A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

Efficacy of pp65-specific TCR-T cell therapy in treating cytomegalovirus infection after hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection remains a major cause of mortality after hematopoietic stem cell transplantation (HSCT). Current treatments, including antiviral drugs and adoptive cell therapy with CMV-specific cytotoxic T lymphocytes (CTLs), only show limited benefits in patients. T-cell receptor (TCR)-T cell therapy offers a promising option to treat CMV infections. Here, using tetramer-based screening and single-cell TCR cloning technologies, we identified various CMV antigen-specific TCRs from healthy donors, and generated TCR-T cells targeting multiple pp65 epitopes corresponding to three major HLA-A alleles. The TCR-T cells showed efficient cytotoxicity toward epitope-expressing target cells in vitro. After transfer into immune-deficient mice bearing pp65+ HLA+ tumor cells, TCR-T cells induced dramatic tumor regression and exhibited long-term persistence. In a phase I clinical trial (NCT04153279), CMV TCR-T cells were applied to treat patients with CMV reactivation after HSCT. Except one patient who withdrew at early treatment stage, all other six patients were well-tolerated and achieved complete response (CR), no more than grade 2 cytokine release syndrome (CRS) and other adverse events were observed. CMV TCR-T cells persisted up to 3 months. Among them, two patients have survived for more than 1 year. This study demonstrates the great potential in the treatment and prevention of CMV infection following HSCT or other organ transplantation.

Experimental implementation of spike-based neuromorphic XOR operation based on polarization-mode competition in a single VCSOA.

We experimentally and numerically propose an approach for implementing spike-based neuromorphic exclusive OR (XOR) operation using a single vertical-cavity semiconductor optical amplifier (VCSOA). XOR operation is realized based on the neuron-like inhibitory dynamics of the VCSOA subject to dual-polarized pulsed optical injections. The inhibitory dynamics based on the polarization-mode competition effect are analyzed, and the inhibitory response can be obtained in a suitable range of wavelength detuning. Here, all input and output bits are represented by spikes that are compatible with the photonic spiking neural network. The experimental and numerical results show that XOR operation can be realized in two polarization modes by adjusting the time offset in the inhibitory window and setting defined reference thresholds. In addition, the influences of delay time and input intensity ratio on XOR operation are studied experimentally. This scheme is energy efficient because VCSOA neuromorphic photonics computing and information processing.

Comparable outcomes among unmanipulated haploidentical, matched unrelated, and matched sibling donors in BU-based myeloablative hematopoietic stem cell transplantation for intermediate and adverse risk acute myeloid leukemia in complete remission: a single-center study.

There are a limited number of studies comparing outcomes of busulfan (BU)-based myeloablative hematopoietic stem cell transplantation using unmanipulated haploidentical donors (HIDs), HLA-matched unrelated donors (MUDs), and HLA-matched sibling related donors (MSDs) in acute myeloid leukemia (AML) patients with complete remission (CR) status. With this background, we compared outcomes among 377 cases of CR following consecutive HID-HSCT for AML (CR) to 86 MUD and 92 MSD-HSCT cases. All patients received BU-based myeloablative conditioning and an unmanipulated graft within the same period. The median patient age was 23 years (range 1.1 to 65 years), and 230 patients (41.4%) were under age18. Among the 555 patients, 432 (77.8%) were of intermediate cytogenetic risk and 123 (22.2%) were of adverse risk. A total of 113 patients (20.5%) had FLT3-ITD+ AML, 425 patients (76.6%) were in first complete remission (CR1) post-transplant, and 130 (23.4%) patients were in second CR (CR2). GVHD prophylaxis included mycophenolate mofetil (MMF), cyclosporine-A (CSA) with short-term methotrexate (MTX) for HID, and MUD-HSCT. MMF is not used for MSD-HSCT. The median survival follow-up time was 42 months (range 18-91 months). The 3-year leukemia-free survival (LFS) among the HID, MUD, and MSD cohorts was 73.8% ± 4.8%, 66.4% ± 8.5%, 74.5% ± 2.4%, respectively (P = 0.637). Three-year overall survival (OS) was 74.9% ± 2.4%, 81.8% ± 4.3%, and 77.5% ± 4.5% among the HID, MUD, and MSD cohorts, respectively (P = 0.322). There were no difference among the relapse rate among the HID, MUD, and MSD donor cohorts (14.3% ± 4.0% vs 20.3% ± 6.4% vs 14.5% ± 2.2, respectively; P = 0.851) or the non-relapse mortality (NRM) (12.3% ± 3.5% vs 9.5% ± 3.2% vs 14.0% ± 1.8%, respectively; P = 0.441). Multivariate analyses showed that MRD-positive pre-HSCT was the only risk factor associated with a lower OS and LFS and higher risk of relapse among all 555 patients. Compared with the use of a MUD or MSD, an HID for HSCT had similar outcomes among AML patients with CR states who underwent an allo-HSCT with BU-based myeloablative conditioning. MFC-MRD-positive pre-HSCT was an independent negative factor impact on outcomes for AML patients in CR. We conclude that for AML patients who do not have a MSD or if an urgent transplant is required, HSCT from an HID is a valid option.

