Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive developmental and epileptic encephalopathy caused by pathogenic variants in the ALDH7A1 gene (PDE-ALDH7A1), which mainly has its onset in neonates and infants. Early diagnosis and treatment are crucial to prevent severe neurological sequelae or death. Sensitive, specific, and stable biomarkers for diagnostic evaluations and follow-up examinations are essential to optimize outcomes. However, most of the known biomarkers for PDE lack these criteria. Additionally, there is little discussion regarding the interdependence of biomarkers in the PDE-ALDH7A1 metabolite profile. Therefore, the aim of this study was to understand the underlying mechanisms in PDE-ALDH7A1 and to discover new biomarkers in the plasma of patients using global metabolomics. Plasma samples from 9 patients with genetically confirmed PDE-ALDH7A1 and 22 carefully selected control individuals were analyzed by ultra high performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS). Two novel and reliable pyridoxine-independent diagnostic markers, 6-hydroxy-2-aminocaproic acid (HACA) and an isomer of C9H11NO4, were identified. Furthermore, a possible reaction mechanism is proposed for HACA. This study demonstrates the capability of global metabolomics in disease screening to detect established and novel biomarkers.

Cordyceps is a genus of ascomycete fungi and used widely in fungal drugs. However, in-depth studies of the metabolites of wild Cordyceps species and their substituents are lacking. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics analysis was carried out to comprehensively profile the metabolites in wild Chinese Cordyceps species (Ophiocordyceps sinensis (Berk.) G.H. Sung, J.M. Sung, Hywel-Jones and Spatafora 2007) from Naqu (NCs) and Yushu (YCs) and their substituents including artificially cultivated Cordyceps species (CCs) and mycelia. A total of 901 metabolites were identified in these samples, including lipids, amino acids, nucleosides, carbohydrates, organic acids, coenzymes, vitamins, alkaloids and their derivatives. Univariate and multivariate statistical analyses revealed remarkable differences and significantly different metabolites among them. Seventy amino acid-relevant metabolites were analyzed quantitatively in four samples for the first time. The four samples contained abundant L-glutamic acid and oxidized glutathione as well as multiple unique amino acid-relevant metabolites (e.g., 3-chloro-L-tyrosine, 6-aminocaproic acid, L-theanine, anserine, γ-glutamyl-cysteine). Collectively, our study provides rich metabolic information of wild Cordyceps species and their substituents, which could facilitate their quality control and optimal utilization.

Fibrinolysis is a natural process that ensures blood fluidity through the removal of fibrin deposits. However, excessive fibrinolytic activity can lead to complications in different circumstances, such as general surgery or severe trauma. The current antifibrinolytic drugs in the market, aminocaproic acid (EACA) and tranexamic acid (TXA), require high doses repetitively to maintain their therapeutic effect. These high doses are related to a number of side effects such as headaches, nasal symptoms, or gastrointestinal discomfort and severely limit their use in patients with renal impairment. Therefore, the discovery of novel antifibrinolytics with a higher specificity and lower dosage could vastly improve the applicability of these drugs. Herein, we synthesized a total of ten compounds consisting of a combination of three key moieties: an oxadiazolone, a triazole, and a terminal amine. The IC50 of each compound was calculated in our clot lysis assays, and the best candidate (1) provided approximately a 2.5-fold improvement over the current gold standard, TXA. Molecular docking and molecular dynamics were used to perform a structure-activity relationship (SAR) analysis with the lysine binding site in the Kringle 1 domain of plasminogen. This analysis revealed that 1,2,3-triazole was crucial for the activity, enhancing the binding affinity through pi-pi stacking and polar interactions with Tyr72. The results presented in this work open the door to further investigate this new family as potential antifibrinolytic drugs.

Titanium is considered to be the most essential metal in the field of implantology. The main factors determining metal biocompatibility, among others, include the morphology and chemical composition of the titanium surface. Therefore, the aim of this work was to develop approaches to control the biological activity of the titanium surface by creating coatings that combine both an inorganic phase with a given morphology and organic molecules containing an integrin-selective peptide that regulate cell adhesion and proliferation. As such, we synthesized new c(RGDfC) derivatives of amino acid bisphosphonates (four examples) with different bisphosphonate anchors and maleimide linkers. These molecules were deposited on a highly developed porous surface obtained via the plasma electrolytic oxidation (PEO) of coarse-grained and nanostructured titanium. In vitro studies demonstrated the increase in the viability degree of mesenchymal stem cells and fibroblasts on the surface of coarse-grained or nanostructured titanium modified with PEO and a c(RGDfC) derivative of ε-aminocaproic acid bisphophonate with an SMCC linker. As a result, the use of conjugates of amino acid bisphosphonates with a cyclic RGD peptide for the modification of PEO-coated titanium opens the ways for the effective control of the biological activity of the metal implant surface.

