Deep Learning-Based Quantitative Blastocyst Assessment.

Selecting the single best blastocyst based on morphological appearance for implantation is a crucial part of in vitro fertilization (IVF). Various deep learning and computer vision-based methods have recently been applied for assessing blastocyst quality. However, to the best of our knowledge, most previous works utilize classification networks to give a qualitative evaluation. It would be challenging to rank blastocyst quality with the same qualitative result. Thus, this paper proposes a regression network combined with a soft attention mechanism for quantitatively evaluating blastocyst quality. The network outputs a continuous score to represent blastocyst quality precisely rather than some categories. As to the soft attention mechanism, the attention module in the network outputs an activation map (attention map) localizing the regions of interest (ROI, i.e., inner cell mass (ICM)) of microscopic blastocyst images. The generated activation map guides the entire network to predict ICM quality more accurately. The experimental results demonstrate that the proposed method is superior to traditional classification-based networks. Moreover, the visualized activation map makes the proposed network decision more reliable.

CD7 targeted "off-the-shelf" CAR-T demonstrates robust in vivo expansion and high efficacy in the treatment of patients with relapsed and refractory T cell malignancies.

T-cell acute lymphoblastic leukemia (T-ALL) represents an area of highly unmet medical needs. Once relapsed, patients have limited treatment options and poor prognosis. T-ALL antigens such as CD7 is extensively expressed in normal T cells and natural killer (NK) cells, and extending the success of CAR-T therapy to T cell malignancies was challenged by CAR-T cell fratricide, high production cost, and potential product contaminations. GC027 is an "off-the-shelf" allogeneic CD7 targeted CAR-T therapeutic product for T cell malignancies. It demonstrated superior cell expansion and antileukemia efficacy in mouse xenograft model. In our previous study, we observed promising efficacy results in the first two relapsed and refractory(R/R) T-ALL patients treated with GC027. In the expanded study, 11 out of 12 patients had rapid eradication of T-lymphoblasts and reached complete response within 1-month after GC027 infusion. GC027 cells expanded quickly beginning at infusion and reached to peak around 5-10 days after infusion. For most patients with a response(9/11), GC027 could not be detected via flow cytometry or qPCR 4 weeks after infusion. One patient had progression free survival of >3 years. With manageable toxicity profile, GC027 demonstrated superior clinical efficacy to standard chemotherapy regimens in (R/R) T cell malignancies.

KCa3.1 Promotes Proinflammatory Exosome Secretion by Activating AKT/Rab27a in Atrial Myocytes during Rapid Pacing.

Purpose: The aim of this study was to investigate the role of the medium-conductance calcium-activated potassium channel (KCNN4, KCa3.1) in the secretion of proinflammatory exosomes by atrial myocytes. Methods: Eighteen beagles were randomly divided into the sham group (n = 6), pacing group (n = 6), and pacing+TRAM-34 group (n = 6). Electrophysiological data, such as the effective refractory period, atrial fibrillation (AF) induction, and AF duration, were collected by programmed stimulation. Atrial tissues were subjected to hematoxylin and eosin, Masson's trichrome, and immunofluorescence staining. The expression of KCa3.1 and Rab27a was assessed by immunohistochemistry and western blotting. The downstream signaling pathways involved in KCa3.1 were examined by rapid pacing or overexpressing KCNN4 in HL-1 cells. Results: Atrial rapid pacing significantly induced electrical remodeling, inflammation, fibrosis, and exosome secretion in the canine atrium, while TRAM-34 (KCa3.1 blocker) inhibited these changes. Compared with those in control HL-1 cells, the levels of exosome markers and inflammatory factors were increased in pacing HL-1 cells. Furthermore, the levels of CD68 and iNOS in macrophages incubated with exosomes derived from HL-1 cells were higher in the pacing-exo group than in the control group. More importantly, KCa3.1 regulated exosome secretion through the AKT/Rab27a signaling pathway. Similarly, inhibiting the downstream signaling pathway of KCa3.1 significantly inhibited exosome secretion. Conclusions: KCa3.1 promotes proinflammatory exosome secretion through the AKT/Rab27a signaling pathway. Inhibiting the KCa3.1/AKT/Rab27a signaling pathway reduces myocardial tissue structural remodeling in AF.

Blockade of SK4 channels suppresses atrial fibrillation by attenuating atrial fibrosis in canines with prolonged atrial pacing.

