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.

Over 18% Efficiency Ternary Organic Solar Cells with 300 nm Thick Active Layer Enabled by an Oligomeric Acceptor.

The development of high-efficiency thickness-insensitive organic solar cells (OSCs) is crucially important for the mass production of solar panels. However, increasing the active layer thickness usually induces a substantial loss in efficiency. Herein, a ternary strategy in which an oligomer DY-TF is incorporated into PM6:L8-BO system as a guest component is adopted to break this dilemma. The S···F intramolecular noncovalent interactions in the backbone endow DY-TF with a high planarity. Upon the addition of DY-TF, the crystallinity of the blend is effectively improved, leading to increased charge carrier mobility, which is highly desirable in the fabrication of thick-film devices. As a result, thin-film PM6:L8-BO:DY-TF-based device (110 nm) shows a power conversion efficiency (PCE) of 19.13%. Impressively, when the active layer thickness increases to 300 nm, an efficiency of 18.23% (certified as 17.8%) is achieved, representing the highest efficiency reported for 300 nm thick OSCs thus far. Additionally, blade-coated thick device (300 nm) delivers a promising PCE of 17.38%. This work brings new insights into the construction of efficient OSCs with high thickness tolerance, showing great potential for roll-to-roll printing of large-area solar cells.

Theoretical Study of the Photocyclization Reaction-Induced Dual Aggregation-Induced Emission Phenomenon.

Photochromic molecules with aggregation-induced emission (AIE) effects are of great value and prospective in various practical applications. To explore its inherent mechanism, the open isomer ap-BBTE and the closed isomer c-BBTE were chosen to perform the theoretical calculation using the quantum mechanics/molecular mechanics model combined with thermal vibration correlation function formalism. The calculations show that the photocyclization (PC) reaction from ap-BBTE to c-BBTE facilitates an improvement in the AIE effect. It is found that the fluorescence quantum yield (ΦF) enhancement of ap-BBTE is attributed to the restriction of the low-frequency rotational motion of the benzothiophene moiety and the high-frequency stretching vibrations of the C-C bond between the benzothiophene and benzylbis(thiadiazole) vinyl groups after aggregation. For c-BBTE, the increase in ΦF upon aggregation is mainly due to the suppression of the high-frequency stretching vibration of the C-C bond between the benzothiophene and the benzobis(thiadiazole) vinyl groups. In addition, the AIE effect was also enhanced from ap-BBTE to c-BBTE, which is consistent with the experimental phenomenon. The corresponding emission spectrum red-shifted from ap-BBTE to c-BBTE in both dilute solution and the crystalline state due to the improved intramolecular conjugation of c-BBTE. Moreover, the PC reaction from ap-BBTE to c-BBTE easily occurs in an excited state with a low energy barrier transition state by forming a C-C bond between benzothiophene groups effectively in dilute solution. Our calculations provide theoretical guidance for the further rational design of efficient AIE luminogens.

Analysis of 60 patients with relapsed or refractory T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma treated with CD7-targeted chimeric antigen receptor-T cell therapy.

While the use of chimeric antigen receptor-T (CAR-T) therapy for T-cell malignancies is in the early stage of clinical trials, it exhibits substantial potential to offer long-term remission for patients with refractory/relapsed (R/R) T-cell malignancies. In our phase I/II clinical trials, 65 pediatric and adult patients with R/R T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (T-ALL/LBL) were enrolled (NCT04572308 and NCT04916860). Of these, 60 participants (T-ALL 35, T-LBL 25) received a single dose of naturally selected anti-CD7 CAR (NS7CAR) T cells at three levels: a low dose (5 × 105 /kg), a medium dose (1 to 1.5 × 106 /kg), and a high dose (2 × 106 /kg). On day 28, 94.4% of patients achieved deep complete remission (CR) in bone marrow. Among the 32 patients with extramedullary disease, 78.1% showed response, with 56.3% in CR and 21.9% in partial remission. The 2-year overall survival and progression-free survival (PFS) were 63.5% (95% CI 47.7-79.4) and 53.7% (95% CI, 38.9-68.6), with no difference between pediatric and adult patients. PFS was significantly higher among the 37 CR patients who proceeded with consolidation transplant than the 10 patients who did not with 1-year PFS 67.2% (95% CI 51.9-82.4) versus 15.0% (95% CI 0-40.2), p < .0001. Of the 10 CR patients without transplants, eight relapsed, while two sustained CR on day 128, and day 180, respectively. Cytokine release syndrome occurred in 91.7% of patients (grade 1/2 in 80.0%, grade 3/4 in 11.7%) and 5% of patients had neurotoxicity. NS7CAR-T therapy is effective in treating R/R T-ALL/LBL patients with promising PFS while maintaining a manageable safety profile.

