Comparative efficacy of bilateral mesh sacrospinous ligament suspension versus laparoscopic sacrocolpopexy in patients with metroptosis.

This study assesses the efficacy of bilateral mesh sacrospinous ligament suspension (MSSLS) compared to laparoscopic sacrocolpopexy (LSC) in patients with uterine prolapse. Ninety-eight patients with uterine prolapse were evaluated at our hospital from January 2021 to January 2023. Patients were equally divided into two groups: the study group (undergoing MSSLS) and the control group (undergoing LSC) using a random number table. Various parameters including operation time, bleeding volume, indwelling catheter time, exhaust time, hospital stay, pelvic organ prolapse stage, postoperative recurrence rate, pain severity, quality of life, pelvic floor function, impact on sexual life, complications, and recurrence rate were recorded. The study group showed significant reductions in operation time, bleeding volume, indwelling catheter time, exhaust time, and hospital stay compared to the control group (P < 0.05). There were no significant differences in Aa, Ba, Ap, Bp, and C between the two groups before surgery (P > 0.05), but six months postoperatively, these indexes were significantly lower in the study group (P < 0.05). Pain severity did not differ significantly between the two groups before surgery (P > 0.05), but was significantly lower in the study group six months postoperatively (P < 0.05). Quality of life, pelvic floor function, and sexual life quality did not significantly differ before surgery, at 6 months, and at 12 months postoperatively (P > 0.05). All patients were followed up for 12-14 months, with an average follow-up time of (13.02 ± 1.36) months. The incidence of complications was significantly lower in the study group (P < 0.05), but there were no recurrences in either group, thus the difference was not statistically significant (P > 0.05). MSSLS emerges as a safe and efficacious treatment for uterine prolapse, notably reducing both complications and recurrence rates, rendering it suitable for broad clinical application.

Remodeling of the bone marrow microenvironment during acute myeloid leukemia progression.

Hematopoiesis requires a complex interplay between the hematopoietic stem and progenitor cells and the cells of the bone marrow microenvironment (BMM). The BMM is heterogeneous, with different regions having distinct cellular, molecular, and metabolic composition and function. Studies have shown that this niche is disrupted in patients with acute myeloid leukemia (AML), which plays a crucial role in disease progression. This review provides a comprehensive overview of the components of vascular and endosteal niches and the molecular mechanisms by which they regulate normal hematopoiesis. We also discuss how these niches are modified in the context of AML, into a disease-promoting niche and how the modified niches in turn regulate AML blast survival and proliferation. We focus on mechanisms of modifications in structural and cellular components of the bone marrow (BM) niche by the AML cells and its impact on leukemic progression and patient outcome. Finally, we also discuss mechanisms by which the altered BM niche protects AML blasts from treatment agents, thereby causing therapy resistance in AML patients. We also summarize ongoing clinical trials that target various BM niche components in the treatment of AML patients. Hence, the BM niche represents a promising target to treat AML and promote normal hematopoiesis.

Transport-Friendly Microstructure in SSC-MEA: Unveiling the SSC Ionomer-Based Membrane Electrode Assemblies for Enhanced Fuel Cell Performance.

The significant role of the cathodic binder in modulating mass transport within the catalyst layer (CL) of fuel cells is essential for optimizing cell performance. This investigation focuses on enhancing the membrane electrode assembly (MEA) through the utilization of a short-side-chain perfluoro-sulfonic acid (SSC-PFSA) ionomer as the cathode binder, referred to as SSC-MEA. This study meticulously visualizes the distinctive interpenetrating networks of ionomers and catalysts, and explicitly clarifies the triple-phase interface, unveiling the transport-friendly microstructure and transport mechanisms inherent in SSC-MEA. The SSC-MEA exhibits advantageous microstructural features, including a better-connected ionomer network and well-organized hierarchical porous structure, culminating in superior mass transfer properties. Relative to the MEA bonded by long-side-chain perfluoro-sulfonic acid (LSC-PFSA) ionomer, noted as LSC-MEA, SSC-MEA exhibits a notable peak power density (1.23 W cm-2), efficient O2 transport, and remarkable proton conductivity (65% improvement) at 65 °C and 70% relativity humidity (RH). These findings establish crucial insights into the intricate morphology-transport-performance relationship in the CL, thereby providing strategic guidance for developing highly efficient MEA.