Background: We previously found that intermediate conductance Ca2+-activated K+ channel (SK4) might be an important target in atrial fibrillation (AF). Objective: To investigate the role of SK4 in AF maintenance. Methods: Twenty beagles were randomly assigned to the sham group (n=6), pacing group (n=7), and pacing+TRAM-34 group (n=7). Rapid atrial pacing continued for 7 days in the pacing and TRAM-34 groups. During the pacing, the TRAM-34 group received TRAM-34 intravenous injection (10 mg/Kg) 3 times per day. Atrial fibroblasts isolated from canines were treated with angiotensin II or adenovirus carrying the SK4 gene (Ad-SK4) to overexpress SK4 channels. Results: TRAM-34 treatment significantly suppressed the increased intra-atrial conducting time (CT) and AF duration in canines after rapid atrial pacing (P<0.05). Compared with the sham group, the expression of SK4 in atria was higher in the pacing group, which was associated with an increased number of myofibroblasts and levels of extracellular matrix in atrium (all P<0.05), and this effect was reversed by TRAM-34 treatment (all P<0.05). In atrial fibroblasts, the increased expression of SK4 induced by angiotensin II stimulation or Ad-SK4 transfection contributed to higher levels of P38, ERK1/2 and their downstream factors c-Jun and c-Fos, leading to the increased expression of α-SMA (all P<0.05), and all these increases were markedly reduced by TRAM-34 treatment. Conclusion: SK4 blockade suppressed AF by attenuating cardiac fibroblast activity and atrial fibrosis, which was realized through not only a decrease in fibrogenic factors but also inhibition of fibrotic signaling pathways.

Median nerve stimulation elevates ventricular fibrillation threshold via the cholinergic anti-inflammatory pathway in myocardial infarction canine model.

Background: Median nerve stimulation (MNS) diminishes regional myocardial ischemia and ventricular arrhythmia; however, the underlying mechanism has not been elucidated. Methods: In this study, we randomly categorized 22 adult mongrel dogs into a control group, MNS group 1, and MNS group 2. After a 4-week experimental myocardial infarction (MI), ventricular electrophysiology was measured in the MNS group 1 before and after 30 min of MNS. The same measurements were performed in the MNS group 2 dogs via bilateral vagotomy. Venous blood and ventricular tissue were collected to detect molecular indicators related to inflammation and cholinergic pathways by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and Western blot (WB). Results: No significant changes were reported in the ventricular effective refractory period (ERP) in the MNS group 1 and MNS group 2 dogs before and after MNS. The ventricular fibrillation threshold (VFT) in the MNS group 1 was significantly higher than that in the MNS group 2 (20.3 ± 3.7 V vs. 8.7 ± 2.9 V, P < 0.01). The levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nuclear transcription factor-κB (NF-κB) were lower (P < 0.01), whereas the levels of Ach were higher in the peri-infarct zone tissues in the MNS group 1 dogs than those in the MNS group 2 dogs (P < 0.01). Conclusion: This study demonstrated that MNS increases VFT in a canine model with MI. The effects of MNS on VFT are potentially associated with the cholinergic anti-inflammatory pathway.

Dapagliflozin Protects Methamphetamine-Induced Cardiomyopathy by Alleviating Mitochondrial Damage and Reducing Cardiac Function Decline in a Mouse Model.

Background: Methamphetamine (METH)-induced cardiovascular toxicity has been attributed to its destructive effect on mitochondrial function at least to some extent. Previous studies highlighted the benefits of dapagliflozin (DAPA) on the cardiovascular system, but the response of METH-induced cardiomyopathy to DAPA is never addressed before. The present study aimed to investigate the potential ability of DAPA in preventing METH-induced cardiomyopathy. Materials and Methods: C57BL/6 mice were randomly divided into control group (n = 24), METH group (n = 24), and METH + DAPA group (n = 24). The METH-induced cardiomyopathy group received intraperitoneal METH injections at gradually increasing doses thrice weekly for 14 weeks. Mice in the METH + DAPA group were simultaneously treated with DAPA 1 mg/kg/day by intragastric administration. Echocardiography was performed to assess cardiac function. Reactive oxygen species (ROS), JC-1, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were performed to evaluate oxidative stress, mitochondrial damage, and apoptosis, respectively. Mitochondrial and apoptosis-related protein expression was measured by western blotting. Results: Mice exposed to METH exhibited reduced cardiac function (left ventricular ejection fraction [LVEF]: 56.51 ± 6.49 vs. 73.62 ± 1.42, p < 0.01), fibrotic remodeling, and mitochondrial dysfunction, leading to apoptosis (apoptotic cells%: 7.4 ± 1.3 vs. 1.3 ± 0.5, p < 0.01). DAPA significantly reduced mitochondrial dynamics and function, ROS, apoptosis (apoptotic cells%: 2.4 ± 0.8 vs. 7.4 ± 1.3, p < 0.01), cardiac function decline (LVEF: 70.99 ± 4.936 vs. 56.51 ± 6.49, p < 0.01), and fibrotic remodeling. These results indicated that DAPA could be considered as an effective therapeutic agent in the protection against METH-associated cardiomyopathy. Conclusion: DAPA protects against METH-induced cardiomyopathy in mice by decreasing mitochondrial damage and apoptosis.

