Browse Articles

Patient-derived xenografts from circulating cancer stem cells as a preclinical model for personalized pancreatic cancer research

Abstract Patient-derived xenografts (PDXs) provide biologically relevant models and potential platforms for the development of treatment strategies for precision medicine in pancreatic cancer. Furthermore, circulating epithelial tumor cells (CETCs/CTCs) are released into the bloodstream by solid tumors and a rare subpopulation—circulating cancer stem cells (cCSCs) – is considered to be responsible for recurrence and plays a key role in metastasis. For the identification of cCSCs, an innovative in vitro assay to generate tumorspheres was established in this study. The number of tumorspheres and CETCs/CTCs was analyzed perioperatively in 25 pancreatic cancer patients. Additionally, an individual in vivo chorioallantoic membrane (CAM) culture system was used to generate PDXs from these tumorspheres. While overall correlations of CETCs/CTCs with clinicopathological parameters did not reach statistical significance, a significant difference in the number of tumorspheres was observed between patient subgroups with lower and higher UICC stages. This finding underscores their potential as biomarkers, providing valuable insights into clinical decision-making and tumor progression. The application of tumorspheres on the CAM successfully established PDXs within 7 days. These xenografts closely resembled the histological features of the primary tumor. Hence, this model represents a novel and fast option for individualized testing of new therapies for PDAC.

Predicting construction waste in Egyptian residential projects: a robust multiple regression model approach

Abstract Effective construction waste (CW) management, mainly concrete, brick, and steel, is a critical challenge due to its significant environmental and economic impacts. This study addresses this challenge by proposing multiple linear regression models to predict waste generation in residential buildings within the Egyptian construction industry, considering the influence of factors such as building design and site management features. Using data from 25 case studies, the models demonstrated high predictive accuracy, with adjusted R² values of 0.877, 0.893, and 0.889 for concrete, bricks, and steel waste, respectively. These R2 values indicate that the models explain approximately 88–89% of the variance in waste generation in residential buildings, highlighting their effectiveness in enhancing resource planning and waste management strategies. The findings suggest that incorporating variables such as total area, design consistency, and site organization significantly improves the accuracy of waste predictions. Although the models show acceptable performance, future research should aim to expand the dataset, incorporate additional variables, and test the models across different types of construction projects to validate further and refine these predictive tools. The models offer valuable insights for enhancing construction practices, minimizing waste, and supporting sustainable development in Egypt’s construction industry. With accurate forecasts of waste generation, the models help project managers and stakeholders to plan CW more effectively, mitigating unnecessary material consumption and reducing environmental impacts. These findings help to adopt sustainable construction practices, such as improved recycling processes and decreased dependence on landfills, to support Egypt’s Vision 2030.

RETRACTED ARTICLE: Heart transplantation: comparing the impact of modified heart preservation with conventional methods

Clinical utility of hematological parameters in aplastic anemia

Field experiment confirms high macroplastic trapping efficiency of wood jams in a mountain river channel

Novel inhibitors of the (VIBVN) NAT protein identified through pharmacophore modeling

Abstract Arylamine N-acetyltransferases (NATs, E.C. 2.3.1.5) constitute a family of phase II drug metabolizing enzymes. These enzymes catalyze the transfer of acetyl groups from acetyl-CoA to a variety of substrates including arylamines, arylhydrazines, and N-hydroxyarylamines. By facilitating these reactions, NATs play a pivotal role in the detoxification and metabolic processing of a wide range of drugs and carcinogens. NAT in marine V. vulnificus plays a role in the metabolism of drugs, leading to the development of drug resistance in marine V. vulnificus. However, inhibitors targeted marine V. vulnificus NAT [(VIBVN)NAT] remain unclear. Therefore, our research aimed to identify potential hit compounds that target (VIBVN)NAT. We integrated multiple computational approaches to screen for effective inhibitors. From this process, we identified two hit compounds, AK-968-11563024 and AG-205-36710025, with IC50 values of 18.86 µM and 33.27 µM, respectively. Molecular dynamics simulations further elucidated the binding mechanism between (VIBVN)NAT and AK-968-11563024. Our study revealed that AK-968-11563024 forms stable interactions with PHE124, HIS167, and TRP230, which may contribute to its biological activity. Our findings provide a valuable foundation for the future development of drugs targeted therapeutics against (VIBVN)NAT.