Heavy-Metal-Free Colloidal Quantum Dots: Progress and Opportunities in Solar Technologies.

Colloidal quantum dots (QDs) hold great promise as building blocks in solar technologies owing to their remarkable photostability and adjustable properties through the rationale involving size, atomic composition of core and shell, shapes, and surface states. However, most high-performing QDs in solar conversion contain hazardous metal elements, including Cd and Pb, posing significant environmental risks. Here, a comprehensive review of heavy-metal-free colloidal QDs for solar technologies, including photovoltaic (PV) devices, solar-to-chemical fuel conversion, and luminescent solar concentrators (LSCs), is presented. Emerging synthetic strategies to optimize the optical properties by tuning the energy band structure and manipulating charge dynamics within the QDs and at the QDs/charge acceptors interfaces, are analyzed. A comparative analysis of different synthetic methods is provided, structure-property relationships in these materials are discussed, and they are correlated with the performance of solar devices. This work is concluded with an outlook on challenges and opportunities for future work, including machine learning-based design, sustainable synthesis, and new surface/interface engineering.

Investigation of select radionuclides stability in urine under various conditions for liquid scintillation counting (LSC).

Liquid Scintillation Counting (LSC) gross alpha/beta screening is a valuable tool for providing rapid laboratory response for the analysis of human clinical urine samples during a large-scale radiation incident event. Verification of method performance, as required for clinical laboratory testing, is accomplished by the evaluation of routine, periodic measurements of radioactive spiked samples for quality control, performance testing, and accuracy checks. Radionuclide stability of alpha and beta emitters in urine for LSC analysis is an important consideration. The purpose of this work is to demonstrate optimal preparations and storage conditions of samples used for method verification.

Unveiling novel insights in acute myeloid leukemia through single-cell RNA sequencing.

Acute myeloid leukemia (AML) is a complex and heterogeneous group of aggressive hematopoietic stem cell disease. The presence of diverse and functionally distinct populations of leukemia cells within the same patient's bone marrow or blood poses a significant challenge in diagnosing and treating AML. A substantial proportion of AML patients demonstrate resistance to induction chemotherapy and a grim prognosis upon relapse. The rapid advance in next generation sequencing technologies, such as single-cell RNA-sequencing (scRNA-seq), has revolutionized our understanding of AML pathogenesis by enabling high-resolution interrogation of the cellular heterogeneity in the AML ecosystem, and their transcriptional signatures at a single-cell level. New studies have successfully characterized the inextricably intertwined interactions among AML cells, immune cells and bone marrow microenvironment and their contributions to the AML development, therapeutic resistance and relapse. These findings have deepened and broadened our understanding the complexity and heterogeneity of AML, which are difficult to detect with bulk RNA-seq. This review encapsulates the burgeoning body of knowledge generated through scRNA-seq, providing the novel insights and discoveries it has unveiled in AML biology. Furthermore, we discuss the potential implications of scRNA-seq in therapeutic opportunities, focusing on immunotherapy. Finally, we highlight the current limitations and future direction of scRNA-seq in the field.

Characterization of CD34+ Cells from Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Using a t-Distributed Stochastic Neighbor Embedding (t-SNE) Protocol.

Using multi-color flow cytometry analysis, we studied the immunophenotypical differences between leukemic cells from patients with AML/MDS and hematopoietic stem and progenitor cells (HSPCs) from patients in complete remission (CR) following their successful treatment. The panel of markers included CD34, CD38, CD45RA, CD123 as representatives for a hierarchical hematopoietic stem and progenitor cell (HSPC) classification as well as programmed death ligand 1 (PD-L1). Rather than restricting the evaluation on a 2- or 3-dimensional analysis, we applied a t-distributed stochastic neighbor embedding (t-SNE) approach to obtain deeper insight and segregation between leukemic cells and normal HPSCs. For that purpose, we created a t-SNE map, which resulted in the visualization of 27 cell clusters based on their similarity concerning the composition and intensity of antigen expression. Two of these clusters were "leukemia-related" containing a great proportion of CD34+/CD38- hematopoietic stem cells (HSCs) or CD34+ cells with a strong co-expression of CD45RA/CD123, respectively. CD34+ cells within the latter cluster were also highly positive for PD-L1 reflecting their immunosuppressive capacity. Beyond this proof of principle study, the inclusion of additional markers will be helpful to refine the differentiation between normal HSPCs and leukemic cells, particularly in the context of minimal disease detection and antigen-targeted therapeutic interventions. Furthermore, we suggest a protocol for the assignment of new cell ensembles in quantitative terms, via a numerical value, the Pearson coefficient, based on a similarity comparison of the t-SNE pattern with a reference.

Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models.

CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 µM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

Determination of 90Sr and 210Pb in food samples by liquid scintillation counting after sequential separation with an extraction chromatographic column.

90Sr and 210Pb are considered to be key radionuclides in internal exposure resulting from dietary intake, however, the established methods employed for their detection are time-comsuming. A method for the sequential separation of 90Sr and 210Pb using a Sr·spec resin by LSC measurement is developed, which is highly suitable for food safety monitoring as its minimal sample requirements. The sequential separation of Sr and Pb from the sample was using 0.05 mol/L HNO3 and 0.05 mol/L C6H5O7(NH4)3. The chemical recoveries of Sr and Pb measured using ICP-OES were 72-83% and 80-88%, respectively. The minimum detectable activities of 90Sr and 210Pb in the food sample were 36.2 mBq/kg and 28.6 mBq/kg, respectively, obtained from a 0.1 kg fresh sample and 300 min counting time. The method was validated using reference materials and compared with other methods. The feasibility of the developed method for other highly complex food matrices needs further investigation.

On the significance of the measurement evaluation method in decision making: A synthesis of JCGM 101 and JCGM 106 applied to gross alpha and gross beta measurements using LSC.

In decision making, e.g. conformity to a specification like a reference value or a requirement, the decision rule applied shall be documented. Furthermore, if the measurement uncertainty is considered in the decision process the associated probability, or risk, that a measurement result is above (or below) a reference value shall be taken into account. In this work it is shown that for gross alpha and gross beta measurements the evaluation method, GUMUF (GUM Uncertainty Framework) or MC (Monte Carlo), may also be important and influence the decisions taken when measurement results are very close to the reference value. Therefore the evaluation method and assumptions of the input quantities may also be important to document. Moreover, decision makers or users of measurement results should be aware of possible differences and/or consequences due to the evaluation method regardless of the decision rule and the choice of evaluation method.

Recent Advances towards the Understanding of Secondary Acute Myeloid Leukemia Progression.

Secondary acute myeloid leukemia (sAML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder (AHD) including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), aplastic anemia (AA), or as a result of exposure to genotoxic chemotherapeutic agents or radiotherapy (therapy related AML, tAML). sAML is diagnosed when the number of blasts is ≥20% in the bone marrow or peripheral blood, and it is characterized by poor prognosis, resistance to therapy and low overall survival rate. With the recent advances in next generation sequencing technologies, our understanding of the molecular events associated with sAML evolution has significantly increased and opened new perspectives for the development of novel therapies. The genetic aberrations that are associated with sAML affect genes involved in processes such as splicing, chromatin modification and genome integrity. Moreover, non-coding RNAs' emerged as an important contributing factor to leukemogenesis. For decades, the standard treatment for secondary AML has been the 7 + 3 regimen of cytarabine and daunorubicin which prolongs survival for several months, but modifications in either dosage or delivery has significantly extended that time. Apart from traditional chemotherapy, hematopoietic stem cell transplantation, CAR-T cell therapy and small molecule inhibitors have also emerged to treat sAML.

An arms-race against resistance: leukemic stem cells and lineage plasticity.

Acute myeloid leukemia (AML) therapy is undergoing rapid development, but primary and acquired resistance to therapy complicates the prospect of a durable cure. Recent functional and single-cell multi-omics approaches have greatly expanded our knowledge of the diversity of lineage trajectories in AML settings. AML cells range from undifferentiated stem-like cells to more differentiated myeloid or megakaryocyte/erythroid cells. Current clinically relevant drugs predominantly target the myeloid progenitor lineage, while monocyte- or stem cell-like states can evade current AML treatment and may be targeted in the future with lineage-specific inhibitors. The extent of aberrant lineage plasticity upon therapeutic pressure in AML cells in conjunction with hijacking of normal differentiation pathways is still a poorly understood topic. Insights into the mechanisms of lineage plasticity of AML stem cells could identify both therapy-specific and cross-drug resistance pathways and reveal novel strategies to overcome them.