Cardiac Fibroblasts Promote Ferroptosis in Atrial Fibrillation by Secreting Exo-miR-23a-3p Targeting SLC7A11.

The exact mechanism of atrial fibrillation (AF) has been not well elucidated. Ferroptosis is an iron-dependent cell death due to excessive accumulation of peroxidized polyunsaturated fatty acids. However, the molecular mechanism underlying AF and ferroptosis has never been reported. Here, we established the rapid pacing model in vivo and vitro to investigate the relationship between AF and ferroptosis. In canine model of rapid atrial pacing, the content of malondialdehyde and total ions in the atrial tissue of the Pacing group was significantly increased and the exosome inhibitor GW4869 reduced ferroptosis, fibrosis, and inflammation and improved histological and electrophysiological remodeling. In rapid pacing h9c2 cells, the expression of antioxidative stress genes associated with ferroptosis presented sequential changes and proteins involved in ferroptosis such as FTH1, SLC7A11, and GPX4 were gradually depleted. Furthermore, pacing cardiac fibroblast-derived exosomes (CF-exos) exacerbated ferroptosis in h9c2 cells and pretreated pacing-CF-exos with GW4869 alleviated injury to h9c2 cells. In mechanism, our results demonstrated that pacing-CF-exos highly expressed miR-23a-3p by informatics analysis and experimental verification. Inhibitor-miR-23a-3p protected h9c2 cells from ferroptosis accompanying with upregulation of SLC7A11. In addition, SLC7A11 was shown to be the target gene of miR-23a-3p. In conclusion, our results suggest that CF-exos-miR-23a-3p may promote ferroptosis. The development of AF in a persistent direction could be prevented by intervening with exosomal miRNAs to reduce oxidative stress injury and ferroptosis.

Blocking Intermediate-Conductance Calcium-Activated Potassium Channels in the Macrophages Around Ganglionated Plexi Suppresses Atrial Fibrillation Vulnerability in Canines With Rapid Atrial Pacing.

Previous studies have indicated that ganglionated plexi (GP) function influences atrial fibrillation (AF) vulnerability, and intermediate-conductance calcium-activated potassium channels (SK4) have a close relationship with cardiomyocyte automaticity and the induction of AF. However, the effects of the SK4 inhibitor on GP function and AF vulnerability are unknown. Eighteen beagles were randomly divided into a control group (n = 6), rapid atrial pacing (RAP) group (n = 6), and triarylmethane-34 (TRAM-34, an SK4 inhibitor) group (n = 6). TRAM-34 (0.3 ml, 15 mmol/L) and saline were locally injected into GPs in the TRAM-34 group dogs and dogs from the other groups, respectively. After that, dogs in the RAP and TRAM-34 groups were subjected to RAP, and the neural activity of anterior right GP (ARGP) and atrial electrophysiology were measured. The levels of inflammatory cytokines and function of macrophages in the ARGP were measured in the three groups. At 10 min after TRAM-34 injection, ARGP activity and atrial electrophysiology did not significantly change. The atrial pacing shortened effective refractory period (ERP) values at all sites and increased the AF vulnerability and ARGP neural activity, while TRAM-34 reversed these changes. The levels of CD68 + cells, induced nitric oxide synthase (iNOS), interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in the ARGP tissues were higher in the RAP group and TRAM-34 group than they were in the control group. Furthermore, the levels of the CD68 + cells, iNOS, and inflammatory cytokines in the ARGP tissues were higher in the pacing group than those in the TRAM-34 group. Based on these results, administration of TRAM-34 into the atrial GP can suppress GP activity and AF vulnerability during atrial pacing. The effects of TRAM-34 might be related to macrophage polarization and the inflammatory response of GP.

