The incidence of cytokine release syndrome and neurotoxicity of CD19 chimeric antigen receptor-T cell therapy in the patient with acute lymphoblastic leukemia and lymphoma.

Our objective was to summarize the side effect of chimeric antigen receptor (CAR)-T cell therapy in patients with acute lymphocytic leukemia (ALL) and lymphoma. Two independent reviewers extracted relevant data. A total of 35 hematologic malignancy studies with CD19 CAR-T cell were included (1412 participants). Severe cytokine release syndrome (sCRS) proportion was experienced by 18.5% (95% confidence interval [CI], 0.128-0.259; P = 0.000) of 982 patients with the National Cancer Institute/Lee/common terminology criteria for adverse events grading system. The pooled neurotoxicity proportion was 21.7% (95% CI, 0.167-0.287; P = 0.000) of 747 patients with the same grading system. For all of the 25 clinical trials with the same grading system, subgroup analysis was performed. Based on the different disease type, a pooled prevalence of 35.7% was observed with event rate (ER) of 0.358 (95% CI, 0.289-0.434; P = 0.000) for ALL in 12 clinical trials. For lymphoma, a pooled prevalence of 13% was observed with ER of 0.073 (95% CI, 0.028-0.179; P = 0.000) in eight clinical trials. It was demonstrated that the patients who were older than 18 years of age have the lower sCRS incidence of 16.1% (95% CI, 0.110-0.250; P = 0.000) compared with 28.6% of the remaining population who were younger than 18 years of age (95% CI, 0.117-0.462: P = 0.023) in our analysis. Based on the different co-stimulatory domain, the sCRS of 16.5% was observed with ER of 0.175 (95% CI, 0.090-0.312; P = 0.000) for 4-1BB. The sCRS of 22.2% was observed with ER of 0.193 (95% CI, 0.107-0.322; P = 0.000) for CD28. For both the CD28 and 4-1BB, the sCRS of 17.3% was observed with ER of 0.170 (95% CI, 0.067-0.369; P = 0.003). Sub-analysis sCRS of the impact with cell dose and specific disease indication were also demonstrated. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. These results are helpful for physicians, patients and the other stakeholders to understand the adverse events and to further promote the improvement of CAR-T cell therapy in the future.

The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies.

Immunotherapy with chimeric antigen receptor T (CAR-T) cells has proved remarkably effective in recently published clinical trials. In this meta-analysis, we performed a systematic review in terms of the clinical response treated with CAR-T cells in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and lymphomas patients. Thirty-eight published clinical studies including 665 patients were eligible for response rate (RR) evaluation. The overall pooled RR of CD19-CAR-T cells was 72% (95% confidence interval: 62-77%). The various clinical parameters were analyzed. RR was 81% in ALL, 68% in lymphoma and 70% in CLL. RR in patients who received interleukin (IL)-2 was 70%, whereas in those who did not receive IL-2, it was 74%. RR was 75% with lymphodepletion and 56% without lymphodepletion. RR with autologous cells was 76% and 57% with allogeneic cells. In conclusion, this meta-analysis showed a high clinical RR of CD19-CAR-T cell-based immunotherapy in patients with refractory B-cell malignancies.

Nondestructive and high-resolution monitoring of inflammation-type skull defects regeneration on adult zebrafish with optical coherence tomography.

Optimized animal models and effective imaging techniques are exceedingly important to study cranial defects in bone loss due to chronic inflammation. In this study, the assessment procedure on a zebrafish inflammation-type skull defects model was monitored in vivo with spectral-domain optical coherence tomography (SD-OCT), and the efficacy of etidronate disodium in bone regeneration was assessed. An acute skull defect injury model was established in adult zebrafish using a stereotaxic craniotomy device. SD-OCT imaging was performed immediately following the mechanical injury. Both SD-OCT and immunohistochemistry results demonstrated an increase in inflammation-induced skull destruction within 5 days, which was confirmed by pathological experiments.

Visualizing the early-stage testicular torsion by dual-modal photoacoustic and ultrasound imaging.