The most common hematological disorder associated with prostate cancer is disseminated intravascular coagulation (DIC). In most cases, cancer patients with DIC have compensated fibrinolysis with a low incidence of bleeding. However, DIC with excessive fibrinolysis is a rare albeit life-threatening variant that can present with massive bleeding and is thought to occur due to the unique properties of neoplastic cells of prostate cancer that activate both procoagulant and anticoagulant pathways simultaneously. Depending on the shift of the intricate balance between the two forces, the net result can be either systemic micro- (DIC) or macro-thrombi, deep venous thrombosis (DVT) or pulmonary embolism, or a bleeding syndrome from excessive vicious activation of fibrinolysis. Here, we present a unique case of suspected prostate cancer who underwent a diagnostic prostatic biopsy. Subsequently, he developed massive hematuria requiring intensive care unit admission with multiple supportive blood products. Additionally, he was administered epsilon-aminocaproic acid with a prophylactic dose of heparin, with prompt resolution of bleeding. After stabilization, he was discharged with planned outpatient chemotherapy. However, he subsequently presented with lower extremity DVT within a week, which led to a stroke in the setting of a patent foramen ovale. This unique case report highlights how a change in the intricate balance of the coagulation cascade causes a polar shift in clinical presentation and complications.

The identification of new colloidal sol-gel routes for the preparation of actinide oxides, which have a homogeneous and accessible porosity that can easily be impregnated by any concentrated actinide solution, opens new perspectives for the preparation of homogeneous nuclear fuel for minor actinide transmutation. This homogeneity allows us to avoid "hot spot" formation due to the local accumulation of more fissile elements. Here, we report the preparation of macro-microporous ThO2 materials by a colloidal sol-gel route. Using a thorium salt with 6-aminocaproic acid as a complexing agent at a controlled pH, we were able to pilot the condensation of thorium hydroxo species forming colloids of tuned nanometric size and thus the sol stability. After a freeze-drying process to concentrate colloids and a thermal treatment allowing complexing agent removal and macroporosity formation by a brutal gas release during combustion, a loose packing of ThO2 nanoparticles with an ordered distribution of interparticular porosity and a fraction of nanometric crystallites, whose size depends on the initial colloidal size, were obtained. The sols, pastes, and final materials were characterized by small- and wide-angle X-ray scattering to determine the colloidal size and the final structure of the materials, which was also confirmed by transmission electron microscopy. The most promising material was finally successfully impregnated by a simulating minor actinide solution and thermally treated to prepare a mixed actinide oxide material. This safe technology, relying on the colloidal sol-gel process and the formulation of complex fluids forming tunable precursors, opens new perspectives for the reuse of nuclear waste solutions as new fuel.

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

A 29-year-old primipara with Glanzmann's thrombasthenia presented for prenatal care at 8 weeks of gestation. Pregnancy remained uncomplicated until 22 weeks of gestation when a subchorionic hematoma, measuring 5.8 × 4.1 × 6.7 cm, was diagnosed and managed outpatient. At 28 weeks of gestation, the subchorionic hematoma was significantly expanding to 11 × 13 × 3.7 cm (∼30% of the placental surface). The patient was admitted for antepartum surveillance and steroid treatment. Fetal and maternal status were reassuring. At 36 weeks of gestation, there was active extravasation from the subchorionic hematoma, prompting interdisciplinary discussion with neonatal intensive care unit, blood bank, pharmacy, anesthesia, hematology, and the patient regarding her options. Immediate delivery risked platelet sensitization because of unavailable human leukocyte antigen-matched platelets. The patient opted for medical management with aminocaproic acid. At 37 weeks of gestation, she underwent a scheduled cesarean delivery. Human leukocyte antigen-matched platelets and additional aminocaproic acid were administered preoperatively. Intrapartum hemorrhage of 1200cc was controlled with uterotonics in addition to the above measures. Antifibrinolytics were continued. The neonate had an uncomplicated postpartum course. The patient had symptomatic anemia on postoperative day 1, which prompted red blood cell transfusion. Discharge was delayed until postoperative day 6 to further monitor her bleeding; oral antifibrinolytics were continued for 2 weeks. This case adds to the growing use of adjuvant medications, including antifibrinolytics such as aminocaproic acid and tranexamic acid, to reduce the reliance on platelet transfusion. This is critical for maintaining a favorable response to platelet transfusions and minimizing the risk of fetal neonatal alloimmune thrombocytopenia in current and subsequent pregnancies among women with lifelong bleeding disorders.