Unmanipulated haplo-identical donor transplantation compared with identical sibling donor had better anti-leukemia effect for refractory/relapsed acute myeloid leukemia not in remission status.

Prior studies have suggested that for leukemia patients with high-risk features, haplo-identical-hematopoietic stem cell transplantation (HID-HSCT) has a stronger anti-leukemia effect compared with HSCT using an identical sibling donor (ISD-HSCT). However, it is unclear whether an HID-HSC transplant also augments the graft-versus-leukemia (GVL) effect among refractory/relapsed (R/R) acute myeloid leukemia (AML) patients who are not in remission (NR). We conducted a retrospective analysis of 124 R/R AML patients with NR status who underwent HID-HSCT between April 2012 and December 2016 and compared these to 27 R/R AML patients who underwent an ISD-HSCT within the same timeframe. Among all of the patients, 68 (45.0%) had primary induction failure (PIF) and 83 (54.9%) were relapsed and had failed to respond to at least one cycle of salvage combination chemotherapy. Myeloablative conditioning regimens were administered to all patients. Here, we present a retrospective multivariate analysis of pre-transplantation risk factors and characteristics of all 151 patients and developed a predictive scoring system to predict patient survival. The median period of follow-up was 46 months for all patients. The HID cohort had a higher 5-year overall survival (OS) compared with the ISD cohort (48.6% ± 4.6% vs 25.9% ± 8.4, respectively; P = 0.017) and higher LFS (leukemia-free survival) (41.6% ± 7.5% vs 25.9% ± 8.4%, respectively; P = 0.019). There was no difference in the 5-year cumulative incidence of non-relapse mortality (NRM) (18.0% ± 3.8% and 34.9% ± 12.6%, respectively; P = 0.212) between the two group. However, the 5-year cumulative incidence of relapse (CIRs) was lower in the HID group compared with the ISD group (55.4% ± 8.9% vs 67.3% ± 9.9%, respectively; P = 0.021). Multivariate analysis showed three risk factors associated with OS and LFS: (1) ISD-HSCT, (2) use of a standardized conditioning regimen, and (3) less than 50% proportional reduction of blast cells in the bone marrow (BM). Based on these three risk factors, we developed a predictive scoring system for R/R AML patients undergoing HSCT. Patients who had a predictive score of 0 and 1 had a 66.6% ± 4.5% and 44.1% ± 3.6% OS rate at 5 years, respectively. Patients with a score ≥ 2 had only a 4.4 ± 0.2% OS rate at 5 years. An HID-HSCT had a better anti-leukemia effect among R/R AML patients with an NR status compared with an ISD-HSCT. We also identified pre-transplantation risk factors to delineate subgroups that could derive maximal benefit from HSCT.