Structural, elastic, electronic, magnetic and thermal properties of X3FeO4 (X = mg, ca and Sr) materials

Epidemiological characteristics of injury in 7–22-year-old badminton players by age and sex

Identification of molecular characteristics in polycystic ovary syndrome using single-cell and transcriptome analysis

CD5-positive high-grade B-cell lymphoma with <i>MYC</i>, <i>BCL2</i>, and <i>BCL6</i> rearrangements

Management of iron overload: lessons from transfusion-dependent hemoglobinopathies

Abstract Before the advent of effective iron chelation, death from iron-induced cardiomyopathy and endocrine failure occurred in the second decade in patients with thalassemia major, and this experience has driven expectation of poor outcomes and caused anxiety in all disorders associated with iron loading to this day. To be clear, severe iron overload still causes significant morbidity and mortality in many parts of the world, but current understanding of iron metabolism, noninvasive monitoring of organ-specific iron loading in humans, and effective iron chelators have dramatically reduced morbidity of iron overload. Furthermore, clinical experience in hemoglobinopathies supports iron biology learned from animal studies and identifies common concepts in the biology of iron toxicity that inform the management of iron toxicity in several human disorders. The resultant significant increase in survival uncovers new complications due to much longer exposure to anemia and to iron, which must be considered in long-term therapeutic strategies. This review will discuss the management of iron toxicity in patients with hemoglobinopathies and transfusion-dependent anemias and how iron biology informs the clinical approach to treatment.

How I treat iron overload in adult MDS

Abstract Although clinical benefits of iron chelation therapy (ICT) in red blood cell (RBC) transfusion–dependent (TD) hereditary anemias such as α-thalassemia major are incontrovertible, the evidence supporting a similar benefit in patients with TD myelodysplastic neoplasms (MDS) and iron overload (IOL) is sometimes debated. MDS presents later in life, has a limited repertoire of life-extending therapies, and patients may have comorbidities acting as competing causes of death. However, refined prognostication identifies patients with MDS with a reasonable life expectancy, and because 50% of patients will ultimately become RBC TD and develop transfusional IOL, ICT should be considered in some. Using illustrative cases, we summarize mechanisms of iron toxicity, strategies for the identification of IOL, and propose definitions of IOL severity. We provide rationale for, and recommend which patients may benefit from, ICT. We discuss currently available chelators, their administration, monitoring, side effects, and their management. Given challenges with the use of iron chelators, we suggest the nuances to be considered when planning chelation initiation to include the rate of iron accumulation, the presence of organ iron and/or dysfunction, and detectable indicators of oxidative stress. Areas for future investigation are identified.

Montoro J, Eikema D-J, Tuffnell J, et al. Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT. <i>Blood.</i> 2024;144(3):323-333.

Cryo-EM structure of the human native plasma coagulation factor XIII complex

Abstract The structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma protransglutaminase that covalently cross-links preformed fibrin polymers, remains elusive until today. The heterotetrameric complex is composed of 2 catalytic FXIII-A and 2 protective FXIII-B subunits. Structural etiology underlying FXIII deficiency has so far been derived from crystallographic structures, all of which are currently available for the FXIII-A2 homodimer only. Here, we present the cryogenic electron microscopy (cryo-EM) structure of a native, human plasma–derived FXIII-A2B2 complex at 2.4 Å resolution. The structure provides detailed information on FXIII subunit interacting interfaces as the 2 subunits interact strongly in plasma. The native FXIII-A2B2 complex reveals a pseudosymmetric heterotetramer of 2 FXIII-B monomers intercalating with a symmetric FXIII-A2 dimer forming a “crown”-like assembly. The symmetry axes of the A2 and B2 homodimers are twisted relative to each other such that Sushi domain 1 interacts with the catalytic core of the A subunit, and Sushi domain 2 with the symmetry related A′ subunit, and vice versa. We also report 4 novel mutations in the F13A1 gene encoding the FXIII-A subunit from a cohort of patients with severe FXIII deficiency. Our structure reveals the etiological basis of homozygous and heterozygous pathogenic mutations and explains the conditional dominant negative effects of heterozygous mutations. This atomistic description of complex interfaces is consistent with previous biochemical data and shows a congruence between the structural biochemistry of the FXIII complex and the clinical features of FXIII deficiency.

