Critical role of tripartite fusion and LBD truncation in certain RARA- and all RARG-related atypical APL.

ABSTRACT: Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X- or X::RAR::Y-type tripartite fusions in certain RARA-aAPL and all RARG-aAPL cases, with shared features and notable differences between these 2 disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.

Diterpenoids from the Aerial Parts of Isodon serra with Selective Cytotoxic Activity.

Four new diterpenoids, isodosins A-D (1-4), together with nine known compounds (5-13) were isolated and identified from the aerial parts of Isodon serra (Maxim.) Hara. The structures of the new diterpenoids were elucidated based on the analysis of HR-ESI-MS data, 1D/2D-NMR-spectroscopic data, and electronic circular dichroism (ECD) calculations. Cytotoxicities of compounds 2, 3, 5, 6, and 9 against the HepG2 and H1975 cell lines were evaluated with the MTT assay. As a result, compounds 2, 3, and 6 revealed higher levels of cytotoxicity against HepG2 cells than against H1975 cells. Moreover, compund 6 demonstrated the most efficacy in inhibiting the proliferation of HepG2 cells, with an IC50 value of 41.13 ± 3.49 µM. This effect was achieved by inducing apoptosis in a dose-dependent manner. Furthermore, the relationships between the structures and activities of these compounds are briefly discussed.

Synthesis and application of multifunctional lignin-modified cationic waterborne polyurethane in textiles.

Waterborne polyurethanes (WPUs) often have limitations like inadequate weathering resistance and thermal stability. To overcome these shortcomings, lignin has been selected as a modifier for its abundant availability, renewability, and biocompatibility. This study synthesized a cationic WPU using isophorone diisocyanate and polyethylene glycol as raw materials. Hydrophilicity was attained through the inclusion of dihydroxyethyl dodecylamine as a chain extender, while the introduction of epoxy monomers and lignin served to modify the polyurethane. Furthermore, a dye dispersion for cotton fabric dyeing was prepared by combining the synthesized polyurethane, chitosan, and dyes. The cationic nature of the polyurethane played a crucial role in facilitating dye adhesion and uptake on the fabric surface, resulting in improved dyeing performance. The incorporation of epoxy side chains and chitosan cross-linking contributed to the excellent color fastness of the dyed fabrics. Moreover, the incorporation of lignin and chitosan endowed the fabric with antibacterial properties. Simultaneously, it provided effective UV protection, characterized by a high UV protection factor value for the fabrics. This lignin-modified WPU exhibits tremendous potential in applications such as textile coatings, adhesives, and color fixation agents. It effectively addresses the limitations of traditional WPUs and offers notable advantages, including a renewable source, cost-effectiveness, and biocompatibility.

Platelet-to-lymphocyte ratio and absolute monocyte count have prognostic potential in primary myelodysplastic neoplasms.

INTRODUCTION: The platelet-to-lymphocyte ratio (PLR), peripheral blood absolute monocyte count (AMC), and monocyte-to-lymphocyte ratio (MLR) are considered biomarkers of systemic immune and inflammation response. However, their prognostic potential in patients with myelodysplastic neoplasms (MDS) remains unclear. This study aimed to explore the predictive impact of PLR, MLR, and AMC on MDS outcomes. METHODS: In total, 334 patients with primary MDS were included between January 2016 and December 2021 and were retrospectively followed up until December 31, 2022. The prognostic significance of PLR, MLR, and AMC was assessed using univariate and multivariate analyses, and predictive models were generated to estimate MDS outcomes. The area under their receiver operating curves was computed to compare the predictive power of these models. RESULTS: Fifty-one patients had disease progression, and 103 patients died during follow-up. In multivariate analyses, a higher PLR was an adverse independent factor for overall survival (OS) (p = 0.011), whereas a higher AMC indicated shorter progression-free survival (p = 0.003). The prognostic model incorporating PLR, MLR, and AMC with the Revised International Prognostic Scoring System (IPSS-R) risk categorization showed higher performance in predicting OS than the model that only utilized the IPSS-R category. CONCLUSION: Elevated PLR and increased AMC had independent prognostic value for adverse outcomes in patients with MDS. PLR, MLR, and AMC enhanced the IPSS-R risk categorization for OS prediction in MDS.