Asymmetric [4 + 2] Annulation of Cyclobutenones and Pyrazolone 4,5-Diones: Access to Novel δ-Lactone-Fused Spiropyrazolones.

Although numerous chiral pyrazolones with a six-membered spirocyclic center at the C4 position have been developed, the asymmetric construction of six-membered oxa-spiropyrazolones is still a challenging task in organic synthesis. Herein, we describe the [4 + 2] annulation of cyclobutanones and pyrazoline-4,5-diones for the efficient synthesis of δ-lactone-fused spiropyrazolone derivatives with generally high yields and good enantioselectivities under mild conditions. The successful scale-up synthesis and further transformation of the final product highlight the practicality and reliability of this reaction.

Blockade of Exosome Release Suppresses Atrial Fibrillation by Alleviating Atrial Fibrosis in Canines With Prolonged Atrial Pacing.

Background: Clinical studies have shown that exosomes are associated with atrial fibrillation (AF). However, the roles and underlying mechanisms remain unclear. Hence, this study aimed to investigate the function of exosomes in AF development. Methods: Twenty beagles were randomly divided into the sham group (n = 6), the pacing group (n = 7), and the pacing + GW4869 group (n = 7). The pacing and GW4869 groups underwent rapid atrial pacing (450 beats/min) for 7 days. The GW4869 group received intravenous GW4869 injection (an inhibitor of exosome biogenesis/release, 0.3 mg/kg, once a day) during pacing. Electrophysiological measurements, transmission electron microscopy, nanoparticle tracking analysis, western blotting, RT-PCR, Masson's staining, and immunohistochemistry were performed in this study. Results: Rapid atrial pacing increased the release of plasma and atrial exosomes. GW4869 treatment markedly suppressed AF inducibility and reduced the release of exosomes. After 7 days of pacing, the expression of transforming growth factor-ß1 (TGF-ß1), collagen I/III, and matrix metalloproteinases was enhanced in the atrium, and the levels of microRNA-21-5p (miR-21-5p) were upregulated in both plasma exosomes and the atrium, while the tissue inhibitor of metalloproteinase 3 (TIMP3), a target of miR-21-5p, showed a lower expression in the atrium. The administration of GW4869 abolished these effects. Conclusions: The blockade of exosome release with GW4869 suppressed AF by alleviating atrial fibrosis in a canine model, which was probably related to profibrotic miR-21-5p enriched in exosomes and its downstream TIMP3/TGF-ß1 pathway.

Diagnostic Value of Endotracheal Tube-Aspirate Soluble Triggering Receptor Expressed on Myeloid Cells-1 Concentration for Neonatal Ventilator-Associated Pneumonia.

Background: Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is regarded as a biological marker of infection. We aimed to evaluate the diagnostic value of endotracheal tube (ETT)-sTREM-1 concentration in neonatal ventilator-associated pneumonia (NVAP), to explore the difference of (ETT)-sTREM-1 between preterm and full-term, and to investigate the influence of extrapulmonary infection on (ETT)-sTREM-1 concentration. Methods: In this multicenter, controlled clinical trial of 60 preterm and 33 full-term neonates on mechanical ventilators, we measured concentrations of ETT-aspirate and serum sTREM-1, serum C-reactive protein, and serum procalcitonin, as well as white blood cell count. We initially divided cases into eight groups, based on three categories: preterm of full-term; NVAP or non-NVAP; and extrapulmonary infection present or absent. Groups were compared, and logistic regression analysis and receiver operating characteristic (ROC) analysis was performed to determine diagnostic value. Results: The mean gestational age (± standard deviation) of preterm and full-term neonates was 28.9 ± 2.2 weeks and 39.5 ± 1.7 weeks, respectively, and 32/60 were male. The ETT-aspirate sTREM-1 concentration was higher in NVAP cases than in non-NVAP cases, irrespective of extrapulmonary infection. ROC analysis revealed that ETT-aspirate sTREM-1 concentration had an area under the curve (AUC) of 0.986 and a cutoff value of 228.0 pg/ml (sensitivity, 94.3%; specificity, 96%) in preterm neonates; the same values in full-term neonates were 0.938 and 245.5 pg/ml (sensitivity, 100%; specificity, 93.7%), respectively. The optimal combination of indicators was ETT-aspirate sTREM-1 and serum C-reactive protein concentration. All indicators were present at lower levels on days 8 and 10 of ventilation in neonates who ultimately recovered than in those who did not. Conclusions: ETT-aspirate sTREM-1 and serum C-reactive protein concentrations may be useful for the diagnosis of NVAP.