Delayed treatment of testicular torsion (TT) can lead to permanent loss of reproductive capacity. Photoacoustic imaging (PAI) and ultrasound imaging (USI) was tested for detecting TT at early stage in mice based on PAI-obtained oxygen saturation (sO2), and USI-collected color pixel density (CPD), peak systolic velocity (PSV) and resistance index (RI). For complete TT, both CPD (9.08 % ± 3.084 to almost zero) and sO2 data (70.09 % ± 1.656-59.84 % ± 1.427) showed an significant change 2 h post-torsion. For incomplete TT, sO2 data exhibited a strong time relationship (Mean values: 6 h, 64.83 % ± 1.898; 12 h, 60.67 % ± 3.555; 24 h, 57.85 % ± 3.575; P < 0.05). However, USI-collected CPD, PSV or IR data from the same TT models showed no significant difference. This study indicated that USI and PAI could identify complete TT. Meanwhile, PAI has shown great potential in the diagnosis of incomplete TT within 24 h based on time-related sO2 map.

High Contrast Detection of Carotid Neothrombus with Strong Near-Infrared Absorption Selenium Nanosphere Enhanced Photoacoustic Imaging.

Background: Carotid artery thrombosis is the leading cause of stroke. Since there are no apparent symptoms in the early stages of carotid atherosclerosis onset, it causes a more significant clinical diagnosis. Photoacoustic (PA) imaging provides high contrast and good depth information, which has been used for the early detection and diagnosis of many diseases. Methods: We investigated thrombus formation by using 20% ferric chloride (FeCl3) in the carotid arteries of KM mice for the thrombosis model. The near-infrared selenium/polypyrrole (Se@PPy) nanomaterials are easy to synthesize and have excellent optical absorption in vivo, which can be used as PA contrast agents to obtain thrombosis information. Results: In vitro experiments showed that Se@PPy nanocomposites have fulfilling PA ability in the 700 nm to 900 nm wavelength range. In the carotid atherosclerosis model, maximum PA signal enhancement up to 3.44, 4.04, and 5.07 times was observed by injection of Se@PPy nanomaterials, which helped to diagnose the severity of carotid atherosclerosis. Conclusion: The superior PA signal of Se@PPy nanomaterials can identify the extent of atherosclerotic carotid lesions, demonstrating the feasibility of PA imaging technology in diagnosing carotid thrombosis lesion formation. This study demonstrates nanocomposites and PA techniques for imaging and diagnosing carotid thrombosis in vivo.

A Flexible Wearable Supernumerary Robotic Limb for Chronic Stroke Patients.

In this study, we present a flexible wearable supernumerary robotic limb that helps chronic stroke patients with finger rehabilitation and grasping movements. The design of this innovative limb draws inspiration from bending pneumatic muscles and the unique characteristics of an elephant's trunk tip. It places a strong emphasis on crucial factors such as lightweight construction, safety, compliance, waterproofing, and achieving a high output-to-weight/pressure ratio. The proposed structure enables the robotic limb to perform both envelope and fingertip grasping. Human-robot interaction is facilitated through a flexible bending sensor, detecting the wearer's finger movements and connecting them to motion control via a threshold segmentation method. Additionally, the system is portable for versatile daily use. To validate the effectiveness of this innovation, real-world experiments involving six chronic stroke patients and three healthy volunteers were conducted. The feedback received through questionnaires indicates that the designed mechanism holds immense promise in assisting chronic stroke patients with their daily grasping activities, potentially improving their quality of life and rehabilitation outcomes.

In vivo real-time assessment of developmental defects in enamel of anti-Act1 mice using optical coherence tomography.

The purpose of this study was to explore the feasibility of using optical coherence tomography (OCT) for real-time and quantitative monitoring of enamel development in gene-edited enamel defect mice. NF-κB activator 1, known as Act1, is associated with many inflammatory diseases. The antisense oligonucleotide of Act1 was inserted after the CD68 gene promoter, which would cover the start region of the Act1 gene and inhibit its transcription. Anti-Act1 mice, gene-edited mice, were successfully constructed and demonstrated amelogenesis imperfecta by scanning electron microscope (SEM) and energy dispersive X-ray (EDX) spectroscopy. Wild-type (WT) mice were used as the control group in this study. WT mice and anti-Act1 mice at 3 weeks old were examined by OCT every week and killed at eight weeks old. Their mandibular bones were dissected and examined by OCT, micro-computed tomography (micro-CT), and SEM. OCT images showed that the outer layer of enamel of anti-Act1 mice was obviously thinner than that of WT mice but no difference in total thickness. When assessing enamel thickness, there was a significant normal linear correlation between these methods. OCT could scan the imperfect developed enamel noninvasively and quickly, providing images of the enamel layers of mouse incisors.

