Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study.

BACKGROUND: Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. METHODS: This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. FINDINGS: Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. INTERPRETATION: This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. FUNDING: The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Long-term follow-up of donor-derived CD7 CAR T-cell therapy in patients with T-cell acute lymphoblastic leukemia.

BACKGROUND: Donor-derived CD7-directed chimeric antigen receptor (CAR) T cells showed feasibility and early efficacy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL), in a previous phase I trial report, at a median follow-up of 6.3 months. Here we report long-term safety and activity of the therapy after a 2-year follow-up. METHODS: Participants received CD7-directed CAR T cells derived from prior stem cell transplantation (SCT) donors or from HLA-matched new donors after lymphodepletion. The target dose was 1 × 106 (± 30%) CAR T cells per kg of patient weight. The primary endpoint was safety with efficacy secondary. This report focuses on the long-term follow-up and discusses them in the context of previously reported early outcomes. RESULTS: Twenty participants were enrolled and received infusion with CD7 CAR T cells. After a median follow-up time of 27.0 (range, 24.0-29.3) months, the overall response rate and complete response rate were 95% (19/20 patients) and 85% (17/20 patients), respectively, and 35% (7/20) of patients proceeded to SCT. Six patients experienced disease relapse with a median time-to-relapse of 6 (range, 4.0-10.9) months, and 4 of these 6 patients were found to have lost CD7 expression on tumor cells. Progression-free survival (PFS) and overall survival (OS) rates 24 months after treatment were respectively 36.8% (95% CI, 13.8-59.8%) and 42.3% (95% CI, 18.8-65.8%), with median PFS and OS of respectively 11.0 (95% CI, 6.7-12.5) months and 18.3 (95% CI, 12.5-20.8) months. Previously reported short-term adverse events (< 30 days after treatment) included grade 3-4 cytokine release syndrome (CRS; 10%) and grade 1-2 graft-versus-host disease (GVHD; 60%). Serious adverse events reported > 30 days after treatment included five infections and one grade 4 intestinal GVHD. Despite good CD7 CAR T-cell persistence, non-CAR T and natural killer cells were predominantly CD7-negative and eventually returned to normal levels in about half of the participants. CONCLUSIONS: In this 2-year follow-up analysis, donor-derived CD7 CAR T-cell treatment demonstrated durable efficacy in a subset of patients with r/r T-ALL. Disease relapse was the main cause of treatment failure, and severe infection was a noteworthy late-onset adverse event. TRIAL REGISTRATION: ChiCTR2000034762.

The Efficacy and Safety of Single-Incision Mini-Slings for Stress Urinary Incontinence: A Network Meta-Analysis.

PURPOSE: To evaluate the efficacy and safety of single-incision mini-sling for stress urinary incontinence based on network Meta-analysis. MATERIALS AND METHODS: We searched PubMed, Embase, and Cochrane libraries from August 2008 to August 2019. Randomized controlled trials comparing two or more indicators of Miniarc (Single Incision Mini-slings), Ajust (Adjustable Single-Incision Sling), C-NDL (Contasure-Needleless), TFS (Tissue Fixation System), Ophria (Transobturator Vaginal Tap), TVT-O (Transobturator Vaginal Tape), and TOT (Trans-obturatortape) in treating female stress urinary incontinence were collected. RESULTS: Totally, 3,428 patients from 21 studies were included. Ajust had the highest subjective cure rate (Rank=0.52), while Ophira had the worst (Rank=0.67). TFS had the highest objective cure rate, and the worst was found in Ophira. TFS required the shortest operating time (Rank=0.40), while TVT-O required the longest operating time (Rank=0.47). Miniarc had the least bleeding (Rank=0.47), while TVT-O had the most bleeding (Rank=0.37). C-NDL had the shortest postoperative hospital stay (Rank=0.77), while Ajust had the longest postoperative hospital stay (Rank=0.36). For postoperative complications, TFS performed best in groin pain (Rank=0.84), urinary retention (Rank=0.78), and repeat surgery (Rank=0.45). TVT-O performed worst in groin pain (Rank=0.36), and urinary retention (Rank=0.58). Miniarc had the highest repeat surgery rate (Rank=0.35). Ajust had the lowest probability of tap erosion (Rank=0.30), while Ophira had the highest tap erosion level (Rank=0.45). Miniarc showed the greatest advantage in urinary tract infections (Rank=0.84) and de novo urgency (Rank=0.60), while C-NDL had the highest incidence of urethral infections (Rank=0.51). Ophira performed worst in de novo urgency (Rank=0.60). C-NDL performed the best in sexual intercourse pain (Rank=0.79) while Ajust was the worst (Rank=0.49). CONCLUSIONS: In view of comprehensive efficacy and safety, we recommend that TFS or Ajust should be selected first for single-incision sling and the application of Ophria should be minimized.