Inhibition of KCa3.1 Channels Suppresses Atrial Fibrillation via the Attenuation of Macrophage Pro-inflammatory Polarization in a Canine Model With Prolonged Rapid Atrial Pacing.

Aims: To investigate the role of KCa3. 1 inhibition in macrophage pro-inflammatory polarization and vulnerability to atrial fibrillation (AF) in a canine model with prolonged rapid atrial pacing. Materials and Methods: Twenty beagle dogs (weighing 8-10 kg) were randomly assigned to a sham group (n = 6), pacing group (n = 7) and pacing+TRAM-34 group (n = 7). An experimental model of AF was established by rapid pacing. TRAM-34 was administered to the Pacing+TRAM-34 group by slow intravenous injection (10 mg/kg), 3 times each day. After 7 days of pacing, the electrophysiology was measured in vivo. The levels of interleukin-1ß (IL-1ß), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), CD68, c-Fos, p38, and NF-κB p65 in both atriums were measured by Western blotting, and the levels of inducible nitric oxide synthase (iNOS) and arginase1 (Arg-1) were measured by real-time PCR. Macrophage and KCa3.1 in macrophage in the atrium were quantized following double labeled immunofluorescent. Results: Greater inducibility of AF, an extended duration of AF and lower atrial effective refractory period (AERP) were observed in the pacing group compared with those in the sham group. Both CD68-labeled macrophage and the expression of KCa3.1 in macrophage were elevated in the pacing group and inhibited by TRAM-34, led to higher iNOS expression, lower Arg-1 expression, elevated levels of IL-1ß, MCP-1, and TNF-α in the atria, which could be reversed by TRAM-34 treatment (all P < 0.01). KCa3.1 channels were possibly activated via the p38/AP-1/NF-κB signaling pathway. Conclusions: Inhibition of KCa3.1 suppresses vulnerability to AF by attenuating macrophage pro-inflammatory polarization and inflammatory cytokine secretion in a canine model with prolonged rapid atrial pacing.

The Role of α7nAChR-Mediated Cholinergic Anti-Inflammatory Pathway in Vagal Nerve Regulated Atrial Fibrillation.

The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.

Left Stellate Ganglion Ablation Inhibits Ventricular Arrhythmias through Macrophage Regulation in Canines with Acute Ischemic Stroke.

AIMS: To investigate the potential mechanism of ventricular arrhythmias (VAs) after acute ischemic stroke and explore the effects of left stellate gangling (LSG) ablation on VAs induced by stroke in canines. Materials and Methods: Twenty canines were randomly divided into the sham-operated group (n=6), AS group (n=7) and SGA group (n=7). Cerebral ischemic model was established in the AS group and the SGA group by right acute middle cerebral artery occlusion (MCAO). LSG ablation was performed in the SGA group as soon as MCAO. After 3 days, atrial electrophysiology and neural activity were measured in vivo. The levels of norepinephrine (NE) in plasma and ventricle were detected by ELISA. The levels of monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and NF-κB p65 in ventricle were detected by western blotting. The pro-inflammatory polarization of macrophages in ventricle was detected by immunofluorescence. Results: Higher ventricular tachycardia (VT) inducibility and lower ventricular fibrillation threshold (VFT) were observed in the AS group compared with those in the sham-operated group, associated with higher LSG activity and NE levels, increased number of M1 macrophages and secretion of inflammatory cytokines in ventricle (all P<0.001). Compared with the AS group, the SGA group had lower VT inducibility and higher VFT, combined with lower NE levels, and reduced number of M1 macrophages and secretion of inflammatory cytokines in ventricle (all P<0.001). Conclusion: LSG ablation could reduce VAs vulnerability after acute stroke by preventing the macrophages polarization and activation induced by sympathetic hyperactivity.

Role of intermediate-conductance calcium-activated potassium channels in atrial fibrillation in canines with rapid atrial pacing.