Report of PRPF19 as a novel partner of RARG and the recurrence of interposition-type fusion in variant acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML) which is characterized by specific clinical and biological features. Typical APL cases are caused by PML::RARA fusion gene and are exquisitely sensitive to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Rarely, APLs are caused by atypical fusions involving RARA or, in fewer cases still, fusions involving other members of the retinoic acid receptors (RARB or RARG). To date, seven partner genes of RARG have been reported in a total of 18 cases of variant APL. Patients with RARG fusions showed distinct clinical resistance to ATRA and had poor outcomes. Here, we report PRPF19 gene as a novel partner of RARG and identify a rare interposition-type gene fusion in a variant APL patient with a rapidly fatal clinical course. The incomplete ligand-binding domain of RARG in the fusion protein may account for the clinical ATRA resistance in this patient. These results broaden the spectrum of variant APL associated molecular aberrations. Accurately and timely identification of these rare gene fusions in variant APL is essential to guide therapeutic decisions.

The diversity and function of the in-situ fungal communities in response to polycyclic aromatic hydrocarbons in the urban wetland.

PAHs (polycyclic aromatic hydrocarbons) increases the potential harm to ecosystem and human health. The fungi is considered as a powerful choice for degradation of PAHs. The researches on the effect of PAHs on fungal population in sediment/soil mostly stayed in the laboratory simulation that is based on extreme pollution. This study investigated the fungal population of the urban wetland by high-throughput sequencing in-situ micro-pollution state. Our statistical analysis revealed significant difference in the whole fungal population at the phylum among three land use types in typical urban wetland. Among them, Ascomycota was the dominant fungi at the phyla in three land use types. Fungal genus of degrading PAHs were significantly correlated with Dibenz[a, h]anthracene (P = 0.018) in ditch wetland, Total Organic Carbon (P = 0.02) and Fluoranthene (P = 0.04) in riverine wetland, and Electrical Conductivity (P = 0.018) in agricultural land. PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) suggested that 20 enzymes were present related to PAHs metabolism in three land use types. Specifically, monoxygenase, dehydrogenase, and laccase were most abundant among inferred enzymes, indicating that the urban wetland had potential for the degradation of PAHs. This study contributed to in-depth understanding of the structure and function of fungal population and provided a theoretical basis for PAHs microbial remediation in the in-situ environment.

Influence of polycyclic aromatic hydrocarbon pollution on the diversity and function of bacterial communities in urban wetlands.

Human disturbance has become the primary driving factor behind declining urban wetland ecological health due to rapid urbanization. Sediment microbial communities are critical for wetland ecosystem functioning but experience a range of natural and anthropogenic stressors due to rapid urbanization and land use changes, especially in developing countries. Polycyclic aromatic hydrocarbons (PAHs) released into the environment primarily come from anthropogenic sources like industrial activities and traffic emissions. Environmental PAH contamination is accelerating due to rapid urbanization, which also increases potential PAH-related dangers to human health. However, PAHs are widely distributed and not easy to centrally control. Microorganisms are the primary mediators of wetland purification, with most PAH-degrading microorganisms being bacteria. To better understand the influence of PAH contamination on urban wetland microbial communities, bacterial community compositions within sediments of urban wetlands in three land use types were investigated using high-throughput DNA sequencing and bioinformatics analyses. Statistical analyses revealed significant differences in overall microbial compositions among the three land use types, although γ-proteobacteria was the dominant phyla across all samples. Among the potential PAH-degrading bacterial taxa in sediments, Sphingomonas was the most prevalent. The distributions of PAH-degrading taxa were primarily affected by variance in organic compound abundances in addition to various physico-chemical variables, among which high-ring PAH content was a key parameter associated with bacterial distributions, except in the riverine wetlands. Functional inference via phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) indicated that 30 of the 43 genes related to PAH metabolism were predicted to be present within the genomes of bacteria among the three land use type. In particular, dioxygenase and dehydrogenase genes involved in PAH degradation were inferred to be prevalent, indicating that the host urban wetlands exhibited strong potential for organic pollutant degradation.

p210BCR-ABL1- Chronic myeloid leukemia presents with monocytosis.