Single-Cell Transcriptomics Reveals Immune Reconstitution in Patients with R/R T-ALL/LBL Treated with Donor-Derived CD7 CAR-T Therapy.

PURPOSE: CD7 chimeric antigen receptor T (CAR-T) therapy has potent antitumor activity against relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), however, immune reconstitution after CAR-T remains largely unknown. PATIENTS AND METHODS: An open-label phase I clinical trial (ChiCTR2200058969) was initiated to evaluate safety and efficacy of donor-derived CD7 CAR-T cells in 7 R/R T-ALL/LBL patients. CAR-T cells were detected by flow cytometry and PCR. Cytokine levels were quantified by cytometric bead arrays. Single-cell RNA sequencing (scRNA-seq) was adopted to profile immune reconstitution. RESULTS: Optimal complete remission (CR) was 100% on day 28, and median followed-up time was 4 months. Leukopenia, thrombocytopenia, and neutropenia were observed in 6 patients, and infections occurred in 5 patients. Two patients died of serious infection and one died of a brain hemorrhage. CAR-T cells expanded efficiently in all patients. CD7+ T cells were eliminated in peripheral blood on day 11 after infusion, and CD7- T cells dramatically expanded in all patients. scRNA-seq suggested that immunologic activities of CD7- T cells were stronger than those of T cells before infusion due to higher expression levels of T-cell function-related pathways, and major characters of such CD7- T cells were activation of autoimmune-related pathways. Monocyte loss was found in 2 patients who died of serious infections, indicating the main cause of the infections after infusion. S100A8 and S100A9 were identified as potential relapse markers due to their notable upregulation in leukocyte lineage in relapsed patients versus non-relapse controls. CONCLUSIONS: Our data revealed cellular level dynamics of immune homeostasis of CD7 CAR-T therapy, which is valuable for optimizing the treatment of R/R T-ALL/LBL.

The removal of floating right heart thrombi and pulmonary embolus using AngioJet device and venoarterial extracorporeal membrane oxygenation: a case report.

Background: Floating right heart thrombi (FRHTS), known as thrombi in transit, are usually located in the atrium or ventricle. Generally, it occurs in patients with pulmonary embolism (PE) and dyspnea, chest pain, syncope and palpitations are the most common symptoms on presentation. The mortality of patients with FRHTS is higher than that of those without FRHTS. Current treatment includes anticoagulation, systemic thrombolysis, catheter directed interventions, and surgical embolectomy. However, there is no consensus on the optimal management options. Case Description: Herein, we report the case of a patient who presented with hypotension and tachycardia accompanied by an asymptomatic right leg deep vein thrombosis, right atrial thrombus, and pulmonary embolus. He had a history of radical resection of colon cancer 1 month prior. And he had developed chest tightness accompanied by stabbing pain in the chest area 1 day ago. He experienced an episode of syncope 8.5 hours ago. So he was referred to the local hospital. After the pulmonary computed tomography angiography (CTA) scan, he was diagnosed with pulmonary embolus and administrated with 5,000 u low molecular weight heparin. Then he was transferred to our hospital. On arrival in the emergency department, the bedside transthoracic echocardiography (TTE) revealed there was an enlarged right atrium and right ventricle, with a floating right atrial mass prolapsing through the tricuspid valve during diastole. The patient accepted anticoagulation treatment, but refused to undergo thrombolysis or surgical embolectomy. Eventually, the right heart thrombi (RiHT) floated to the left main branch of pulmonary artery. It was successfully treated by using AngioJet device and venoarterial extracorporeal membrane oxygenation (VA-ECMO). Our case provides clinical evidence supporting the feasibility and efficacy of AngioJet device and VA-ECMO in the treatment of the RiHT and PE. Conclusions: Patients with PE combined with RiHT have higher mortality than those without RiHT, VA-ECMO could be used to maintain the circulation, and the AngioJet device could be used as an alternative treatment for patients who are reluctant to receive thrombolysis or surgical embolectomy.

Donor-Derived CD7 Chimeric Antigen Receptor T Cells for T-Cell Acute Lymphoblastic Leukemia: First-in-Human, Phase I Trial.

PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL. METHODS: In this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105 or 1 × 106 (±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary. RESULTS: Twenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range, 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency. CONCLUSION: Among 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress (NCT04689659).

