalation composite has a great potential for application in the field of intestinal hemostasis.

Genome-wide analysis reveals the emergence of multidrug resistant Stenotrophomonas acidaminiphila strain SINDOREI isolated from a patient with sepsis.

Stenotrophomonas acidaminiphila, the most recent reported species in genus Stenotrophomonas, is a relatively rare bacteria and is an aerobic, glucose non-fermentative, Gram-negative bacterium. However, little information of S. acidaminiphila is known to cause human infections. In this research, we firstly reported a multidrug-resistant strain S. acidaminiphila SINDOREI isolated from the blood of a patient with sepsis, who was dead of infection eventually. The whole genome of strain SINDOREI was sequenced, and genome comparisons were performed among six closely related S. acidaminiphila strains. The core genes (2,506 genes) and strain-specific genes were identified, respectively, to know about the strain-level diversity in six S. acidaminiphila stains. The presence of a unique gene (narG) and essential genes involved in biofilm formation in strain SINDOREI are important for the pathogenesis of infections. Strain SINDOREI was resistant to trimethoprim/sulfamethoxazole, ciprofloxacin, ofloxacin, cefepime, ceftazidime, and aztreonam. Several common and specific antibiotic resistance genes were identified in strain SINDOREI. The presence of two sul genes and exclusive determinants GES-1, aadA3, qacL, and cmlA5 is responsible for the resistance to multidrug. The virulence factors and resistance determinants can show the relationship between the phenotype and genotype and afford potential therapeutic strategies for infections.