Rare cases of CML present with monocytosis as well as morphologic dysplasia and harbor p210BCR-ABL1. Cytogenetic and molecular studies must be performed to confirm the diagnosis of this kind of CML.

Polycyclic Aromatic Hydrocarbons in Sediments/Soils of the Rapidly Urbanized Lower Reaches of the River Chaohu, China.

Polycyclic aromatic hydrocarbons (PAHs) are highly teratogenic, persistent carcinogens, and ubiquitous environmental pollutants. To determine the impact of rapid urbanization on sediment/soil PAHs, we collected 30 cm soil cores in ditch wetlands, riverine wetlands, and agricultural lands along the lower reaches of the Shiwuli River feeding Chaohu Lake, China. Ecological risk effects were evaluated by two models based upon Benzo[a]pyrene toxic equivalency (TEQ-BaP) and total toxic units (TUs). The presence of PAHs, such as BbF, BkF, InP, and BgP, that are known pollutants of concern, suggests certain ecological risks. The concentration of PAHs in the surface layer followed in the order of: ditch wetlands (617.2 ng/g average), riverine wetlands (282.1 ng/g average), agricultural lands (103.7 ng/g average). PAHs in ditch sediments were vertically distributed evenly, and PAHs in agricultural soils were concentrated in the surface soil. In riverine wetland sediments, the 2-, 3-, and 4-ring PAHs had a uniform distribution, whereas the 5- and 6-ring PAHs were concentrated in the surface soil. Redundancy analysis (RDA) explored the correlation between the environmental properties and the occurrence of PAHs. Total organic carbon (p = 0.010), percent clay (p = 0.020), and distance (p = 0.020) were the primary factors in ditch wetlands. Depth (p = 0.010) and distance (p = 0.006) were the main factors in agricultural lands. There were no significant correlations in riverine wetlands. The correlation between the distance from the built-up urban areas and pollutant concentration showed that the closer the distance, the greater the concentration of PAHs.

Core-shell poly(lactide-co-ε-caprolactone)-gelatin fiber scaffolds as pH-sensitive drug delivery systems.

Dual-drug-loaded pH-responsive fiber scaffolds were successfully prepared by coaxial electrospinning. These were designed with the aim of being sutured into the resection site after tumor removal, to aid recovery and prevent cancer recurrence. The shell was made up of a mixture of gelatin and sodium bicarbonate (added to provide pH-sensitivity), and was loaded with the anti-inflammatory drug ciprofloxacin; the core comprised poly(lactide-co-ε-caprolactone) with the chemotherapeutic doxorubicin hydrochloride. Scanning electron microscopy revealed most fibers were smooth and homogeneous. Transmission electron microscopy demonstrated the presence of a clear core/shell structure. The fiber scaffolds were further characterized using infrared spectroscopy and X-ray diffraction, which proved that both drugs were present in the fibers in the amorphous form. The gelatin shells were cross-linked with glutaraldehyde to enhance their stability, and water contact angle measurements used to confirm they remained hydrophilic after this process, with angles between 10 and 35°. This is important for onward applications, since a hydrophilic surface is known to encourage cell proliferation. During in vitro drug release studies, a rapid and acid-responsive release of ciprofloxacin was seen, accompanied by sustained and long-term doxorubicin release. Both the release profiles and the mechanical strength of the fibers can effectively be tuned through the sodium bicarbonate content of the fibers: for instance, the break stress varies from 2.00 MPa to 2.57 MPa with an increase in sodium bicarbonate content. The pH values of aqueous media exposed to the scaffolds decrease only slightly, by less than 0.5 pH units, over the two-month timescale, suggesting that only minimal fiber degradation occurs during this time. The fiber scaffolds also have good biocompatibility, as revealed by in vitro cytotoxicity experiments. Overall, our results demonstrate that the novel scaffolds reported here are promising pH-sensitive drug delivery systems, and may be candidates for use after tumor resection surgery.