Evolution of the Shear Band in Cold-Rolling of Strip-Cast Fe-1.3% Si Non-Oriented Silicon Steel.

Cube texture and microstructural evolution of as-cast non-oriented silicon steel (1.3% Si) during cold rolling and annealing were studied. The results showed that the as-cast microstructure with grain size in the range of 100-500 µm had a weak texture. The strong orientation was mainly located at {100} and {110} planes. A significant content of shear-deformed grains oriented with {110}<110> were obtained by cold-rolling, and many regions oriented with Cube texture were distributed in the shear bands. During cold-rolling, the orientation of the shear-deformed microstructure tilted towards the {111}<112> orientation, while the matrix orientation retained {110}<110>. On further cold-rolling, the residual part of {110}<110> experienced shear deformation, forming more shear bands, strengthening the Cube orientation. During annealing, Cube orientation grains nucleated in the shear bands leading to strong Cube texture, and corresponding B50 was 1.83T/1.79T.

A novel molecular-clinicopathologic nomogram to improve prognosis prediction of hepatocellular carcinoma.

BACKGROUND: Emerging evidence suggests that long non-coding RNA (lncRNA) plays a crucial part in the development and progress of hepatocellular carcinoma (HCC). The objective was to develop novel molecular-clinicopathological prediction methods for overall survival (OS) and recurrence of HCC. RESULTS: An 8-lncRNA-based classifier for OS and a 14-lncRNA-based classifier for recurrence were developed by LASSO COX regression analysis, both of which had high accuracy. The tdROC of OS-nomogram and recurrence-nomogram indicates the satisfactory accuracy and predictive power. The classifiers and nomograms for predicting OS and recurrence of HCC were validated in the Test and GEO cohorts. CONCLUSIONS: These two lncRNA-based classifiers could be independent prognostic factors for OS and recurrence. The molecule-clinicopathological nomograms based on the classifiers could increase the prognostic value. METHODS: HCC lncRNA expression profiles from the cancer genome atlas (TCGA) were randomly divided into 1:1 training and test cohorts. Based on least absolute shrinkage and selection operator method (LASSO) COX regression model, lncRNA-based classifiers were established to predict OS and recurrence, respectively. OS-nomogram and recurrence-nomogram were developed by combining lncRNA-based classifiers and clinicopathological characterization to predict OS and recurrence, respectively. The prognostic value was accessed by the time-dependent receiver operating characteristic (tdROC) and the concordance index (C-index).

The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury.

Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.

KRT17 Functions as a Tumor Promoter and Regulates Proliferation, Migration and Invasion in Pancreatic Cancer via mTOR/S6k1 Pathway.

BACKGROUND: Pancreatic cancer (PC) is one of the most well-known malignancies with high mortality, but the underlying mechanism of PC remains unknown. Keratin17 (KRT17) expression has been reported in many malignancies, but its functions in PC are not clear. The aim of our study was to evaluate KRT17 expression and its potential role in PC. METHODS: The online databases GEPIA and THPA were used to identify KRT17 expression in tissues. Quantitative real-time PCR (qRT-PCR) was used to determine KRT17 expression in cell lines. Ki67 and ROS levels were detected by immunofluorescence assay and a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. KRT17 downregulation was induced by the small interfering RNA (siRNA) technique. Proliferation function was evaluated by colony formation assay and RTCA. Migration and invasion were evaluated by transwell migration assay. A Western blot assay was used to detect protein levels. RESULTS: KRT17 was overexpressed in PC tissues compared to that in normal tissues. The results showed that Ki67 and ROS levels were decreased in pancreatic cancer cells after transfection with siKRT17. After KRT17 downregulation in PC cell lines, cell viability functions, including proliferation, migration and invasion, and mTOR/S6K1 phosphorylation levels were attenuated. CONCLUSION: KRT17 knockdown significantly inhibited proliferation, migration and invasion in pancreatic cancer cells.

Thermalization and possible signatures of quantum chaos in complex crystalline materials.

Analyses of thermal diffusivity data on complex insulators and on strongly correlated electron systems hosted in similar complex crystal structures suggest that quantum chaos is a good description for thermalization processes in these systems, particularly in the high-temperature regime where the many phonon bands and their interactions dominate the thermal transport. Here we observe that for these systems diffusive thermal transport is controlled by a universal Planckian timescale [Formula: see text] and a unique velocity [Formula: see text] Specifically, [Formula: see text] for complex insulators, and [Formula: see text] in the presence of strongly correlated itinerant electrons ([Formula: see text] and [Formula: see text] are the phonon and electron velocities, respectively). For the complex correlated electron systems we further show that charge diffusivity, while also reaching the Planckian relaxation bound, is largely dominated by the Fermi velocity of the electrons, hence suggesting that it is only the thermal (energy) diffusivity that describes chaos diffusivity.

