Sequential autologous CAR-T and allogeneic CAR-T therapy successfully treats central nervous system involvement relapsed/refractory ALL: a case report and literature review.

Background: The central nervous system (CNS) is the most common site of extramedullary invasion in acute lymphoblastic leukemia (ALL), and involvement of the CNS is often associated with relapse, refractory disease, and poor prognosis. Chimeric antigen receptor-T (CAR-T) cell therapy, a promising modality in cancer immunotherapy, has demonstrated significant advantages in the treatment of hematological malignancies. However, due to associated adverse reactions such as nervous system toxicity, the safety and efficacy of CAR-T cell therapy in treating CNSL remains controversial, with limited reports available. Case report: Here, we present the case of a patient with confirmed B-ALL who experienced relapse in both bone marrow (BM) and cerebrospinal fluid (CSF) despite multiple cycles of chemotherapy and intrathecal injections. The infusion of autologous CD19 CAR-T cells resulted in complete remission (CR) in both BM and CSF for 40 days. However, the patient later experienced a relapse in the bone marrow. Subsequently, allogeneic CD19 CAR-T cells derived from her brother were infused, leading to another achievement of CR in BM. Significantly, only grade 1 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) events were detected during the treatment period and showed improvement with symptomatic management. During subsequent follow-up, the patient achieved a disease-free survival of 5 months and was successfully bridged to hematopoietic stem cell transplantation. Conclusion: Our study provides support for the argument that CNS involvement should not be deemed an absolute contraindication to CAR-T cell therapy. With the implementation of suitable management and treatment strategies, CAR-T therapy can proficiently target tumor cells within the CNS. This treatment option may be particularly beneficial for relapsed or refractory patients, as well as those with central nervous system involvement who have shown limited response to conventional therapies. Additionally, CAR-T cell therapy may serve as a valuable bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT) in these patients.

Venetoclax combined with hypomethylating agents and the CAG regimen in relapsed/refractory AML: a single-center clinical trial.

Objective: This study aimed to evaluate the efficacy and safety of venetoclax in combination with hypomethylating agents and CAG (VEN-DCAG) regimens in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Methods: The treatment response was analyzed by retrospective methods in R/R AML patients treated with the VEN-DCAG regimen at our institution. This included, but was not limited to, CR/CRi (complete remission/complete remission with incomplete hematologic recovery) rate, measurable residual disease (MRD) negative rate, and overall survival (OS). Results: 20 patients with R/R AML were recruited, with a median age of 40 years (10-70), 11 of whom were male (55%), and a median follow-up of 10.4 months (0.7-21.8). The overall response rate (ORR) after receiving 1 course of VEN-DCAG was 90% (18/20), with 17 (85%) CR/CRi (10 MRD-CR), 1 (5%) PR, and 2 (10%) NR. Subsequently, 12 patients (7 MRD-CR, 4 MRD+CR, 1 NR) were treated with the VEN-DCAG regimen, and 3 MRD+CR patients turned negative, and 13 patients finally achieved MRD-CR. Among them, 7 patients were in the relapse group, all achieving CR/CRi (6 MRD-CR), and 13 patients in the refractory group, with 10 CR/CRi (7 MRD-CR). The ORR for patients in the relapse and refractory groups was 100% (7/7) and 84.6% (11/13), respectively. Further, all patients experienced adverse events (AEs) of varying degrees of severity, with hematologic AEs primarily consisting of myelosuppression, while non-hematologic AEs were more common in the form of fever, gastrointestinal distress, and infections. 11 patients were followed up with bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT) therapy. At the last follow-up, 11 patients (7 MRD-CR, 4 MRD+CR) who received allo-HSCT, 1 (MRD+CR) died, and 9 patients (6 MRD-CR, 1 PR, 2 NR) who did not receive allo-HSCT, 5 (2 MRD-CR, 1 PR, 2 NR) died as well. Conclusion: The VEN-DCAG regimen may be an effective treatment option for R/R AML patients, with high ORR and MRD negative remission rates in both the relapsed and refractory groups. It is recommend that patients should be bridged to allo-HSCT as soon as possible after induction to CR by the VEN-DCAG regimen, which can lead to a significant long-term survival benefit. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2300075985.