PURPOSE: The aim of the present study was to explore the role of intermediate-conductance Ca2+-activated K+ (SK4) in atrial fibrillation (AF) inducibility in canines with rapid atrial pacing. METHODS: Eighteen dogs were divided into the control group, the pacing group and the stellate ganglion ablation (SGA) + pacing group. In the pacing group, dogs were subjected to rapid atrial pacing, and the atrial effective refractory period (AERP) and AF inducibility were measured. After cessation of 7-h pacing, SK4 inhibitor (TRAM-34) was administered. After SGA, the SGA + pacing group received the same procedure of pacing and electrophysiological measurement as the pacing group. The expression of SK4 was measured in the left atrium (LA) and the right atrium (RA) in the three groups. RESULTS: The duration of the AERP decreased, while the number of AF episodes, the duration of induced AF, and the amplitude of stellate ganglion neural activity all increased after rapid atrial pacing. TRAM-34 completely inhibited AF induction in the pacing group. There was no significant difference in AERP shortening or AF vulnerability between the SGA + pacing group and the control group. The expression of SK4 in the LA and RA was higher in the pacing group than in the control and SGA + pacing groups. However, there was no significant difference in the expression of SK4 in the LA or the RA between the SGA + pacing group and the control group. CONCLUSION: The higher expression of SK4 plays an important role in AF induction and the increased expression of SK4 in the atrium is related to SG activity during rapid atrial pacing.

Eradication of T-ALL Cells by CD7-targeted Universal CAR-T Cells and Initial Test of Ruxolitinib-based CRS Management.

PURPOSE: Although chimeric antigen receptor T-cell (CAR-T) therapy development for B-cell malignancies has made significant progress in the last decade, broadening the success to treating T-cell acute lymphoblastic leukemia (T-ALL) has been limited. We conducted two clinical trials to verify the safety and efficacy of GC027, an "off-the-shelf" allogeneic CAR-T product targeting T-cell antigen, CD7. Here, we report 2 patients as case reports with relapsed/refractory T-ALL who were treated with GC027. PATIENTS AND METHODS: Both the trials reported here were open-label and single-arm. A single infusion of GC027 was given to each patient after preconditioning therapy. RESULT: Robust expansion of CAR-T cells along with rapid eradication of CD7+ T lymphoblasts were observed in the peripheral blood, bone marrow, and cerebrospinal fluid. Both patients achieved complete remission with no detectable minimal residual disease. At data cutoff, 30 September 2020, 1 of the 2 patients remains in ongoing remission for over 1 year after CAR T-cell infusion. Grade 3 cytokine release syndrome (CRS) occurred in both patients and was managed by a novel approach with a ruxolitinib-based CRS management. Ruxolitinib showed promising activity in a preclinical study conducted at our center. No graft-versus-host disease was observed. CONCLUSIONS: The two case reports demonstrate that a standalone therapy with this novel CD7-targeted "off-the-shelf" allogeneic CAR-T therapy may provide deep and durable responses in select patients with relapsed/refractory T-ALL. GC027 might have a potential to be a promising new approach for treating refractory/relapsed T-ALL. Further studies are warranted.

Subterahertz Momentum Drag and Violation of Matthiessen's Rule in an Ultraclean Ferromagnetic SrRuO_{3} Metallic Thin Film.

SrRuO_{3}, a ferromagnet with an approximately 160 K Curie temperature, exhibits a T^{2}-dependent dc resistivity below ≈30 K. Nevertheless, previous optical studies in the infrared and terahertz range show non-Drude dynamics at low temperatures, which seem to contradict Fermi-liquid predictions. In this work, we measure the low-frequency THz range response of thin films with residual resistivity ratios, ρ_{300K}/ρ_{4K}≈74. At temperatures below 30 K, we find both a sharp zero frequency mode which has a width narrower than k_{B}T/ℏ as well as a broader zero frequency Lorentzian that has at least an order of magnitude larger scattering. Both features have temperature dependences consistent with a Fermi liquid with the wider feature explicitly showing a T^{2} scaling. Above 30 K, there is a crossover to a regime described by a single Drude peak that we believe arises from strong interband electron-electron scattering. Such two channel Drude transport sheds light on reports of the violation of Matthiessen's rule and extreme sensitivity to disorder in metallic ruthenates.

A Large Effective Phonon Magnetic Moment in a Dirac Semimetal.