Aminocaproic acid, an antifibrinolytic agent, is a medication used to manage and treat acute bleeding disorders. This activity outlines the indications, mechanism of action, and contraindications for aminocaproic acid as a valuable agent in managing hyperfibrinolysis-induced hemorrhage. This activity will also highlight other key factors, including the adverse event profile, off-label indications, dosing, and monitoring, pertinent for the healthcare team members in the management of patients with acute hyperfibrinolysis-induced hemorrhage and related conditions.

Nephron-sparing surgery is a well-established treatment in patients with T1a renal cell carcinoma; however, the complex suturing process prolongs warm ischaemia time, affects the preservation of normal renal parenchymal function, and causes avoidable postoperative tissue adhesion complications, including chronic abdominal pain, intestinal obstruction, and female infertility. Hence, the design of multifunctional biomaterials with haemostasis, postoperative wound management, and postoperative tissue adhesion prevention properties for nephron-sparing surgeries is urgently needed. In this study, a series of injectable adhesive multifunctional biocompatible hydrogels were designed based on the free-radical polymerisation of monomers acryloyl-6-aminocaproic acid (AA) and N-acryloyl 2-glycine (NAG), and the ionic coordination between Ca2+ and the abundant carboxyl groups in AA and NAG. AA/NAG/Ca (AA, NAG, and Ca refer to acryloyl-6-aminocaproic acid, N-acryloyl 2-glycine and calcium chloride, respectively) hydrogel exhibited good mechanical properties, swelling and adhesion properties, flexibility, in vitro blood-clotting ability, and cytocompatibility. In vivo experiments on liver injury models and rat/rabbit nephron-sparing surgery models elucidated that the AA/NAG/Ca hydrogel had haemostasis performance and wound healing properties that led to short bleeding time, reduced bleeding volume, and well-organised nephron structures. An abdomen-caecum adhesion model indicated that the AA/NAG/Ca hydrogel showed excellent anti-adhesion properties. In summary, this multifunctional hydrogel exhibited potential for improving haemostasis and wound management in nephron-sparing surgeries, showing potential for clinical application. STATEMENT OF SIGNIFICANCE: Extended warm ischemia time during nephron sparing surgery negatively affected postoperative renal function due to the need for hemostasis at the wound with abundant blood supply, and postoperative wound healing and additional adhesions caused by the surgical procedure deserve attention. Based on the efficient and stable adhesion properties of hydrogels and the ability to promote wound healing. Herein, a series of adhesive self-healing biocompatible hydrogels were prepared based on free-radical polymerization of acryloyl-6-aminocaproic acid (AA) and N-acryloyl 2-glycine (NAG) and the ionic coordination between Ca2+ with the abundant carboxyl groups in AA and NAG. AA/NAG/Ca hydrogel showed hemostasis property in nephron sparing surgery model, promote kidney wound healing, and could perform anti-postoperative adhesion efficacy in an abdomen-caecum adhesion model.

Enolase, a multifunctional protein expressed by multiple pathogens activates plasminogen to promote proteolysis on components of the extracellular matrix, an important event in early host-pathogen interactions. A secreted form of enolase that is released upon the interaction of trophozoites with epithelial cells has been detected in the secretome of G. duodenalis. However, the role of enolase in the host-pathogen interactions remains largely unknown. In this work, the effects of G. duodenalis enolase (Gd-eno) on the epithelial cell model (IEC-6) were analyzed. Firstly, the coding sequence of Giardia enolase was cloned and the recombinant protein used to raise antibodies that were then used to define the localization and role of enolase in epithelial cell-trophozoite interactions. Gd-eno was detected in small cytoplasmic vesicles as well as at the surface and is enriched in the region of the ventral disk of Giardia trophozoites. Moreover, the blocking of the soluble monomeric form of the enzyme, which is secreted upon interaction with IEC-6 cells by the anti-rGd-eno antibodies, significantly inhibited trophozoite attachment to intestinal IEC-6 cell monolayers. Further, rGd-eno was able to bind human plasminogen (HsPlg) and enhanced plasmin activity in vitro when the trophozoites were incubated with the intrinsic plasminogen activators of epithelial cells. In IEC-6 cells, rGd-eno treatment induced a profuse cell damage characterized by copious vacuolization, intercellular separation and detachment from the substrate; this effect was inhibited by either anti-Gd-eno Abs or the plasmin inhibitor ϵ- aminocaproic acid. Lastly, we established that in epithelial cells rGd-eno treatment induced a necroptotic-like process mediated by tumor necrosis factor α (TNF-α) and the apoptosis inducing factor (AIF), but independent of caspase-3. All together, these results suggest that Giardia enolase is a secreted moonlighting protein that stimulates a necroptotic-like process in IEC-6 epithelial cells via plasminogen activation along to TNFα and AIF activities and must be considered as a virulence factor.