Experimental investigation of the time-delay signature of chaotic output and dual-channel physical random bit generation in 1550 nm mutually coupled VCSELs with common FBG filtered feedback.

Here we propose and experimentally demonstrate mutually coupled 1550 nm vertical-cavity surface-emitting lasers (VCSELs), subject to common fiber Bragg grating (FBG) feedback (FMC-VCSELs), to conceal the time-delay signature (TDS) of chaotic outputs. The autocorrelation function and delayed mutual information are used to quantitatively identify the TDS of chaotic output. For comparison, the evolution of the TDS of chaotic output in mutually coupled VCSELs (MC-VCSELs) is also presented. The effects of injection power, frequency detuning between two VCSELs, and frequency detuning between FBG and VCSELs on the TDS concealment are experimentally measured. Experimental results show that FMC-VCSELs have a better TDS suppression performance than MC-VCSELs for varying injection power. In addition, for the FMC-VCSELs system, the TDS can be suppressed to below 0.1 when the VCSELs x-polarization component is located at the edge of the main FBG lobe. Furthermore, dual-channel physical random numbers with verified randomness at a rate of 800 Gbps (2×5LSBs×80GHz) are achieved by utilizing the chaotic outputs with a low TDS from two VCSELs in the FMC-VCSELs system.

Time-delay signature concealment and physical random bits generation in mutually coupled semiconductor lasers with FBG filtered injection.

We propose and demonstrate experimentally the generation of chaos with suppressed time-delay signature (TDS) and physical random bits in two mutually coupled semiconductor lasers (MCSL) by introducing an auxiliary fiber Bragg grating (FBG) filtered injection path. The measurements show that, even by simply adding a single FBG path, the TDS of chaotic signals generated by both lasers in our proposed scheme can be better concealed compared to the conventional MCSL system. Moreover, better TDS concealment can be achieved in the laser with smaller wavelength. Additionally, two random bit streams extracted from the two chaotic lasers in the proposed scheme are achieved with minimal post-processing. The total generation rate reaches 640-Gbps.

Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Achieved Outcomes Comparable With Matched Unrelated Donor Transplantation in Young Acquired Severe Aplastic Anemia.

Salvage haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is considered in patients with severe aplastic anemia (SAA) if a matched unrelated donor (MUD) is unavailable. However, studies on haplo- and MUD transplantation in SAA are lacking. The present study retrospectively analyzed the outcomes of 89 young SAA patients who underwent unmanipulated alternative HSCT between September 2012 and September 2016 at our single center. Forty-one patients received haploidentical donors and forty-eight patients MUDs for HSCT. Most were heavily transfused and refractory to previous immunotherapy. The median durations for myeloid engraftment in the haplo- and MUD cohorts were 14 (range, 10 to 21) and 13 (range, 10 to 18) days, respectively. Compared with the MUD cohort, haplo-HSCT cohorts had an increased cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV (43.9% ± 7.8% versus 12.5% ± 4.8%, P = .001) and grades III to IV (21.1% ± 6.7% versus 6.6% ± 3.7%, P = .045) and similar limited chronic GVHD (47.7% ± 8.5% versus 38.5% ± 7.3%, P = .129) and extensive chronic GVHD (12.1% ± 6.8% versus 9.1% ± 4.3%, P = .198). The median follow-up time of the surviving patients was 26 months (range, 6 to 45). No significant differences were observed between haplo-HSCT and MUD HSCT cohorts in 3-year overall survival (80.3% ± 5.1% versus 89.6% ± 7.0%, P = .210), disease-free survival (76.4% ± 5.1% versus 89.4% ± 7.7%, P = .127), and GVHD-free failure-free survival (79.0% ± 8.6% versus 71.6% ± 9.3%, P = .976). Thus, haplo-HSCT, as salvage therapy, achieved similar outcomes as MUD HSCT in young SAA patients, thereby rendering it as an effective and safe option for SAA.

Exploring the correlation and difference between cerebrospinal fluid in the lateral ventricle and lumbar subarachnoid based on infants with intraventricular hemorrhage treated by the ommaya reservoir.

