Avatrombopag as alternative therapy for severe aplastic anemia patients who are intolerant or unresponsive to eltrombopag.

Introduction: Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage. Methods: Twenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023. Results: Eight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred. Conclusion: The conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory. Clinical trial registration: http://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.

Bioinspired Tumor-Targeting and Biomarker-Activatable Cell-Material Interfacing System Enhances Osteosarcoma Treatment via Biomineralization.

Osteosarcoma is an aggressive malignant tumor that primarily develops in children and adolescents. The conventional treatments for osteosarcoma often exert negative effects on normal cells, and chemotherapeutic drugs, such as platinum, can lead to multidrug resistance in tumor cells. Herein, this work reports a new bioinspired tumor-targeting and enzyme-activatable cell-material interface system based on DDDEEK-pY-phenylboronic acid (SAP-pY-PBA) conjugates. Using this tandem-activation system, this work selectively regulates the alkaline phosphatase (ALP) triggered anchoring and aggregation of SAP-pY-PBA conjugates on the cancer cell surface and the subsequent formation of the supramolecular hydrogel. This hydrogel layer can efficiently kill osteosarcoma cells by enriching calcium ions from tumor cells and forming a dense hydroxyapatite layer. Owing to the novel antitumor mechanism, this strategy neither hurts normal cells nor causes multidrug resistance in tumor cells, thereby showing an enhanced tumor treatment effect than the classical antitumor drug, doxorubicin (DOX). The outcome of this research demonstrates a new antitumor strategy based on a bioinspired enzyme-responsive biointerface combining supramolecular hydrogels with biomineralization.

A rare case of fluid overload-associated large B-cell lymphoma and antigen loss at relapse.

Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a new addition to the list of large B-cell lymphomas in the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5). This report presents an unusual case of FO-LBCL with partial B cell antigen loss at relapse and reviews the characteristics, treatment, and prognosis of these patients to enhance our understanding of this disease. Immunophenotyping was performed through immunohistochemistry and flow cytometry. Immunoglobulin gene rearrangements were analyzed using BIOMED-2 multiplex primers. MYC, BCL2, and BCL6 gene rearrangements were detected by fluorescent in situ hybridization (FISH). Cell-free DNA (cfDNA) from pleural effusion and peripheral blood was subjected to somatic mutation evaluation using next-generation sequencing (NGS). In 2020, the patient was initially diagnosed with tuberculous pleurisy and received anti-tuberculous drugs. Subsequent testing of the pleural effusion cell block revealed that the large cells to be positive for CD10, CD20, CD79a, PAX5, MUM1, Bcl-2, Bcl-6, and c-myc and negative for CD3, CD30, Cyclin D1, and HHV8. In situ hybridization for Epstein-Barr virus (EBV)-associated mRNA (EBER-ISH) was negative. Additionally, a clonal rearrangement of immunoglobulin heavy locus (IGH) FR2-JH was detected; the results of MYC, BCL2, and BCL6 gene rearrangements were all negative. Following pleural drainage treatment, the patient achieved symptom remission and was diagnosed with large B-cell lymphoma (HHV8-unrelated PEL-like lymphoma). In 2022, the patient was readmitted due to the recurrence of pleural effusion. The pleural effusion cell block revealed a distinct immunophenotype compared to previous findings, positivity for PAX5 and negativity for CD20, CD10, CD3, CD5, CD30, CD38, CD138, CD79a, MUM1, Bcl-2, Bcl-6, Cyclin D1, c-myc, ALK, and HHV8. Identical IGH FR2-JH clonal rearrangement suggested the recurrence of the original clone. CfDNA analysis showed mutations in CD79B, MYD88, CCND3, and DTX1. The patient was ultimately diagnosed with FO-LBCL based on the WHO-HAEM5 classification. Diagnosis of FO-LBCL should be differentiated from primary effusion lymphoma (PEL). The features of this case align with the description of "FO-LBCL" in WHO-HAEM5 and "HHV8 and EBV-negative primary effusion-based lymphoma" in International Consensus Classification (ICC). FO-LBCL patients generally have a more favorable prognosis compared to PEL. In this case, the patient exhibited a favorable prognosis for over 22 months without additional treatment apart from pleural drainage.

Expression and prognosis of the B7 family in acute myeloid leukemia.

BACKGROUND: B7 family molecules affect both immune responses and cancer progression via immunological and non-immunological pathways. However, the specific expression and prognostic value of B7 members in acute myeloid leukemia (AML) remains unclear; hence, an investigation using online bioinformatics databases is required. METHODS: In this study, we explored the expression of B7 molecules using the ONCOMINE, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and UALCAN databases, while the prognostic value of B7 molecules in AML was analyzed using the LinkedOmics, GEPIA2, UALCAN, and TCGAportal databases. Additionally, genetic alteration and gene co-expression analysis of the B7 family was performed via the cBioPortal and LinkedOmics databases, while functional and pathway enrichment analyses were conducted using the Metascape databases for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: The message RNA (mRNA) levels of B7 family members varied in AML patients, and aberrant highly expressed B7 members were correlated with poor prognosis in AML, including B7.1, B7-DC, B7-H3, B7-H5, and B7-H7. B7-H6 acted as a protective molecule for overall survival (OS), while B7-H1 overexpression was inclined to predict poor prognosis. B7 family gene alteration occurred frequently in AML, and the altered B7 group seemed to exhibit a trend towards worse OS. The co-expression genes and relative signaling pathways of the B7 family might be involved in oncogenesis and be associated with prognosis in AML. CONCLUSIONS: Our study showed that aberrantly expressed B7 family molecules affected the prognosis of AML patients, and thus, could be promising prognostic biomarkers and new therapeutic targets.