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.

Diazulenorubicene as a Non-benzenoid Isomer of peri-Tetracene with Two Sets of 5/7/5 Membered Rings Showing Good Semiconducting Properties.

Non-benzenoid polycyclic aromatic hydrocarbons (PAHs) have received a lot of attention because of their unique optical, electronic, and magnetic properties, but their synthesis remains challenging. Herein, we report a non-benzenoid isomer of peri-tetracene, diazulenorubicene (DAR), with two sets of 5/7/5 membered rings synthesized by a (3+2) annulation reaction. Compared with the precursor containing only 5/7 membered rings, the newly formed five membered rings switch the aromaticity of the original heptagon/pentagon from antiaromatic/aromatic to non-aromatic/antiaromatic respectively, modify the intermolecular packing modes, and lower the LUMO levels. Notably, compound 2 b (DAR-TMS) shows p-type semiconducting properties with a hole mobility up to 1.27 cm2  V-1 s-1 . Moreover, further extension to larger non-benzenoid PAHs with 19 rings was achieved through on-surface chemistry from the DAR derivative with one alkynyl group.

Elucidation of the key role of isomerization in the self-assembly and luminescence properties of AIEgens.

Due to the hierarchical nature of the self-assembly process, it is effective to control assembled nanostructures by tuning the spatial configurations of the building blocks through Z-/E-isomerization. A pair of AIE stereoisomers termed (Z)-/(E)-TPE-UPy was reported with different self-assembly mechanisms, morphologies and luminescence properties. In this study, we present a multiscale modeling combining MD simulations, hybrid QM/MM calculations and the PCM model, to systematically clarify the molecular configuration-molecular assembly-photophysical property relationship of (Z)-/(E)-TPE-UPy. Our study shows that (Z)-TPE-UPy follows a concentration-dependent ring-chain polymerization mechanism. At low concentration, (Z)-TPE-UPy tends to form ring-like (Z)-close-dimers with all H-bond sites occupied, while at high concentration, the H-bond backbone in the chain-like structures is more planar and stronger, making the zig-zag chain-like conformations more favorable. For the (E)-isomer, the H-bond backbone is quite planar and rigid, which makes it linearly elongate one-by-one at the whole range of concentrations via the isodesmic polymerization mechanism. (Z)-TPE-UPy oligomers exhibit large flexibility and diverse conformations, leading to sharply enhanced viscosity at high concentration in experiments. Moreover, the fluorescence spectrum of (Z)-/(E)-TPE-UPy aggregate is conformation-dependent and the enhanced emission in the aggregated state is attributed to the restriction of the low-frequency intramolecular rotations of the phenyl rings and the distortion of the CC plane, as well as the reduction of electron-vibration couplings. Our work not only offers valuable insights into the key role of stereoisomerism in assembled morphologies and luminescence properties, but also provides a theoretical basis for the rational design of new building blocks based on stereoisomers.

Midterm comparison of laparoscopic high uterosacral ligament suspension and sacrocolpopexy in the treatment of moderate to severe apical prolapse.