Objective: To explore the relationship and difference between ventricular and lumbar cerebrospinal fluid(CSF), this study presents equations transforming their measures. By assessing the viability of substituting lumbar puncture, we aim to minimize the associated medical risks and trauma faced by infants with intraventricular hemorrhage(IVH) from anesthesia and lumbar puncture. Methods: We retrospectively analyzed CSF data from 27 infants diagnosed with IVH treated by Ommaya reservoir and lumbar puncture at our center, comprising 35 paired samples. Paired-sample and regression analyses were employed to determine test correlations, differences, and to derive transformation equations for the measurements. Results: Comparative analyses between the CSF from the lateral ventricle and the lumbar vertebrae revealed significant differences in the levels of chloride, glucose, protein, erythrocytes, total cells, and Pandy's test. Specifically:1. Levels of chloride, glucose, protein, and Pandy's test were higher in the lumbar vertebrae.2. Conversely, erythrocyte and total cell counts were higher in the lateral ventricle.There were no significant differences observed for lumbar lactate dehydrogenase(LDH), leukocytes, occult blood, clot, clarity, and color. Nevertheless, significant correlations were identified between various measures, including LDH, glucose, chloride, protein, erythrocyte, leukocyte, total cell count, Pandy's test, occult blood, clot, transparency, and color. Interestingly, the correlation strength and equation fit for each component are inversely proportional to its molecular weight.Notably, well-fitting regression equations were found for LDH, glucose, chloride, protein, leukocytes, erythrocytes, and total cells. Conclusion: In infants with IVH and unobstructed CSF channels, a robust correlation was noted between ventricular CSF sourced via the Ommaya reservoir and lumbar CSF. This correlation tended to be inversely related to molecular weight, with smaller molecular weights showing lesser disparities. Ventricular CSF data could anticipate lumbar CSF trends, and using regression equations with Ommaya-obtained CSF, one can derive approximate values for lumbar CSF.

Novel insights into RB1 in prostate cancer lineage plasticity and drug resistance.

Prostate cancer is the second most common malignancy among men in the world, posing a serious threat to men's health and lives. RB1 is the first human tumor suppressor gene to be described, and it is closely associated with the development, progression, and suppression of a variety of tumors. It was found that the loss of RB1 is an early event in prostate cancer development and is closely related to prostate cancer development, progression and treatment resistance. This paper reviews the current status of research on the relationship between RB1 and prostate cancer from three aspects: RB1 and prostate cell lineage plasticity; biological behavior; and therapeutic resistance. Providing a novel perspective for developing new therapeutic strategies for RB1-loss prostate cancer.

Work stress and changes in heart rate variability among employees after first acute coronary syndrome: a hospital-based longitudinal cohort study.

Background: Work stress is considered as a risk factor for coronary heart disease, but its link with heart rate variability (HRV) among heart attack survivors is unknown yet. The aim of this study was to investigate associations between baseline work stress and the changes of HRV over one-year after onset of acute coronary syndrome (ACS). Methods: Hundred and twenty-two patients with regular paid work before their first ACS episode were recruited into this hospital-based longitudinal cohort study. During hospitalization (baseline), all patients underwent assessments of work stress by job strain (JS) and effort-reward imbalance (ERI) models, and were assigned into low or high groups; simultaneously, sociodemographic and clinical data, as well depression, anxiety, and job burnout, were collected. Patients were followed up 1, 6, and 12 months after discharge, with HRV measurements at baseline and each follow-up point. Generalized estimating equations were used to analyze the effects of baseline work stress on HRV over the following 1 year. Results: After adjusting for baseline characteristics and clinical data, anxiety, depression, and burnout scores, high JS was not associated with any HRV measures during follow-up (all p > 0.10), whereas high ERI was significantly related to slower recovery of 5 frequency domain HRV measures (TP, HF, LF, VLF, and ULF) (all p < 0.001), and marginally associated with one time domain measure (SDNN) (p = 0.069). When mutually adjusting for both work stress models, results of ERI remained nearly unchanged. Conclusion: Work stress in terms of ERI predicted lower HRV during the one-year period after ACS, especially frequency domain measures.