Simultaneous determination of 226Ra and 228Ra in food samples using liquid scintillation counting.

The 228Ra and 226Ra isotopes of radium are significant contaminants in food, raising public concern because of their radiotoxicity. Several methods are available for determining 228Ra and 226Ra. However, the application of these procedures is not focused on food but only on water and environmental matrices. In this study, a cost-effective method for the simultaneous determination of 226Ra and 228Ra radioactivity in food samples using liquid scintillation counting was developed. The overall efficiencies of 226Ra and 228Ra in the food samples are 69.4-78.4% and 30.1-35.8%, respectively. The minimum detectable activities of 226Ra and 228Ra are 11.3 mBq/g and 33.4 mBq/g, respectively, in our food sample, obtained using a 1.0 g ash sample and 60 min of counting time. The method was validated using IAEA-certified reference materials and compared with data obtained using gamma spectrometry in tea, kelp, and oyster samples.

Influence of irrigation approaches and spatial geolocation on tritium speciation, uptake and depuration.

Pine needles and tree cores from a tritium (T) contaminated phytoremediation forest at the Savannah River Site (SRS in Aiken, SC) Mixed Waste Management Facility (MWMF) were measured for total T and T speciation and compared to other locations at the SRS and the surrounding area. Tree core ages ranged from 9 to 14 years old, covering over half of the ∼20-year on-going remediation efforts, while pine needles represent more recent time periods of 1-to-2-year increments. Remedial irrigation efforts at the MWMF are found to directly influence the pine needle T concentrations. The T content in the MWMF samples is higher than non-irrigated needle samples from other locations around the SRS. Further, the different forms of organic bound T are preferentially stored in tree core tissue, compared to pine needles where tritiated water dominates.

Production, expression, and function of dual-specific monoclonal antibodies in a single plant.

MAIN CONCLUSION: LSC CO17-1AK and anti-HER2 VHH-FcK can be produced in a single plant and exhibit anti-tumor activities comparable to those of their respective parent antibodies. Recombinant monoclonal antibodies (mAbs) which can be applied to treat various cancers, are primarily produced using mammalian, insect, and bacteria cell culture systems. Plant expression systems have also been developed to produce antibodies. Plant expression systems present several advantages, including a lack of human pathogenic agents, efficient production costs, and easy large-scale production. In this study, we generated a transgenic plant expressing anti-colorectal cancer large single chain (LSC) CO17-1AK and anti-human epidermal growth factor receptor 2 (HER2) VHH-FcK mAbs by cross-pollinating plants expressing LSC CO17-1AK and anti-HER2 VHH-FcK, respectively. F1 siblings expressing both LSC CO17-1AK and anti-HER2 VHH-FcK were screened using polymerase chain reaction and Western-blot analyses. The cell enzyme-linked immunosorbent assay (Cell ELISA) confirmed the binding of LSC CO17-1AK and anti-HER2 VHH-FcK to target proteins in the SW620 human colorectal cancer and the SKBR-3 human breast cancer cell lines, respectively. The wound healing assay confirmed the inhibitory activity of both antibodies against SW620 and SKBR-3 cell migration, respectively. In conclusion, both LSC CO17-1AK mAb and anti-HER2 VHH-FcK can be produced in a single plant, achieve binding activities to SW620 and SKBR-3 cancer cells, and inhibitory activity against SW620 and SKBR-3 cell migration similar to their parental antibodies, respectively.

Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells.