INTRODUCTION AND HYPOTHESIS: The objective was to retrospectively analyze the midterm efficacy of laparoscopic high uterosacral ligament suspension (HUS) and sacrocolpopexy (SC) in the treatment of moderate to severe apical prolapse. METHODS: Patients who underwent laparoscopic HUS and SC in our center from 2013 to 2019 with follow-ups were included, consisting of laparoscopic HUS (group A, n=72) or SC (mesh added, group B, n=54). The general data of patients, pelvic organ prolapse quantitative examination (POP-Q) score, Pelvic Floor Distress Inventory short form 20 score (PFDI-20) before and after operation, perioperative conditions, Patient Global Impression of Improvement (PGI-I), and postoperative complications were collected for statistical analysis and comparison between groups. RESULTS: There was no statistical difference in preoperative data between groups. The median follow-up time was 48 months. The objective recurrence rate of group A was higher than that of group B, without statistical significance. One patient in group B had a second operation owing to recurrence. The exposure rate of mesh in group B was 3.70%. There was no significant difference in deviation of POP-Q and PFDI-20 pre- and post-operation. The proportion of new defecation abnormalities in group A was lower. The total hospitalization expenses and surgical consumables in group B were significantly higher than those in group A. CONCLUSIONS: The midterm curative effect of laparoscopic HUS is similar to that of SC in the treatment of moderate to severe apical prolapse. The former has the advantages of less intraoperative blood loss, shorter postoperative hospital stay, lower cost, fewer new defecation abnormalities, and there were no complications related to mesh.

An improved semantic segmentation model based on SVM for marine oil spill detection using SAR image.

In the oil industry, oil spills occur due to offshore rig explosions, ship collisions, and other reasons. It is crucial to accurately and rapidly identify oil spills to protect marine ecosystems. Synthetic aperture radar (SAR) can all-weather and all-time work and provide a wealth of polarization information for identification of oil spills based on semantic segmentation model. However, the performance of classifiers in the semantic segmentation model has become a significant challenge to improving recognition ability. To solve this problem, an improved semantic segmentation model named DRSNet was proposed, which uses ResNet-50 as the backbone in DeepLabv3+ and support vector machines (SVM) as the classifier. The experiment was conducted using ten polarimetric features from SAR images and results demonstrate that the DRSNet performs best compared to other semantic segmentation models. Current work provides a valuable tool to enhance maritime emergency management capabilities.

Comparison of the anterior pelvis and levator ani muscle on MRI in women with and without anterior pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: The objective was to compare the differences in pelvic and levator ani muscle diameters in women with and without anterior pelvic organ prolapse. METHODS: Three groups were included, including 50 nulliparous women (nulliparous group), 50 women with stage III-IV anterior vaginal prolapse (prolapse group), and 50 women of the same age as the prolapse group but without prolapse (nonprolapse control group). The ischial interspinous diameter (ISD), anterior pelvic area (APA), levator defect score (LDS), levator ani hiatus width (LH-W), H-line, M-line, levator ani plate length, levator ani plate angle, and cervix length (CL) were measured. RESULTS: There were no significant differences in ISD (10.6±0.8 vs 10.6±0.9 cm), LH-W (3.0±0.4 vs 3.3±0.4 cm), or CL (2.9±0.6 vs 3.0±0.5 cm) between the nulliparous group and the nonprolapse control group (p>0.05). However, there were significant differences between them and the prolapsed group (11.2±0.6 cm, 3.6±0.4 cm, 4.2±1.5 cm; p<0.05). There were no significant differences in LDS (0.70±0.61 vs 0.70±0.65) or APA (58.4±8.4 vs 60.1±7.4 cm2) between the nonprolapse control group and the prolapse group (p>0.05), but they were significantly different from those of the nulliparous group (0.08±0.34, 55.1±6.0 cm2) (p<0.05). The area under the receiver-operating characteristic curve for the ISD of nonprolapse control and prolapse groups was 0.713, and the cutoff value was 10.95 cm. CONCLUSIONS: The levator ani hiatus width and cervix length were larger in patients with anterior vaginal prolapse than in those without prolapse. An ischial ISD greater than 10.95 cm was associated with prolapse.

Clinical observation of 2 patients and a literature review of pregnancy outcome after uterine-sparing apical suspension for pelvic organ prolapse.