Apoptosis signaling and BCL-2 pathways provide opportunities for novel targeted therapeutic strategies in hematologic malignances.

Apoptosis is an essential biological process involved in tissue homeostasis and immunity. Aberrations of the two main apoptotic pathways, extrinsic and intrinsic, have been identified in hematological malignancies; many of these aberrations are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Targeting components of the apoptotic pathways, especially the chief regulatory BCL-2 family in the intrinsic pathway, has proved to be a promising therapeutic approach for patients with hematological malignances, with the expectation of enhanced efficacy and reduced adverse events. Continuous investigations regarding the biological importance of each of the BCL-2 family components and the clinical rationale to achieve optimal therapeutic outcomes, using either monotherapy or in combination with other targeted agents, have generated inspiring progress in the field. Genomic, epigenomic and biological analyses including BH3 profiling facilitate effective evaluation of treatment response, cancer recurrence and drug resistance. In this review, we summarize the biological features of each of the components in the BCL-2 apoptotic pathways, analyze the regulatory mechanisms and the pivotal roles of BCL-2 family members in the pathogenesis of major types of hematologic malignances, and evaluate the potential of apoptosis- and BCL-2-targeted strategies as effective approaches in anti-cancer therapies.

Regenerated chitin fibers reinforced with bacterial cellulose nanocrystals as suture biomaterials.

The objective of this work was to prepare a novel filament with good biocompatibility and mechanical performance which can meet the demands of surgical sutures. Bacterial cellulose nanocrystals (BCNCs) were used to reinforce regenerated chitin (RC) fibers to form BCNC/RC filaments. Mechanical performance measurements demonstrated that the strength of the BCNC/RC filament was increased dramatically over the RC analogue. A yarn made of 30 BCNC-loaded fibers also achieved satisfactory mechanical performance, with a knot-pull tensile strength of 9.8±0.6N. Enzymatic degradation studies showed the BCNC/RC materials to have good biodegradability, the rate of which can be tuned by varying the concentration of BCNCs in the yarn. The RC and the BCNC/RC materials had no cytotoxicity and can promote cell proliferation. In vivo experiments on mice demonstrated that suturing with the BCNC/RC yarn can promote wound healing without obvious adverse effects.

Electrospun gelatin/sodium bicarbonate and poly(lactide-co-ε-caprolactone)/sodium bicarbonate nanofibers as drug delivery systems.

In this work, we report electrospun nanofibers made of model hydrophobic (poly(lactide-co-ε-caprolactone); PLCL) and hydrophilic (gelatin) polymers. We explored the effect on drug release of the incorporation of sodium bicarbonate (SB) into these fibers, using the potent antibacterial agent ciprofloxacin as a model drug. The fibers prepared are smooth and have relatively uniform diameters lying between ca. 600 and 850nm. The presence of ciprofloxacin in the fibers was confirmed using IR spectroscopy. X-ray diffraction showed the drug to be incorporated into the fibers in the amorphous form. In vitro drug release studies revealed that, as expected, more rapid drug release was seen with gelatin fibers than those made of PLCL, and a greater final release percentage was obtained. The inclusion of SB in the gelatin fibers imparts them with pH sensitivity: gelatin/SB fibers showed faster release at pH5 than pH7.4, while fibers without SB gave the same release profiles at both pHs. The PLCL fibers have no pH sensitivity, even when SB was included, as a result of their hydrophobic structure precluding the ingress of solvent. In vitro cell culture studies showed that all the fibers are able to promote cell proliferation. The ciprofloxacin loaded fibers are effective in inhibiting Escherichia coli and Staphylococcus aureus growth in antibacterial tests. Thus, the gelatin-based fibers can be used as pH-responsive drug delivery systems, with potential applications for instance in the treatment of tumor resection sites. Should these become infected, the pH would drop, resulting in ciprofloxacin being released and the infection halted.