Study on promoting regeneration of zebrafish skull by phycocyanin characterized by in vivo optical coherence tomography.

In this study, the efficacy of phycocyanin in bone defect repairing was tested on a zebrafish skull defect model, and the evaluating process was monitored in vivo using optical coherence tomography (OCT). Thirty zebrafish were randomly divided into three groups, which were immersed in water and phycocyanin solution (50 and 100 mg/L) after skull defect creating. All zebrafish were examined by OCT immediately after craniotomy, and on the 10th and 20th days of phycocyanin treatment. All the model fish were euthanized to enable a histological evaluation of skull after 20 days of recovery. OCT images demonstrated that phycocyanin (50 mg/L) could repair a cranial defect within 20 days. A high concentration (100 mg/L) of phycocyanin may favor the recovery of bone abnormalities in 10 days, but with the extended treatment time to 20 days, a deformation of the skull occurs.

Au nanobipyramids with Pt decoration enveloped in TiO2 nanoboxes for photocatalytic reactions.

Noble metal nanocrystals and core-shell nanocomposites have attracted particular interest due to their unique optical properties originating from surface plasmon resonance (SPR) and wide applications related to the SPR effect. In this work, we designed and fabricated a new Au-Pt@TiO2 nanocomposite, in which Au nanobipyramids (AuNBPs) decorated with platinum (Pt) clusters were enveloped in mesoporous TiO2 nanoboxes with nanocavities. AuNBPs provide strong SPR absorption and localized field enhancement restricted to the cavities of TiO2 nanoboxes. The Pt nanoclusters decorated on the surface of AuNBPs can effectively modulate the charge movement and energy transfer in the photocatalytic process. The enhanced electric field provides a local thermal effect for the photocatalytic reaction and promotes the injection process of hot electrons which facilitates carrier separation. The nanoboxes with nanocavities can effectively manage the usage of localized energy and provide space for reaction. Under the cooperative effects, the photocatalytic performance was remarkably improved along with durability and stability. For the AuNBP-Pt@TiO2 nanoboxes, the rhodamine-B degradation efficiency was ∼6.5 times that of AuNBP@TiO2 nanoboxes. The mechanism of the photocatalysis process was proposed based on experimental results and simulations. Benefiting from the excellent structure and properties, the obtained nanostructure is a promising candidate in the fields of pollutant degradation and chemical reaction catalysis.

Photoacoustic imaging as a highly efficient and precise imaging strategy for the evaluation of brain diseases.

Photoacoustic imaging (PAI) is an emerging imaging strategy with a unique combination of rich optical contrasts, high ultrasound spatial resolution, and deep penetration depth without ionizing radiation. Taking advantage of the features mentioned above, PAI has been widely applied to preclinical studies in diverse fields, such as vascular biology, cardiology, neurology, ophthalmology, dermatology, gastroenterology, and oncology. Among various biomedical applications, photoacoustic brain imaging has great importance due to the brain's complex anatomy and the variability of brain disease. In this review, we aimed to introduce a novel and effective imaging modality for diagnosing brain diseases. Firstly, a brief overview of two major types of PAI system was provided. Then, PAI's major preclinical applications in brain diseases were introduced, including early diagnosis of brain tumors, subtle changes in the chemotherapy response, epileptic activity and brain injury, foreign body, and brain plaque. Finally, a perspective of the remaining challenges of PAI was given for future advancements.

Real-Time Monitoring and Quantitative Evaluation of Resin In-Filtrant Repairing Enamel White Spot Lesions Based on Optical Coherence Tomography.