OBJECTIVE: To observe pregnancy postoperatively and long-term follow-up after uterine-sparing apical suspension for pelvic organ prolapsed (POP). STUDY DESIGN: We report 2 patients who delivered newborns after uterine-sparing apical suspension for pelvic organ prolapse at our center and a literature review on this topic. RESULTS: The patients' ages were 26 and 32 years at their respective times of surgery. The follow-up times were 7 and 8 years. These patients became pregnant at 52 and 46 months after surgery, and delivered by cesarean section at term. There was no re-prolapse at follow-ups of 15 and 10 months postpartum. The results were consistent with those reported in the literature. CONCLUSION: Patients with POP who have reproductive requirements can benefit from surgical treatment, and this benefit is maintained after cesarean section. SYNOPSIS: Observation of 2 patients who delivered newborns after uterine-sparing apical suspension for pelvic organ prolapsed at our center and a literature review.

Long-term retrospective study of retinoic acid combined with arsenic and chemotherapy for acute promyelocytic leukemia.

Chemotherapy, all-trans retinoic acid (ATRA), and arsenic are effective options for acute promyelocytic leukemia (APL). We conducted a 20-year retrospective analysis of newly diagnosed (ND) APL patients treated with arsenic, ATRA and mitoxantrone. After achieving complete remission (CR), patients received 3-5 cycles of chemotherapy followed by AS4S4 maintenance for 3 years. Eighty-eight ND APL patients were treated with either oral AS4S4 (n = 42) or arsenic trioxide (ATO) (n = 46). The 8-year overall survival (OS) rate was 100% in the AS4S4 group and 90% in the ATO group. The disease-free survival (DFS) rates were 100% and 87.1% (p = 0.027), respectively. Patients in the ATO group had more side effects. A subsequent cohort of 33 ND APL patients received triple therapy with oral AS4S4, ATRA, and chemotherapy. The 13-year OS and DFS rates were 100% and 90.9%. Our long-term analyses show that APL patients with oral AS4S4 had better outcomes compared to ATO, with no need for hospitalization.

Outcome of a novel porcine-derived UBM/SIS composite biological mesh in a rabbit vaginal defect model.

INTRODUCTION AND HYPOTHESIS: To investigate the tissue reactions of a novel porcine-derived urinary bladder matrix/small intestinal submucosa (UBM/SIS) biological mesh and SIS mesh implanted in a rabbit vaginal defect model. METHODS: Thirty-two rabbits were implanted with UBM/SIS mesh (Group A) and SIS mesh (Group B), respectively. Rabbits were sacrificed at 7, 14, 60, and 180 days after implantation. The tensile strength, elongation at break, and elastic modulus of the tissue were measured using biomechanical methods. The inflammatory response, cell infiltration, vascularization, and collagen fibers were observed. RESULTS: Compared with Group B, the tensile strength and elongation at break of group A was higher at 14, 60, and 180 days. The elastic modulus of group A was lower at 180 days. Inflammatory response of group A was milder at 14, 60, and 180 days. There was more cell infiltration in group A at 7 and 14 days. Vascularization was higher in group A at 7 days and 14 days. The order of collagen in group A was better at 14, 60, and 180 days. The proportion of thick red fibers in both groups showed an increasing trend. At 14 days, group A had more thick red fibers. CONCLUSIONS: The novel UBM/SIS composite mesh had a milder inflammatory response; earlier induction of cell infiltration, angiogenesis, and collagen regeneration. Collagen fibers had a better order. It has a higher tensile strength and greater elongation at break, and can be used as a potential material for the treatment of pelvic organ prolapse.

Safety and Efficacy of Humanized Versus Murinized CD19 and CD22 CAR T-Cell Cocktail Therapy for Refractory/Relapsed B-Cell Lymphoma.