Safety and efficacy of pegcetacoplan treatment for cold agglutinin disease and warm antibody autoimmune hemolytic anemia

Abstract Cold agglutinin disease (CAD) and warm antibody autoimmune hemolytic anemia (wAIHA) are rare autoimmune hemolytic anemias characterized by red blood cell destruction, largely attributable to complement activation resulting in intravascular and extravascular hemolysis. Pegcetacoplan is a subcutaneously administered C3-targeted therapy, which may be suitable for treating CAD and wAIHA. In this open-label phase 2 study, analyses were conducted in 2 cohorts, 1 for patients with CAD and the other for those with wAIHA. In each cohort, patients were randomly assigned to receive pegcetacoplan 270 mg/d or 360 mg/d for up to 48 weeks. Safety end points included the incidence and severity of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI). Efficacy end points included change from baseline in hemoglobin (Hb), lactate dehydrogenase, absolute reticulocyte count, haptoglobin, indirect bilirubin, and functional assessment of chronic illness therapy (FACIT)-fatigue scale. Thirteen of 13 (100%) and 10 of 11 (91%) patients with CAD and wAIHA, respectively, experienced at least 1 TEAE. Ten patients had at least 1 serious AE; none were considered related to pegcetacoplan. The only treatment-related AESIs were injection site reactions. Pegcetacoplan increased Hb levels, reduced hemolysis, and increased FACIT-fatigue scale scores in the first weeks; at week 48 the median (interquartile range) change from baseline Hb for the CAD and wAIHA total groups was 2.4 (0.90-3.00) and 1.7 g/dL (−1.40 to 2.90), respectively, and improvements in hemolysis and FACIT-fatigue scale scores were maintained. This study demonstrated that pegcetacoplan is generally well tolerated and suggests it can be effective for patients with CAD and wAIHA. This trial was registered at www.ClinicalTrials.gov as #NCT03226678.

Another cryo-EM success: structure of FXIII

Menopause research is globally underfunded. It’s time to change that

IKZF1: born to be the repressor

Conserved helical motifs in the IKZF1 disordered region mediate NuRD interaction and transcriptional repression

Abstract The transcription factor (TF) Ikaros zinc finger 1 (IKZF1) is essential for B-cell development, and recurrently mutated in human B-cell acute lymphoblastic leukemia (B-ALL). IKZF1 has been ascribed both activating and repressive functions via interactions with coactivator and corepressor complexes, but the relative abundance of IKZF1-associated coregulators and their contribution to IKZF1-mediated gene regulation are not well understood. To address this, we performed an unbiased identification of IKZF1-interacting proteins in pre-B cells and found that IKZF1 interacts overwhelmingly with corepressors and heterochromatin-associated proteins. Time-resolved analysis of transcription and chromatin state identified transcriptional repression as the immediate response to IKZF1 induction. Transcriptional repression preceded transcriptional activation by several hours, manifesting as a decrease in the fraction of transcriptional bursts at the single-molecule level. Repression was accompanied by a rapid loss of chromatin accessibility and reduced levels of histone H3 lysine 27 acetylation (H3K27ac), particularly at enhancers. We identified highly conserved helical motifs within the intrinsically disordered region of IKZF1 that mediate its association with the nucleosome remodeling and deacetylase (NuRD) corepressor complex through critical “KRK” residues that bind the NuRD subunit retinoblastoma binding protein 4 (RBBP4), a mechanism shared with the TFs FOG1, BCL11A, and SALL4. Functional characterization reveals that this region is necessary for the efficient silencing of target genes and antiproliferative functions of IKZF1 in B-ALL.

How I manage iron overload in the hematopoietic cell transplantation setting

Abstract The success of hematopoietic transplantation for hemoglobinopathies and hematological malignancies has been accompanied by the new challenge of how to identify, risk stratify, and treat iron overload and toxicity before and after transplantation. Substantial progress has been made in our understanding of iron metabolism and the pathophysiology of iron overload, making us aware that not only the total amount of iron in the body is important but also the effect of toxic iron species and duration of exposure are equally relevant. Challenges still remain in how to assess cellular and tissue damage and define the mechanism that may detrimentally affect the outcome of hematopoietic transplantation. In this article, I discuss the impact of iron toxicity in relation to the different phases of hematopoietic transplantation, before, during, and after, for both malignant and nonmalignant diseases. Different clinical scenarios and possibilities for therapeutic intervention are also outlined and discussed.