Micro Plastic Deformation Behavior of Carbide-Free Bainitic Steel during Tensile Deformation Process.

The microstructure of carbide-free bainitic steel has been widely reported because of its excellent mechanical properties. However, no work has explored the deformation behavior of each phase in the microstructure, namely, retained austenite (RA) and bainitic ferrite (BF). In this paper, the deformation behavior of RA and BF during tension was investigated through the in situ electron backscatter diffusion method. The results showed that the RA surrounded by BF with a high Schmid factor (SF) was accelerated towards being transformed into martensite, but the surrounding BF with low SF value retarded the transformation. The kernel average misorientation (KAM) findings revealed that the strain of the RA and BF rapidly increased initially, slowed down after the critical points of 0.25 and 0.54, respectively, and then increased again. The calculated result for the KAM fraction indicated that the contribution of RA to the total plastic deformation gradually decreased throughout the total tensile process, whereas that of BF increased in the presence of RA.

Study on Bainitic Transformation by Dilatometer and In Situ LSCM.

This study investigates the bainitic transformation kinetics of carbide-free bainitic steel with Si + Al and carbide-bearing bainitic steel without Si + Al, as well as the phase transformation and microstructure through in situ high-temperature laser scanning confocal microscopy. Results show that bainitic ferrite plates preferentially nucleate at the grain boundary. New plates nucleate on previously formed ones, including two dimensions which appear on a plane where a three-dimensional space of bainitic ferrite forms. Nucleation on the formed bainitic ferrite is faster than that at the grain boundary in some grains. The bainitic ferrite growth at the austenite grain boundary is longer and has a faster transformation rate. The bainitic ferrite growth on the formed bainitic ferrite plate is shorter and has a slower transformation rate. The location and number of nucleation sites influence the thickness of the bainitic ferrite. The higher the number of plates preferentially nucleating at the original austenite grain boundary, the greater the thickness of the bainitic ferrite.

Effect of Two-Step Austempering Process on Transformation Kinetics of Nanostructured Bainitic Steel.

The two-step austempering process has been reported to be an effective method to accelerate the bainitic transformation process by introducing martensite (Q-M-B). However, in this study, it was found that the Q-M-B process reduced the incubation time, but the transformation duration remained nearly unchanged. The notably reduced activation energy barrier for nucleation of bainitic ferrite on the preformed martensite should be responsible for the reduced duration time of the Q-M-B process. A process that both of the two steps were above, Ms (Q-B-B), has been demonstrated to increase transformation rate and improve the amount of bainitic ferrite, which probably results from the additional hysteresis free energy provided by the first quenching process.

Self-Selected and Prescribed Intensity Exercise to Improve Physical Activity Among Inactive Retirees.

A randomized controlled study explored the effects of two intensity-oriented exercise interventions on affect to exercise and physical activity behavior. Inactive retirees finished the 12-week group-based exercise intervention and 3-month telephone follow-up with 27 in self-selected intensity group and 26 in prescribed intensity group. Repeated measures of daily step counts (measured by Yamax pedometers), positive and negative affect to exercise, weight, height, waist circumference, and blood pressure were done at baseline, postintervention, and 3-month follow-up. Increased daily step counts and positive affect, and reduced body mass index, waist circumference, blood pressure of both groups, and negative affect of self-selected intensity group were found at different measuring times. Although self-selected intensity group had no significantly different daily step counts from prescribed intensity group, the former had a more positive and less negative affect to exercise. Findings suggest that future exercise programs use self-selected intensity exercise programs to improve pleasure affect to exercise.

Rolling Contact Fatigue Performances of Carburized and High-C Nanostructured Bainitic Steels.

In the present work, the nanostructured bainitic microstructures were obtained at the surfaces of a carburized steel and a high-C steel. The rolling contact fatigue (RCF) performances of the two alloy steels with the same volume fraction of undissolved carbide were studied under lubrication. Results show that the RCF life of the carburized nanostructured bainitic steel is superior to that of the high-C nanostructured bainitic steel in spite of the chemical composition, phase constituent, plate thickness of bainitic ferrite, hardness, and residual compressive stress value of the contact surfaces of the two steels under roughly similar conditions. The excellent RCF performance of the carburized nanostructured bainitic steel is mainly attributed to the following reasons: finer carbide dispersion distribution in the top surface, the higher residual compressive stress values in the carburized layer, the deeper residual compressive stress layer, the higher work hardening ability, the larger amount of retained austenite transforming into martensite at the surface and the more stable untransformed retained austenite left in the top surface of the steel.

Dislocation-twin boundary interactions induced nanocrystalline via SPD processing in bulk metals.

This report investigated dislocation-twin boundary (TB) interactions that cause the TB to disappear and turn into a high-angle grain boundary (GB). The evolution of the microstructural characteristics of Hadfield steel was shown as a function of severe plastic deformation processing time. Sessile Frank partial dislocations and/or sessile unit dislocations were formed on the TB through possible dislocation reactions. These reactions induced atomic steps on the TB and led to the accumulation of gliding dislocations at the TB, which resulted in the transition from coherent TB to incoherent GB. The factors that affect these interactions were described, and a physical model was established to explain in detail the feasible dislocation reactions at the TB.