CD19 chimeric antigen receptor T-cell (CAR-T) therapy is efficacious for refractory/relapsed (R/R) B-cell hematological malignancies, yet relapse due to CD19 antigen escape remains a challenge. Our trial explored simultaneous targeting of multiple B-cell antigens as a therapeutic approach that may reduce the risk of relapse. We tested the safety and efficacy of CAR19/22 T-cell cocktail therapy including murinized and humanized products among patients with R/R aggressive B-cell lymphoma. In the group that received the humanized product, 11/12 (91.7%) patients achieved an objective response, including 9/12 (75%) complete responses (CRs) by day 28. The overall response rate and CR rate in the murinized group was 92.9% (13/14) and 42.9% (6/14), respectively. Nine of 12 (75%) patients in the humanized group maintained CR at month 3 following infusion, compared to 5/14 patients (35.7%) in the murinized group. Progression-free survival (PFS) was more favorable in the humanized compared to the murinized group. Most patients had mild cytokine release syndrome (CRS) (grade 1-2) in both groups. This study demonstrates that CAR19/22 T-cell cocktail therapy is safe and effective for R/R B-cell lymphoma and that patients treated with a humanized CAR-T exhibited better efficacy compared to patients treated with a murinized CAR-T therapy.

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma.

BACKGROUND: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study developed C-CAR088, a novel second-generation humanized anti-BCMA CAR T-cell therapy, and assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM. METHODS: Patients received lymphodepletion with three doses of cyclophosphamide (300 mg/m2) and three doses of fludarabine (30 mg/m2) on days -5, -4, and -3, followed by an infusion of C-CAR088 on day 0. Doses of 1.0×106, 3.0×106, and 6.0×106 CAR T cells/kg (±20%) were tested in the dose-escalation cohorts and expansion cohorts. The primary endpoint was treatment safety, including the rate of treatment-emergent adverse events after cell infusion. Secondary endpoints were the overall response rate and progression-free survival. The exploratory endpoints were the quantification of C-CAR088 CAR T cells, selection of cytokines and chemokines in blood, and measurement of tumor BCMA expression. RESULTS: As of July 2, 2021, 31 patients had been infused with C-CAR088. Any grade cytokine release syndrome (CRS) occurred in 29 patients (93.5%), and grade 3 CRS occurred in 3 patients (9.7%). One patient from the high-dose group (4.5-6.0×106 CAR T cells/kg) developed grade 1 neurotoxicity. No dose-limiting toxicities were observed in any dose group, and all adverse events were reversible after proper management. The overall response, stringent complete response, complete response (CR), and very good partial response rates were 96.4%, 46.4%, 10.7%, and 32.1%, respectively. The CR rate in the medium-dose (3.0×106 CAR T cells/kg) and high-dose (4.5-6.0×106 CAR T cells/kg) groups was 54.5% and 71.4%, respectively. In the CR group, 15 (93.7%) patients achieved minimal residual disease (MRD) negativity (test sensitivity >1/10-5). All seven patients with double-hit or triple-hit multiple myeloma achieved MRD-negative CR. CONCLUSIONS: The present study demonstrated that C-CAR088 had a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM. TRIAL REGISTRATION NUMBER: NCT03815383, NCT03751293, NCT04295018, and NCT04322292.

Long-Term Safety and Efficacy of CD19 Humanized Selective CAR-T Therapy in B-ALL Patients Who Have Previously Received Murine-Based CD19 CAR-T Therapy.