Acute myeloid leukemia (AML) is a rare subtype of acute leukemia in the pediatric and adolescent population but causes disproportionate morbidity and mortality in this age group. Standard chemotherapeutic regimens for AML have changed very little in the past 3-4 decades, but the addition of targeted agents in recent years has led to improved survival in select subsets of patients as well as a better biological understanding of the disease. Currently, one key paradigm of bench-to-bedside practice in the context of adult AML is the focus on leukemia stem cell (LSC)-targeted therapies. Here, we review current and emerging immunotherapies and other targeted agents that are in clinical use for pediatric AML through the lens of what is known (and not known) about their LSC-targeting capability. Based on a growing understanding of pediatric LSC biology, we also briefly discuss potential future agents on the horizon.

Estimation of gross α-ß and tritium activities in groundwater samples using LSC-TDCR technique in and around the geothermal region of Eastern India.

The present study is an attempt to assess the radiogenic quality of groundwater on the basis of gross α, gross ß and tritium (3H or H-3) activities in the Bakreswar-Tantloi geothermal region of Chotanagpur Plateau, West Bengal and Jharkhand, India. The aforesaid parameters in groundwater samples were measured using liquid scintillation counting triple to double coincidence ratio (LSC-TDCR) technique. Groundwater samples collected from Bakreswar-Tantloi geothermal region show gross α activities from below the minimum detectable activity (BMDA) to 0.5 ± 0.05 Bq/L, gross ß activities from BMDA to 0.2 ± 0.01 Bq/L and H-3 activities from BMDA to 63.42 Bq/L. The average gross α, gross ß and H-3 activities are also within the permissible limits prescribed by the World Health Organization (WHO). Though the annual effective doses in some samples were higher than the reference dose level of 0.1 mSv, the overall result suggests that the groundwater in the Bakreswar-Tantloi geothermal region is radiologically safe considering the radionuclides covered in this study.

A guide to epigenetics in leukaemia stem cells.

Leukaemia stem cells (LSCs) are the critical seed for the growth of haematological malignancies, driving the clonal expansion that enables disease initiation, relapse and often resistance. Specifically, they display inherent phenotypic and epigenetic plasticity resulting in complex heterogenic diseases. In this review, we discuss the key principles of deregulation of epigenetic processes that shape this disease evolution. We consider measures to define and quantify clonal heterogeneity, combining information from recent studies assessing mutational, transcriptional and epigenetic landscapes at single cell resolution in myeloid neoplasms (MN). We highlight the importance of integrating epigenetic and genetic information to better understand inter- and intra-patient heterogeneity and discuss how this understanding further informs evolution and progression trajectories and subsequent clinical response in MN. Under this topic, we also discuss efforts to identify mechanisms of resistance, by longitudinal analyses of patient samples. Finally, we highlight how we might target these aberrant epigenetic processes for better therapeutic outcomes and to potentially eradicate LSCs.

A comparison of different approaches for the analysis of 36Cl in graphite samples.

This study compares different approaches for the quantification of the massic activity of 36Cl in graphite samples. All approaches consisted of a combustion step in combination with a trapping solution to collect the volatile elements. Two different resins were used to separate 36Cl from the matrix (CL resin and PS resin). Liquid scintillation counting (LSC), scintillation counting (SC) and tandem inductively coupled plasma mass spectrometry (ICP-MS/MS) were used to quantify 36Cl activity. The chemical yield in all approaches was determined by means of ion chromatography (IC). In addition, the methods were applied to a real activated graphite sample.

A Leukemic Target with a Thousand Faces: The Mitochondria.

In the era of personalized medicine greatly improved by molecular diagnosis and tailor-made therapies, the survival rate of acute myeloid leukemia (AML) at 5 years remains unfortunately low. Indeed, the high heterogeneity of AML clones with distinct metabolic and molecular profiles allows them to survive the chemotherapy-induced changes, thus leading to resistance, clonal evolution, and relapse. Moreover, leukemic stem cells (LSCs), the quiescent reservoir of residual disease, can persist for a long time and activate the recurrence of disease, supported by significant metabolic differences compared to AML blasts. All these points highlight the relevance to develop combination therapies, including metabolism inhibitors to improve treatment efficacy. In this review, we summarized the metabolic differences in AML blasts and LSCs, the molecular pathways related to mitochondria and metabolism are druggable and targeted in leukemia therapies, with a distinct interest for Venetoclax, which has revolutionized the therapeutic paradigms of several leukemia subtype, unfit for intensive treatment regimens.