Fabrication and investigation of a biocompatible microfilament with high mechanical performance based on regenerated bacterial cellulose and bacterial cellulose.

A high-strength regenerated bacterial cellulose (RBC)/bacterial cellulose (BC) microfilament of potential use as a biomaterial was successfully prepared via a wet spinning process. The BC not only consists of a 3-D network composed of nanofibers with a diameter of several hundred nanometers but also has a secondary structure consisting of highly oriented nanofibrils with a diameter ranging from a few nanometers to tens of nanometers which explains the reason for the high mechanical strength of BC. Furthermore, a strategy of partially dissolving BC was used and this greatly enhanced the mechanical performance of spun filament and a method called post-treatment was utilized to remove residual solvents from the RBC/BC filaments. A comparison of structure, properties, as well as cytocompatibility between BC nanofibers and RBC/BC microfilaments was achieved using morphology, mechanical properties, X-ray Diffraction (XRD) and an enzymatic hydrolysis assay. The RBC/BC microfilament has a uniform groove structure with a diameter of 50-60µm and XRD indicated that the crystal form was transformed from cellulose Iα to cellulose IIII and the degree of crystallinity of RBC/BC (33.22%) was much lower than the original BC (60.29%). The enzymatic hydrolysis assay proved that the RBC/BC material was more easily degraded than BC. ICP detection indicated that the residual amount of lithium was 0.07mg/g (w/w) and GC-MS analysis showed the residual amount of DMAc to be 8.51µg/g (w/w) demonstrating that the post-treatment process is necessary and effective for removal of residual materials from the RBC/BC microfilaments. Also, a cell viability assay demonstrated that after post-treatment the RBC/BC filaments had good cytocompatibility.

Glucose- and temperature-sensitive nanoparticles for insulin delivery.

Glucose- and temperature-sensitive polymers of a phenylboronic acid derivative and diethylene glycol dimethacrylate (poly(3-acrylamidophenyl boronic acid-b-diethylene glycol methyl ether methacrylate); p(AAPBA-b-DEGMA)) were prepared by reversible addition-fragmentation chain transfer polymerization. Successful polymerization was evidenced by 1H nuclear magnetic resonance and infrared spectroscopy, and the polymers were further explored in terms of their glass transition temperatures and by gel permeation chromatography (GPC). The materials were found to be temperature sensitive, with lower critical solution temperatures in the region of 12°C-47°C depending on the monomer ratio used for reaction. The polymers could be self-assembled into nanoparticles (NPs), and the zeta potential and size of these particles were determined as a function of temperature and glucose concentration. Subsequently, the optimum NP formulation was loaded with insulin, and the drug release was studied. We found that insulin was easily encapsulated into the p(AAPBA-b-DEGMA) NPs, with a loading capacity of ~15% and encapsulation efficiency of ~70%. Insulin release could be regulated by changes in temperature and glucose concentration. Furthermore, the NPs were non-toxic both in vitro and in vivo. Finally, the efficacy of the formulations at managing blood glucose levels in a murine hyperglycemic diabetes model was studied. The insulin-loaded NPs could reduce blood glucose levels over an extended period of 48 h. Since they are both temperature and glucose sensitive and offer a sustained-release profile, these systems may comprise potent new formulations for insulin delivery.

Core-Sheath Nanofibers as Drug Delivery System for Thermoresponsive Controlled Release.