Murine-based CD19 CAR-T (CD19m CAR-T) therapy can lead to a relatively high CR rate when administered to B-ALL patients for the first time. However, the DOR is sub-optimal and a subset of patients even show primary resistance to CD19m CAR-T. To address these issues, we employed a humanized selective CD19CAR-T (CD19hs CAR-T) and evaluated the long-term safety and efficacy of treating 8 R/R B-ALL patients who had relapsed or failed to achieve CR following CD19m CAR-T infusion (Clinical trials' number: ChiCTR1800014761 and ChiCTR1800017439). Of the 8 patients, 7 achieved CR on Day 30 after the 1st infusion of CD19hs CAR-T. The median CRS grade was 1 without significant neurotoxicity seen in any of the 8 patients. The median DOR was 11 months, significantly longer than the DOR following CD19mCAR-T infusions. Anti-CAR antibodies were induced in patients who had received prior CD19m CAR-T infusions but not in those following a single or repeated CD19hsCAR-T treatment, which probably had contributed to the sub-optimal DOR and/or failure of effective response in these patients. CD19hs CAR-T, in contrast, induced low immunogenicity compared with CD19m CAR-T, suggesting that a repeat dosing strategy might be feasible and efficacious for patients who have relapsed and/or show primary resistance to CD19m CAR-T therapy. In this clinical study, CD19hs CAR-T showed a significant clinical efficacy with mild side effect among patients with R/R B-ALL who had previously received CD19m CAR-T. Clinical Trial Registration: https://www.chictr.org.cn/showprojen.aspx?proj=25199 (ChiCTR1800014761). https://www.chictr.org.cn/showproj.aspx?proj=29174 (ChiCTR1800017439).

Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study.

To improve clinical outcomes and shorten the vein-to-vein time of chimeric antigen receptor T (CAR-T) cells, we developed the FasT CAR-T (F-CAR-T) next-day manufacturing platform. We report the preclinical and first-in-human clinical studies evaluating the safety, feasibility, and preliminary efficacy of CD19 F-CAR-T in B-cell acute lymphoblastic leukemia (B-ALL). CD19 F-CAR-T cells demonstrated excellent proliferation with a younger cellular phenotype, less exhaustion, and more effective tumor elimination compared to conventional CAR-T cells in the preclinical study. In our phase I study (NCT03825718), F-CAR-T cells were successfully manufactured and infused in all of the 25 enrolled pediatric and adult patients with B-ALL. CD19 F-CAR-T safety profile was manageable with 24% grade 3 cytokine release syndrome (CRS) and 28% grade 3/4 neurotoxicity occurring predominantly in pediatric patients. On day 14, 23/25 patients achieved minimal residual disease (MRD)-negative complete remission (CR), and 20 subsequently underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 3 months post F-CAR-T therapy. Fifteen of 20 patients were disease-free with a median remission duration of 734 days. One patient relapsed and 4/20 died from transplant-related mortality. Of the three patients who did not undergo allo-HSCT, two remained in CR until 10 months post-F-CAR-T. Our data indicate that anti-CD19 FasT CAR-T shows promising early efficacy for B-ALL. Further evaluations in larger clinical studies are needed.

Analysis of the Effect of Sichs on Gastric Ulcer Rats Based on RNA Sequencing Technique.

Objective: To research the mechanism of action and transcriptomic characteristics for the intervention effect of self-made Chaihuang decoction (Sichs) on gastric ulcer (GU) rats with liver qi stagnation and spleen deficiency and to clarify the therapeutic pathway and effective target. Methods: Thirty SD rats were randomly divided into the control group, model group, and Sichs group (10 rats per group). The model of GU rats with liver qi stagnation and spleen deficiency was established through multifactor compound simulation of traditional Chinese medical (TCM) etiology and acetic acid method. Histopathological changes in the gastric antrum tissue were observed with H&E staining. RNA sequencing (RNA-seq) was utilized to check differentially expressed genes (DEGs) in the gastric antrum tissues of rats, and gene ontology (GO) and KEGG pathway enrichment analyses were performed. The key DEGs were validated using qRT-PCR. Results: Sichs could ameliorate gastric antrum tissue injury in GU rats with liver qi stagnation and spleen deficiency. After RNA-seq, it was found that Sichs could reverse 225 upregulated genes and 26 downregulated genes in the model group. And the DEGs between the Sichs group and the model group were related to cell division, complement activation, and phospholipase A2 (Pla2g2a) activity. According to KEGG pathway analysis, DEGs between the two groups were mainly enriched in signaling pathways such as cell cycle, p53 signaling pathway, and linolenic acid metabolism. The validation results of the four key DEGs were consistent with the analysis trend of sequencing results. Conclusion: Sichs can effectively improve GU with liver qi stagnation and spleen deficiency in rats through the signaling pathways related to cell cycle and lipid metabolism.