Identification of NPAC as a novel biomarker and regulator for hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) has a high morbidity and mortality around the world, yet the effective therapeutic option for HCC is still limited. NPAC, also known as glyoxylate reductase 1 homolog, is a new nuclear protein recently implicated in tumor biology. However, the role of NPAC in HCC remains unclear. The present study aimed to evaluate the clinical significance and potential role of NPAC in HCC. METHODS: The NPAC expression in HCC tissues and matched adjacent normal tissues was detected by real-time polymerase chain reaction, immunohistochemistry (IHC), and Western blot analysis. The clinical significance of the expression of NPAC in HCC was assessed by the Kaplan-Meier survival curve and the Cox regression model. In addition, we established a doxiline-induced overexpression of the NPAC system. The effects of NPAC on HCC cell proliferation, migration, and apoptosis were checked by CCK-8 proliferation assays, transwell, and flow cytometry, respectively. RESULTS: The NPAC expression was significantly downregulated in HCC tissues and HCC cell lines. NPAC reduction was significantly correlated with poorer survival among patients with HCC, and the multivariate analysis confirmed its independent prognostic value. Furthermore, overexpression of NPAC dramatically suppressed the proliferation of HCC cells and promoted HCC cells apoptosis. Besides, the levels of phosphorylation of janus kinase 2 (JAK2) and signal transduction and activator 3 (STAT3) were significantly reduced after overexpression of NPAC in HCC cell lines. CONCLUSIONS: These results suggest that NPAC may play an important role in the development and progression of HCC, and can act as a novel potential prognostic biomarker and therapeutic target for HCC.

LipoxinA4 attenuates acute pancreatitis-associated acute lung injury by regulating AQP-5 and MMP-9 expression, anti-apoptosis and PKC/SSeCKS-mediated F-actin activation.

An essential component of acute pancreatitis(AP)-induced acute lung injury(ALI) is the inflammation that is part of the body's systemic inflammatory response to a variety of systemic stimuli. Lipoxins(LXs) are considered important endogenous lipids that mediate the resolution of inflammation. In previous studies, we found that Lipoxin A4 (LXA4) reduced AP-induced pulmonary oedema and TNF-α production in lung. However, the underlying mechanism remains unclear. Due to the above studies, we investigated the aquaporin, matrix metalloprotein, apoptosis and PKC/SSeCKS signal pathway in cellular and animal models of AP-associated lung injury following LXA4 intervention. In this study, we first proved LXA4 could effectively promote F-actin reconstruction and regulate its expression in pulmonary microvascular endothelial cells both in vivo and vitro via suppressing PKC/SSeCKS signalling pathway. Next, we found that LXA4 attenuated cell growth inhibition and apoptosis in lung tissues of AP-ALI mice and HPMECs. Additionally, we demonstrated that LXA4 could regulate the expression of AQP-5 and MMP-9 to stabilize the permeability of pulmonary microvascular endothelial cell. In summary, our results suggest that the anti-inflammatory eff ;ects of LXA4 may be due to the inhibition of both the PKC/SSeCKS pathway and apoptosis to reduce alveolar fluid exudation and to the regulation of AQP-5 and MMP-9 expression to maintain the clearance of alveolar fluid. Thus, LXA4 is capable of exerting protective eff ;ects on AP-induced ALI.

Anomalous thermal diffusivity in underdoped YBa2Cu3O6+x.

The thermal diffusivity in the [Formula: see text] plane of underdoped YBCO crystals is measured by means of a local optical technique in the temperature range of 25-300 K. The phase delay between a point heat source and a set of detection points around it allows for high-resolution measurement of the thermal diffusivity and its in-plane anisotropy. Although the magnitude of the diffusivity may suggest that it originates from phonons, its anisotropy is comparable with reported values of the electrical resistivity anisotropy. Furthermore, the anisotropy drops sharply below the charge order transition, again similar to the electrical resistivity anisotropy. Both of these observations suggest that the thermal diffusivity has pronounced electronic as well as phononic character. At the same time, the small electrical and thermal conductivities at high temperatures imply that neither well-defined electron nor phonon quasiparticles are present in this material. We interpret our results through a strongly interacting incoherent electron-phonon "soup" picture characterized by a diffusion constant [Formula: see text], where [Formula: see text] is the soup velocity, and scattering of both electrons and phonons saturates a quantum thermal relaxation time [Formula: see text].