In this work, a smart drug delivery system of core-sheath nanofiber is reported. The core-sheath nanofibers were prepared with thermoresponsive poly-(N-isopropylacrylamide) (as core) and hydrophobic ethyl cellulose (as sheath) by coaxial electrospinning. Analogous medicated fibers were prepared by loading with a model drug ketoprofen (KET). The fibers were cylindrical without phase separation and have visible core-sheath structure as shown by scanning and transmission electron microscopy. X-ray diffraction patterns demonstrated the drug with the amorphous physical form was present in the fiber matrix. Fourier transform infrared spectroscopy analysis was conducted, finding that there were significant intermolecular interactions between KET and the polymers. Water contact angle measurements proved that the core-sheath fibers from hydrophilic transformed into hydrophobic when the temperature reached the lower critical solution temperature. In vitro drug-release study of nanofibers with KET displayed that the coaxial nanofibers were able to synergistically combine the characteristics of the 2 polymers producing a temperature-sensitive drug delivery system with sustained-release properties. In addition, they were established to be nontoxic and suitable for cell growth. These findings show that the core-sheath nanofiber is a potential candidate for controlling drug delivery system.

Thermosensitive nanofibers loaded with ciprofloxacin as antibacterial wound dressing materials.

To obtain wound dressings which could be removed easily without secondary injuries, we prepared thermoresponsive electrospun fiber mats containing poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA). Blend fibers of PDEGMA and poly(l-lactic acid-co-ε-caprolactone) (P(LLA-CL) were fabricated via electrospinning, and analogous fibers containing the antibiotic ciprofloxacin (CIF) were also prepared. Smooth cylindrical fibers were obtained, albeit with a small amount of beading visible for the ciprofloxacin-loaded fibers. X-ray diffraction showed the drug to exist in the amorphous physical form post-electrospinning. The composite fibers showed distinct thermosensitive properties and gave sustained release of CIF over more than 160h in vitro. The fibers could promote the proliferation of fibroblasts, and by varying the temperature cells could easily be attached to and detached from the fibers. Antibacterial tests demonstrated that fibers loaded with ciprofloxacin were effective in inhibiting the growth of E. coli and S. aureus. In vivo investigations on rats indicated that the composite PDEGMA/P(LLA-CL) fibers loaded with CIF had much more potent wound healing properties than a commercial gauze and CIF-loaded fibers made solely of P(LLA-CL). These results demonstrate the potential of PDEGMA/P(LLA-CL)/ciprofloxacin fibers as advanced wound dressing materials.

Routine blood examinations combined with morphological analysis for the diagnosis of myelodysplastic/myeloproliferative neoplasms.

In 2008, the World Health Organization (WHO) introduced a new hematological neoplasm category; myelodysplastic/myeloproliferative neoplasms (MDS/MPN), which included four main subcategories. This disease is often misdiagnosed, which delays effective therapy. The present study evaluated the role of routine blood examinations and morphological analysis of peripheral blood cells in the reliable diagnosis of MDS/MPN. In total, 236 adult MDS/MPN patients were analyzed. The analysis included 10 routine blood parameters measured using a Sysmex XE-2100™, 3 differential percentage parameters and 7 morphological features of peripheral blood cells which were analyzed by optical microscopy, and 3 differential absolute count numbers obtained based on the corresponding differential percentages and absolute count of blood cells. The parameters were compared among the subcategories and a value of P<0.05 was considered to indicate a statistically significant difference. The median white blood cell and hemoglobin counts of the patients were 18.0×109/l and 88 g/l, respectively. The proportion of monocytes increased to 8% (1.82×109/l), the proportion of blast cells increased to 1% (0.5×109/l) and that of neutrophil precursors increased to 10% (1.98×109/l). A total of 87% of all patients presented with hypogranulation and 71% presented with abnormal condensed nuclear chromatin in granulocytes. Atypical monocytes were observed in 73% of all patients and Pseudo-Pelger cells were observed in 60%. Significant differences were detected among the subcategories. The present study demonstrated that combining blood routine parameters and the morphological analysis of peripheral blood cells have an essential role in the reliable diagnosis of MDS/MPN based on WHO categories.