Exploring the mechanism of ShenGui capsule in treating heart failure based on network pharmacology and molecular docking: A review.

ShenGui capsule (SGC), as a herbal compound, has significant effects on the treatment of heart failure (HF), but its mechanism of action is unclear. In this study, we aimed to explore the potential pharmacological targets and mechanisms of SGC in the treatment of HF using network pharmacology and molecular docking approaches. Potential active ingredients of SGC were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform database and screened by pharmacokinetic parameters. Target genes of HF were identified by comparing the toxicogenomics database, GeneCards, and DisGeNET databases. Protein interaction networks and gene-disorder-target networks were constructed using Cytoscape for visual analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes were also performed to identify protein functional annotations and potential target signaling pathways through the DAVID database. CB-DOCK was used for molecular docking to explore the role of IL-1ß with SGC compounds. Sixteen active ingredients in SGC were screened from the traditional Chinese medicine systems pharmacology database and analysis platform, of which 36 target genes intersected with HF target genes. Protein-protein interactions suggested that each target gene was closely related, and interleukin-1ß (IL-1ß) was identified as Hub gene. The network pharmacology analysis suggested that these active ingredients were well correlated with HF. Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that target genes were highly enriched in pathways such as inflammation. Molecular docking results showed that IL-1ß binds tightly to SGC active components. This experiment provides an important research basis for the mechanism of action of SGC in the treatment of HF. In this study, the active compounds of SGC were found to bind IL-1ß for the treatment of heart failure.

Characteristics and literature review of ETV6::ABL1 fusion gene-positive acute myeloid leukemia.

OBJECTIVE: To describe the features of ETV6::ABL1 AML as well as the clinical treatment and outcomes. METHODS: Clinical data were collected from three patients diagnosed with ETV6::ABL1 AML at Hebei Yanda Lu Daopei Hospital and Beijing Lu Daopei Hospital. Their clinical and laboratory features were analyzed, and the treatment process and outcomes were described. Ten reported cases of ETV6::ABL1 AML from the literature were also included for analysis. RESULTS: The median age of the patients was 34 years, and 2 patients were male. No patient had a history of blood disorders before diagnosis. After relapse, they were referred to our hospital, where the ETV6::ABL1 gene was detected. Unfortunately, Patient 1 died rapidly after leukemia relapse due to severe infection. Patients 2 and 3 received salvage therapy with a dasatinib-containing regimen, followed by allo-HSCT, and are currently alive and disease-free. CONCLUSION: ETV6::ABL1 is a rare but recurrent genetic aberration in AML, and the combined use of fluorescence in situ hybridization and PCR can better identify this fusion gene. Patients carrying ETV6::ABL1 have a high relapse rate and a poor prognosis. TKIs are a reasonable treatment option for this group, and allo-HSCT may be curative.

Anisotropic Bi-Layer Hydrogel Actuator with pH-Responsive Color-Changing and Photothermal-Responsive Shape-Changing Bi-Functional Synergy.

Stimuli-responsive color-changing and shape-changing hydrogels are promising intelligent materials for visual detections and bio-inspired actuations, respectively. However, it is still an early stage to integrate the color-changing performance and shape-changing performance together to provide bi-functional synergistic biomimetic devices, which are difficult to design but will greatly expand further applications of intelligent hydrogels. Herein, we present an anisotropic bi-layer hydrogel by combining a pH-responsive rhodamine-B (RhB)-functionalized fluorescent hydrogel layer and a photothermal-responsive shape-changing melanin-added poly (N-isopropylacrylamide) (PNIPAM) hydrogel layer with fluorescent color-changing and shape-changing bi-functional synergy. This bi-layer hydrogel can obtain fast and complex actuations under irradiation with 808 nm near-infrared (NIR) light due to both the melanin-composited PNIPAM hydrogel with high efficiency of photothermal conversion and the anisotropic structure of this bi-hydrogel. Furthermore, the RhB-functionalized fluorescent hydrogel layer can provide rapid pH-responsive fluorescent color change, which can be integrated with NIR-responsive shape change to achieve bi-functional synergy. As a result, this bi-layer hydrogel can be designed using various biomimetic devices, which can show the actuating process in the dark for real-time tracking and even mimetic starfish to synchronously change both the color and shape. This work provides a new bi-layer hydrogel biomimetic actuator with color-changing and shape-changing bi-functional synergy, which will inspire new strategies for other intelligent composite materials and high-level biomimetic devices.