The aim of the present study was to explore the feasibility of real-time monitoring and quantitative guiding the repair of enamel white spot lesions (WSLs) with resin infiltration by optical coherence tomography (OCT). Seven New Zealand rabbits were treated with 37% phosphoric acid etchant for 15 min to establish the model of enamel demineralization chalk spots of upper incisors, which were repaired by Icon resin infiltrant. OCT, stereo microscope (SM) imaging, scanning electron microscope (SEM) imaging and hematoxylin eosin (HE) staining were used to image each operation step. The changes of WSLs of enamel before and in the process of restoration with resin infiltrant showed specific performance in OCT images, which were consistent with the corresponding results of stereomicroscope and SEM. OCT can non-invasively and accurately image the whole process of repairing enamel demineralization layer with resin infiltration real-time, which can effectively guide the clinical use of resin infiltrant to repair enamel WSLs and be used as an imaging tool to evaluate the process and effect of restoration with resin infiltrant at the same time.

Combined Photothermotherapy and Chemotherapy of Oral Squamous Cell Carcinoma Guided by Multifunctional Nanomaterials Enhanced Photoacoustic Tomography.

BACKGROUND: Squamous cell carcinoma of the head and neck is the sixth most common cancer worldwide, with 40% occurring in the oral cavity. Although the level of early diagnosis and treatment of OSCC has improved significantly, the five-year survival rate of advanced patients remains unsatisfactory. However, the main challenges before us are how to get an early and accurate diagnosis and how to formulate effective treatment. Nanoparticle-based chemo-photothermal therapy has proven to be a promising non-invasive approach to treating oral squamous cell carcinoma treatment. METHODS: In this study, we tried to design and synthesize multifunctional hyaluronic acid (HA) modified gold nanorods/mesoporous silica-based nanoparticles loaded with doxorubicin hydrochloride (DOX) for photoacoustic imaging (PAI) guided cooperative chemo-photothermal therapy. RESULTS: The resultant nanocomposite shows favorable biocompatibility, relatively low cytotoxicity, ideal drug loading capability and strong PAI signals. In addition, they showed an excellent photothermal conversion efficiency of 49.02% for photothermal therapy (PTT). Moreover, in vivo and in vitro experiments have shown that synergistic chemo-photothermal therapy has better therapeutic effects than chemotherapy alone or PTT (P < 0.05). After being injected into the CAL-27 tumor-bearing mice, the DOX-AuNRs@mSiO2-HA nanoparticles could accumulate rapidly at the tumor sites and achieve complete ablation of tumors when combined with near-infrared laser irradiation, without obvious side effects on normal tissues. CONCLUSION: Our research provides a solid demonstration of the potential of DOX-AuNRs@mSiO2-HA as a multifunctional platform in PAI-guided photothermal chemotherapy for oral squamous cell carcinoma.

Assessment of the efficacy of passive cellular immunotherapy for glioma patients.

To evaluate the therapeutic efficacy of passive cellular immunotherapy for glioma, a total of 979 patients were assigned to the meta-analysis. PubMed and the Cochrane Central Register of Controlled Trials were searched initially from February 2018 and updated in April 2019. The overall survival (OS) rates and Karnofsky performance status (KPS) values of patients who underwent passive cellular immunotherapy were compared to those of patients who did not undergo immunotherapy. The proportion of survival rates was also evaluated in one group of clinical trials. Pooled analysis was performed with random- or fixed-effects models. Clinical trials of lymphokine-activated killer cells, cytotoxic T lymphocytes, autologous tumor-specific T lymphocytes, chimeric antigen receptor T cells, cytokine-induced killer cells, cytomegalovirus-specific T cells, and natural killer cell therapies were selected. Results showed that treatment of glioma with passive cellular immunotherapy was associated with a significantly improved 0.5-year OS (p = 0.003) as well as improved 1-, 1.5-, and 3-year OS (p ≤ 0.05). A meta-analysis of 206 patients in one group of clinical trials with 12-month follow-up showed that the overall pooled survival rate was 37.9% (p = 0.003). Analysis of KPS values demonstrated favorable results for the immunotherapy arm (p < 0.001). Thus, the present meta-analysis showed that passive cellular immunotherapy prolongs survival and improves quality of life for glioma patients, suggesting that it has some clinical benefits.

[Effects of chloride channel blockers on excitatory junction potentials in smooth muscle cells of cochlear spiral modiolar artery in guinea pigs].