Prediction of redox potentials of adrenaline and its supramolecular complex with glycine: theoretical and experimental studies.

Protonated adrenaline (PAd) can be oxidized to protonated adrenaline quinone (PAdquinone) through a one-step, two-electron redox reaction. The electron-transfer property of PAd and its supramolecular complex with glycine has been investigated by cyclic voltammetry (CV) experiment and theoretical calculations. From CV curves, the conditional formal redox potential E°' of PAd/PAdquinone couple at the pH value of 0.29 is determined to be 0.540 V. The calculated E°' using the G3MP2//B3LYP method and the B3LYP method with 6-31G(d,p), 6-31+G(d,p), 6-311G(d,p), and B3LYP/6-311+G(d,p) basis sets are in reasonable agreement with the experimental value. PAd can form supramolecular complex (PAd-Gly) with glycine (Gly) through hydrogen bond (H-bond), and the calculated E°' values of PAd-Gly/PAdquinone-Gly redox couple are larger than those of PAd/PAdquinone couple. The theoretical results are in good agreement with the experimental finding that the formation of H-bonds weaken the electron-donating ability of PAd.

Experimental and theoretical study on the 1:1 supramolecular complexes of formamide with adrenaline.

The electron transfer properties were investigated for supramolecular complexes of formamide (FA) with adrenaline (Ad) at graphite electrode and paraffine soaked graphite electrode using cyclic voltammetry (CV). The experimental results show that FA affected the electron transfer properties of Ad. The formed supramolecular complexes by hydrogen bond (H-bond) interaction between FA and Ad slowed down the diffusion ability of adrenaline, which makes it hard to donate electron and be oxidized. The H-bond interaction energies calculation for the supramolecular complexes of FA with Ad at MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p) level have also been performed. The calculational results confirm the experimental fact that FA can form stable supramolecular complexes with Ad.

Theoretical and experimental study on the molecular recognition of adrenaline by supramolecular complexation with crown ethers.

The protonated adrenaline (PAd(+)) forms supramolecular complexes with crown ethers by extensive hydrogen bond and ion-dipole interactions. Recent experiments and calculations have demonstrated the molecular recognition of PAd(+) through the supramolecular complexes formed between 12-crown-4 (12C4) and 15-crown-5 (15C5). In the present article, 18-crown-6 (18C6), 21-crown-7 (21C7), and dibenzo-24-crown-8 (DB24C8) are selected as model molecules of crown ethers to investigate systematically the cavity effect on the molecular recognition between the crown ethers and protonated adrenaline. The calculational results demonstrate that the capabilities of molecular recognition increase with the size of cavity of crown ethers. The experimental results of cyclic voltammetry (CV) are consistent with the calculational results that crown ethers can form stable supramolecular complexes with PAd(+), and the supramolecular complexes become more stable with the increasing size of crown ether.

Aqua-[1-(4-carb-oxy-phen-yl)-1H-imidazole-κN](pyridine-2,6-dicarboxyl-ato-κO,N,O)copper(II) monohydrate.

In the title complex, [Cu(C(7)H(3)NO(4))(C(10)H(8)N(2)O(2))(H(2)O)]·H(2)O, the Cu(II) ion is in a slightly distorted square-pyramidal geometry. Two carboxyl-ate O atoms and one pyridine N atom from a pyridine-2,6-dicarboxyl-ate ligand chelate the Cu(II) ion, forming two stable five-membered metalla rings. One imidazole N atom from a 1-(4-carb-oxy-phen-yl)imidazole ligand and one water mol-ecule complete the five-coordination. O-H⋯O hydrogen bonds involving the coordinated water mol-ecules and carboxyl-ate groups link the complex mol-ecules into chain-containing dinuclear macrocycles. O-H⋯O hydrogen bonds involving the uncoordinated water mol-ecules link the chains into a layer extending parallel to (10[Formula: see text]).