Polyurethane Shape Memory Polymer/pH-Responsive Hydrogel Hybrid for Bi-Function Synergistic Actuations.

Stimuli-responsive actuating hydrogels response to the external stimulus with complex deformation behaviors based on the programmable anisotropic structure design are one of the most important smart soft materials, which have great potential applications in artificial muscles, smart values, and mini-robots. However, the anisotropic structure of one actuating hydrogel can only be programmed one time, which can only provide single actuating performance, and subsequently, has severely limited their further applications. Herein, we have explored a novel SMP/hydrogel hybrid actuator through combining polyurethane shape memory polymer (PU SMP) layer and pH-responsive polyacrylic-acid (PAA) hydrogel layer by a napkin with UV-adhesive. Owing to both the super-hydrophilicity and super-lipophilicity of the cellulose-fiber based napkin, the SMP and the hydrogel can be bonded firmly by the UV-adhesive in the napkin. More importantly, this bilayer hybrid 2D sheet can be programmed by designing a different temporary shape in heat water which can be fixed easily in cool water to achieve various fixed shapes. This hybrid with a fixed temporary shape can achieve complex actuating performance based on the bi-functional synergy of temperature-triggered SMP and pH-responsive hydrogel. The relatively high modulus PU SMP achieved high to 87.19% and 88.92% shape-fixing ratio, respectively, correspond to bending and folding shapes. The hybrid actuator can actuate with the 25.71 °/min actuating speed. Most importantly, one SMP/hydrogel bi-layer hybrid sheet was repeatedly programmed at least nine times in our research to fix various temporary 1D, 2D and 3D shapes, including bending, folding and spiraling shapes. As a result, only one SMP/hydrogel hybrid can provide various complex stimuli-responsive actuations, including the reversable bending-straightening, spiraling-unspiraling. A few of the intelligent devices have been designed to simulate the movement of the natural organisms, such as bio-mimetic "paw", "pangolin" and "octopus". This work has developed a new SMP/hydrogel hybrid with excellent multi-repeatable (≥9 times) programmability for high-level complex actuations, including the 1D to 2D bending and the 2D to 3D spiraling actuations, which also provides a new strategy to design other new soft intelligent materials and systems.

An Anisotropic Hydrogel by Programmable Ionic Crosslinking for Sequential Two-Stage Actuation under Single Stimulus.

As one of the most important anisotropic intelligent materials, bi-layer stimuli-responsive actuating hydrogels have proven their wide potential in soft robots, artificial muscles, biosensors, and drug delivery. However, they can commonly provide a simple one-actuating process under one external stimulus, which severely limits their further application. Herein, we have developed a new anisotropic hydrogel actuator by local ionic crosslinking on the poly(acrylic acid) (PAA) hydrogel layer of the bi-layer hydrogel for sequential two-stage bending under a single stimulus. Under pH = 13, ionic-crosslinked PAA networks undergo shrinking (-COO-/Fe3+ complexation) and swelling (water absorption) processes. As a combination of Fe3+ crosslinked PAA hydrogel (PAA@Fe3+) with non-swelling poly(3-(1-(4-vinylbenzyl)-1H-imidazol-3-ium-3-yl)propane-1-sulfonate) (PZ) hydrogel, the as-prepared PZ-PAA@Fe3+ bi-layer hydrogel exhibits distinct fast and large-amplitude bidirectional bending behavior. Such sequential two-stage actuation, including bending orientation, angle, and velocity, can be controlled by pH, temperature, hydrogel thickness, and Fe3+ concentration. Furthermore, hand-patterning Fe3+ to crosslink with PAA enables us to achieve various complex 2D and 3D shape transformations. Our work provides a new bi-layer hydrogel system that performs sequential two-stage bending without switching external stimuli, which will inspire the design of programmable and versatile hydrogel-based actuators.

Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high-risk AML.

BACKGROUND: Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated. OBJECTIVE: To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML. STUDY DESIGN: From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed. RESULTS: At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52-632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2-36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9-26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5-81.4%) and 3.2% (95%CI, 0.4-22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5-93.6%) and 81.3% (95%CI, 64.2-93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8-26.3%) and 11.7% (95%CI, 3.9-35.0%). CONCLUSION: Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.

Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant.

Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. Methods: A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. Results: The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). Conclusions: Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.

Gut microbiome-based noninvasive diagnostic model to predict acute coronary syndromes.

Background: Previous studies have shown that alterations in the gut microbiota are closely associated with Acute Coronary Syndrome (ACS) development. However, the value of gut microbiota for early diagnosis of ACS remains understudied. Methods: We recruited 66 volunteers, including 29 patients with a first diagnosis of ACS and 37 healthy volunteers during the same period, collected their fecal samples, and sequenced the V4 region of the 16S rRNA gene. Functional prediction of the microbiota was performed using PICRUSt2. Subsequently, we constructed a nomogram and corresponding webpage based on microbial markers to assist in the diagnosis of ACS. The diagnostic performance and usefulness of the model were analyzed using boostrap internal validation, calibration curves, and decision curve analysis (DCA). Results: Compared to that of healthy controls, the diversity and composition of microbial community of patients with ACS was markedly abnormal. Potentially pathogenic genera such as Streptococcus and Acinetobacter were significantly increased in the ACS group, whereas certain SCFA-producing genera such as Blautia and Agathobacter were depleted. In addition, in the correlation analysis with clinical indicators, the microbiota was observed to be associated with the level of inflammation and severity of coronary atherosclerosis. Finally, a diagnostic model for ACS based on gut microbiota and clinical variables was developed with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.963 (95% CI: 0.925-1) and an AUC value of 0.948 (95% CI: 0.549-0.641) for bootstrap internal validation. The calibration curves of the model show good consistency between the actual and predicted probabilities. The DCA showed that the model had a high net clinical benefit for clinical applications. Conclusion: Our study is the first to characterize the composition and function of the gut microbiota in patients with ACS and healthy populations in Southwest China and demonstrates the potential effect of the microbiota as a non-invasive marker for the early diagnosis of ACS.

Production of polyunsaturated fatty acids by Schizochytrium (Aurantiochytrium) spp.

Diverse health benefits are associated with dietary consumption of omega-3 long-chain polyunsaturated fatty acids (ω-3 LC-PUFA), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Traditionally, these fatty acids have been obtained from fish oil, but limited supply, variably quality, and an inability to sustainably increase production for a rapidly growing market, are driving the quest for alternative sources. DHA derived from certain marine protists (heterotrophic thraustochytrids) already has an established history of commercial production for high-value dietary use, but is too expensive for use in aquaculture feeds, a much larger potential market for ω-3 LC-PUFA. Sustainable expansion of aquaculture is prevented by its current dependence on wild-caught fish oil as the source of ω-3 LC-PUFA nutrients required in the diet of aquacultured animals. Although several thraustochytrids have been shown to produce DHA and EPA, there is a particular interest in Schizochytrium spp. (now Aurantiochytrium spp.), as some of the better producers. The need for larger scale production has resulted in development of many strategies for improving productivity and production economics of ω-3 PUFA in Schizochytrium spp. Developments in fermentation technology and metabolic engineering for enhancing LC-PUFA production in Schizochytrium spp. are reviewed.