Chloride channels have been identified in vascular smooth muscle cells (SMCs). It has been shown that these channels are involved in myogenic tone regulation and neuromuscular transmission in various vascular beds. However, whether the chloride channels are responsible for the formation of excitatory junction potentials (EJPs) of SMCs in the spiral modiolar artery (SMA) remains unelucidated. In the present study, the effects of chloride channel blockers (niflumic acid, NFA; indanyloxyacetic acid 94, IAA-94; disodium 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonate, DIDS) on EJP were explored in guinea pigs, using intracellular recording techniques on acutely isolated SMA. It was found that EJP was evoked in the majority of the SMCs (75%, n=49) with an adequate electronic stimulation. The amplitude of the EJP was partially blocked (30% approximately 80%) by combined application of alpha(1) receptor antagonist (prazosin) and alpha(2) receptor antagonist (idazoxan) at concentration of up to 1 micromol/L, and P(2x) receptor antagonist (PPADS, 10 approximately 100 micromol/L). NFA (100 micromol/L) could further inhibit the residual EJP in the presence of alpha(1), alpha(2)-adrenergic and P(2x) receptor antagonists. IAA-94 or DIDS not only inhibited the amplitude but also shortened the duration of EJP. Decrease of extracellular chloride concentration from 135.6 mmol/L to 60 mmol/L would enhance EJP. Moreover, IAA-94 (100 micromol/L) and DIDS (200 mumol/L) could reverse the enhancement of EJP by low extracellular Cl(-). NFA (100 micromol/L) could also block the residual depolarizations evoked by norepinephrine (NE, 1 approximately 50 micromol/L). Based on these results, it is inferred that NE could activate a novel adrenoceptor to open the chloride channel on the membrane of the SMCs, leading to a transmembrane Cl(-) current. This current is involved, at least partially, in the formation of EJP.

[Study on the characteristics and compositions of fine particles left in the solution after decomposition of plant samples].

After decomposition of plant standard reference materials bush twigs and leaves (GBW07602, GBW07603), poplar leaves (GBW07604) and tea (GBW07605) with either dry ashing method or wet digestion method, all kinds of fine particles left in the solution were collected and examined carefully by a scanning electron microscope (SEM), and their chemical composition were investigated by a SEM-affiliated energy-dispersive X-ray spectrometer at the same time. Moreover, the concentrations of some metal elements distributed among four different tea SRM-originated particle fractions extracted following the BCR sequential extraction procedure were determined by AAS and ICP-AES. It was found that decomposition methods have a great influence on the structure of fine particles. When dry ashing method is used, grey-colored, fluffy and porous partices can be produced, whereas fewer white-colored, compact particles can be produced when another method is used. As for chemical composition, all kinds of fine particles are almost the same, with silicon and aluminium as their main constituents, and calcium, iron, potassium, titanium and so on as their minor ones. The elementaI distribution percentages in four different particle fractions in two kinds of plant-originated particles differ from element to element, which can result in severe negative errors when plant samples are decomposed and determined for elemental concentrations.

[The positive inotropic effect after washout of acetylcholine in isolated rabbit hearts].

AIM: To study the regular pattern and mechanism of positive inotropic effect after washout of ACh (rebound of myocardial contractile force) in isolated rabbit hearts. METHODS: The changes of myocardial contractile force after perfusion and washout of ACh were observed in isolated Langendorff perfused rabbit hearts. RESULTS: Maximum rebound rate induced by ACh of 10(-8)-10(-3) mol/L were 2.20% +/- 1.70%, 6.71% +/- 3.40%, 9.18% +/- 3.54%, 14.16% +/- 3.27%, 4.37% +/- 5.86% and 1.03% +/- 6.86%, respectively. Compared with the ACh of 10(-5) mol/L in control group, adrenaline enhanced rebound of myocardial contractile force, maximum rebound rate in adrenaline group was 29.25% +/- 5.83% (P < 0.05), propranolol reduced rebound, and maximum rebound rate in propranolol group was 5.15% +/- 4.45% (P < 0.05), we had not detected rebound of myocardial contractile force in 800 s after addition ACh in verapamil group. CONCLUSION: In isolated rabbit heart, positive inotropic effect after washout of ACh has relevance to the activities of calcium current channel and beta-adrenergic receptor. Perhaps there are some different aspects in the mechanism of positive inotropic effect between perfusion of high concentration and after washout of ACh.