BackgroundStorage pool deficiency (SPD) is a rare bleeding disorder characterized by reduction in the number of delta granules within platelets, interfering with hemostasis. Current literature lacks well-designed studies from which to draw concrete conclusions regarding pre-procedural management of bleeding complications. Objective: The purpose of this study is to describe bleeding and safety outcomes of SPD patients receiving either pre-procedural platelet transfusions or platelet-sparing regimens. Methods: An exploratory retrospective cohort study was conducted among SPD patients, comparing major bleeding events between those who received platelet transfusion and those who received desmopressin, tranexamic acid, and/or aminocaproic acid within 24 hours prior to procedure. Results: Rates of major bleeding were not found to be higher among patients who received a platelet-sparing regimen [platelet-sparing: 2/25 (8%); platelet transfusion: 2/29 (6.9%); P = .99]. Incidence of non-major bleeding was higher in the platelet transfusion group, but this was not statistically significant [platelet-sparing: 0/25 (0%); platelet transfusion: 3/29 (10.3%); P = .24]. Treatment-related adverse effects were observed following 8 of 54 procedures (14.8%). Conclusion: Use of a platelet-sparing regimen was not associated with a significantly higher incidence of major or non-major bleeding events. Future prospective trials are recommended to compare outcomes between therapies.

Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting cell metabolism for cancer cell growth; targeting GLU metabolism by inhibiting GLS has attracted interest as a potential cancer management strategy. Herein, we employed a sequential screening of traditional Chinese medicine (TCM) database followed by drug-likeness and molecular dynamics simulations against the active site of GLS. We report 12 potent compounds after screening the TCM database against GLS, followed by a drug-likeness filter with Lipinski and Veber rule criteria. Among them, ZINC03978829 and ZINC32296657 were found to have higher binding energy (BE) values than the control compound 6-Diazo-5-Oxo-L-Norleucine, with BEs of -9.3 and -9.7 kcal/mol, respectively, compared to the BE of 6-Diazo-5-Oxo-L-Norleucine (-4.7 kcal/mol) with GLS. Molecular dynamics simulations were used to evaluate the results further, and a 100 ns MD simulation revealed that the hits form stable complexes with GLS and formed 2-5 hydrogen bond interactions. This study indicates that these hits might be employed as GLS inhibitors in the battle against cancer. However, more laboratory tests are a prerequisite to optimize them as GLS inhibitors.

Glutamine is a conditionally essential amino acid consumed by rapidly proliferating cancer cells, which deprives the same fuel from immune cells and contributes to tumor immune evasion. As such, the broad antagonism of glutamine in tumors and the tumor microenvironment may lead to direct antitumor activity and stimulation of antitumoral immune responses. DRP-104 (sirpiglenastat) was designed as a novel prodrug of the broad-acting glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). DRP-104 is an inactive form that is preferentially converted to DON within tumors. Metabolomic profiling of tumors treated with DRP-104 revealed widespread changes indicative of the disruption of tumor anabolism and canonical cancer metabolism pathways; including altered glutamine metabolism while several immunosuppressive metabolites were decreased. Gene expression profiling revealed broad immunological modulation, confirmed by flow cytometry indicating that DRP-104 treatment resulted in substantial and broad changes in various immune cell infiltrates, such as increased TIL, T, NK, and NK T cells. Functionally, T cells became more proliferative and less exhausted; tumor-associated macrophages were polarized to the M1 phenotype; MDSCs and protumorigenic proteins were decreased in TME. Finally, DRP-104 demonstrated significant antitumor activity as a monotherapy, which was further enhanced in combination with checkpoint blockade therapies, leading to improved survival and long-term durable cures. In summary, DRP-104 broadly remodels the tumor microenvironment by inducing extensive tumor metabolism effects and enhancing the infiltration and function of multiple immune cells distinct from those obtained by checkpoint inhibitor therapy. This unique mechanism of action supports the ongoing clinical development of DRP-104 alone and in combination with checkpoint inhibitors.

Surgical correction of craniosynostosis can involve significant blood loss. Rates of allogenic blood transfusion have been reported to approach 100%. Multiple interventions have been described to reduce blood loss and transfusion requirements. The aim of this study was to analyze various approaches over the last 4 decades to optimize blood loss and management during craniosynostosis surgery.

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.