We investigated the magnetoterahertz response of the Dirac semimetal Cd3As2 and observed a particularly low frequency optical phonon as well as a very prominent and field-sensitive cyclotron resonance. As the cyclotron frequency is tuned with the field to pass through the phonon, the phonon becomes circularly polarized, as shown by a notable splitting in its response to right- and left-hand polarized light. This splitting can be expressed as an effective phonon magnetic moment that is approximately 2.7 times the Bohr magneton, which is almost 4 orders of magnitude larger than ab initio calculations predict for phonon magnetic moments in nonmagnetic insulators. This exceedingly large value is due to the coupling of the phonons to the cyclotron motion and is controlled directly by the electron-phonon coupling constant. This field-tunable circular-polarization-selective coupling provides new functionality for nonlinear optics to create light-induced topological phases in Dirac semimetals.

SK4 calcium-activated potassium channels activated by sympathetic nerves enhances atrial fibrillation vulnerability in a canine model of acute stroke.

BACKGROUND: New-onset atrial fibrillation (AF) is common in patients with acute stroke (AS). Studies have shown that intermediate-conductance calcium-activated potassium channel channels (SK4) play an important role in cardiomyocyte automaticity. The aim of this study was to investigate the effects of SK4 on AF vulnerability in dogs with AS. EXPERIMENTAL: Eighteen dogs were randomly divided into a control group, AS group and left stellate ganglion ablation (LSGA) group. In the control group, dogs received craniotomy without right middle cerebral artery occlusion (MCAO). AS dogs were established using a cerebral ischemic model with right MCAO. LSGA dogs underwent MCAO, and LSGA was performed. RESULTS: Three days later, the dispersion of the effective refractory period (dERP) and AF vulnerability in the AS group were significantly increased compared with those in the control group and LSGA group. However, no significant difference in dERP and AF vulnerability was found between the control group and the LSGA group. The SK4 inhibitor (TRAM-34) completely inhibited the inducibility of AF in AS dogs. SK4 expression and levels of noradrenaline (NE), ß1-AR, p38 and c-Fos in the atrium were higher in the AS dogs than in the control group or LSGA group. However, no significant difference in SK4 expression or levels of NE, ß1-AR, p38 and c-Fos in the left atrium was observed between the control group and LSGA group. CONCLUSION: SK4 plays a key role in AF vulnerability in a canine model with AS. The effects of LSGA on AF vulnerability were associated with the p38 signaling pathways.

A brain-stellate ganglion-atrium network regulates atrial fibrillation vulnerability through macrophages in acute stroke.

AIMS: New-onset atrial fibrillation (AF) is frequently observed following acute stroke. The aim of this study was to investigate the effects of the brain-stellate ganglion-atrium network on AF vulnerability in a canine model with acute middle cerebral artery occlusion (MCAO). MATERIALS AND METHODS: Twenty-six dogs were randomly divided into the sham-operated group (n = 6), acute stroke (AS) group (n = 7), stellate ganglion ablation (SGA) group (n = 6) and clodronate liposome (CL) group (n = 7). In the sham-operated group, dogs received craniotomy without MCAO. Cerebral ischemic model was established in AS dogs by right MCAO. Right MCAO along with SGA and CL injection into the atrium was performed in SGA and CL dogs, respectively. After 3 days, atrial electrophysiology, neural activity, and the phenotype and function of macrophages in the atrium were studied in all the dogs. KEY FINDINGS: Higher AF inducibility (24.4 ±â€¯4.4% versus 4.4 ±â€¯2.2%, P < 0.05) and AF duration (15.7 ±â€¯3.8 s versus 2.6 ±â€¯1.1 s, P < 0.05) were observed in the AS group compared with the sham-operated group, and were associated with increased left stellate ganglion activity, higher macrophage infiltration and higher levels of inflammatory cytokines in the atrium. SGA or CL injection sharply suppressed AF inducibility (5.5 ±â€¯2.7% versus 24.4 ±â€¯4.4%; 5.3 ±â€¯3.2% versus 24.4 ±â€¯4.4%, both P < 0.05) and AF duration (2.9 ±â€¯1.2 s versus 15.7 ±â€¯3.8 s; 3.6 ±â€¯1.0 s versus 15.7 ±â€¯3.8 s, both P < 0.05) in canines with acute stroke. SIGNIFICANCE: A brain-stellate ganglion-atrium network may increase AF vulnerability through macrophage activation after acute stroke.