Experimental and theoretical study on the supramolecular complexes of 15-crown-5 with adrenaline.

The electron transfer properties of supramolecular complexes of 15-crown-5 (15C5) with protonated adrenaline (PAd(+)) at different electrodes using cyclic voltammetry (CV) have been investigated in the article. The experimental results show that 15C5 will affect the electron transfer properties of adrenaline. The formed supramolecular complexes by ion-dipole and hydrogen bond interaction between PAd(+) and 15C5 will slow down the diffusion ability of adrenaline and make it hard to donate electron and be oxidized. The interaction energies and NPA calculations for the supramolecular complexes of 15C5 with PAd(+) at B3LYP/6-31+G(d) level have been performed. The calculational results confirm the experimental fact that 15C5 can form stable supramolecular complexes with PAd(+).

Theoretical investigation on triagonal symmetry copper trimers: magneto-structural correlation and spin frustration.

The mechanisms of the magnetic coupling interactions for two trigonal-bipyramid trinuclear Cu(II) complexes Cu3(mu3-X)2(mu-pz)3X3 (X = Cl and Br, respectively) and three trigonal trinuclear Cu(II) complexes Cu3(mu3-X)(mu-pz)3Cl3 (X = Cl, Br, and O) are investigated by the calculations based on density functional theory combined with broken-symmetry approach (DFT-BS). The research on the magneto-structural correlation reveals that the magnetic coupling interaction is sensitive to the Cu-(mu3-X)-Cu angle. With the Cu-(mu3-X)-Cu angle changing from 76 to 120 degrees, the magnetic coupling interaction is switched from ferromagnetic to antiferromagnetic. According to the analysis of the molecular orbitals and the variation of the spin-state energies versus the ratio of the magnetic coupling constants, it is found that there exists spin frustration phenomenon in these complexes.

Electron delocalization and charge transfer in polypeptide chains.

In this work, the electron structure and charge-transfer mechanism in polypeptide chains are investigated according to natural bond orbitals (NBO) analysis at the level of B3LYP/6-311++G**. The results indicate that the delocalization of electrons between neighboring peptide subgroups can occur in two opposite directions, and the delocalization effect in the direction from the carboxyl end to the amino end has an obvious advantage. As a result of a strong hyperconjugative interaction, the lowest unoccupied NBO of the peptide subgroup, pi*C-O, has significant delocalization to neighboring subgroups, and the energies of these NBOs decrease from the carboxyl end to the amino end. The formation of intramolecular O...H-N type hydrogen bonds also helps to delocalize the electron from the carboxyl end to the amino end. Thus, the electron will flow to the amino end. The superexchange mechanism is suggested in the electron-transfer process.

Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase.

Phenolic marine natural product is a kind of new potential aldose reductase inhibitors (ARIs). In order to investigate the binding mode and inhibition mechanism, molecular docking and dynamics studies were performed to explore the interactions of six phenolic inhibitors with human aldose reductase (hALR2). Considering physiological environment, all the neutral and other two ionized states of each phenolic inhibitor were adopted in the simulation. The calculations indicate that all the inhibitors are able to form stable hydrogen bonds with the hALR2 active pocket which is mainly constructed by residues TYR48, HIS110 and TRP111, and they impose the inhibition effect by occupying the active space. In all inhibitors, only La and its two ionized derivatives La_ion1 and La_ion2, in which neither of the ortho-hydrogens of 3-hydroxyl is substituted by Br, bind with hALR2 active residues using the terminal 3-hydroxyl. While, all the other inhibitors, at least one of whose ortho-sites of 3- and 6-hydroxyls are substituted by Br substituent which take much electron-withdrawing effect and steric hindrance, bind with hALR2 through the lactone group. This means that the Br substituent can effectively regulate the binding modes of phenolic inhibitors. Although the lactone bound inhibitors have relatively high RMSD values, our dynamics study shows that both binding modes are of high stability. For each inhibitor molecule, the ionization does not change its original binding mode, but it does gradually increase the binding free energy, which reveals that besides hydrogen bonds, the electrostatic effect is also important to the inhibitor-hALR2 interaction.