Efficacy of formic acid in combination with cDMARDs in rheumatoid arthritis.

OBJECTIVE: The immune system of the body mistakenly targets its own joints in rheumatoid arthritis (RA), a chronic autoimmune disease that causes pain, inflammation, and damage. The complexity of RA often requires the simultaneous use of several different management strategies. This study examines the potential enhancement of conventional RA treatments, specifically conventional Disease-Modifying Anti-Rheumatic Drugs (cDMARDs), by the addition of formic acid, a naturally occurring substance that may possess anti-inflammatory properties. PATIENTS AND METHODS: A total of 90 children diagnosed with rheumatoid arthritis were examined at our hospital from 2020 to 2022. We segregated them into two cohorts, each consisting of 45 children. One cohort was administered conventional rheumatoid arthritis (RA) treatments, referred to as cDMARDs, which specifically included methotrexate and leflunomide. The other group was administered the standard treatments in addition to a low dosage of a specialized medication known as all-trans retinoic acid. We conducted follow-up assessments on the children at 6 months and 1-year post-treatment. We sought to evaluate the efficacy of the treatments by assessing the subjective reports of the children and their physicians, analyzing the outcomes of medical examinations, and examining diagnostic images, such as X-rays. Furthermore, we took measures to ensure the safety of the treatments. RESULTS: Among the cohort exclusively administered cDMARDs, approximately 26.7% exhibited significant improvement, 24.4% demonstrated moderate improvement, and 6.7% displayed minor improvement after a duration of 6 months. Approximately 57.8% of the children in this group experienced positive outcomes as a result of the treatment. The group that received retinoic acid also demonstrated superior outcomes. Approximately one-third (33.3%) of the participants demonstrated significant improvement, while another one-third showed moderate improvement. Additionally, 11.1% of the participants displayed minor improvement after a period of six months. Upon comparing the two groups, it was observed that the group receiving retinoic acid demonstrated a significantly superior outcome (p<0.05). CONCLUSIONS: Overall, the incorporation of all-trans retinoic acid alongside conventional treatments for children with RA appears to enhance their efficacy.

[Analysis of problems and management of in vitro diagnostic reagent clinical trials in medical laboratory].

Clinical trials are an important method for evaluating the safety and efficacy of in vitro diagnostic reagents, and are a key basis for product registration review and approval. In order to strengthen the management of clinical trials of in vitro diagnostic reagents, the National Medical Products Administration and relevant departments have formulated a series of regulations at the regulatory level, and require applicants and clinical trial institutions to establish a quality management system for clinical trials of in vitro diagnostic reagents. Medical laboratory is the main department and implementer of in vitro diagnostic reagent clinical trials in medical institutions. In recent years, with the rapid development of the in vitro diagnostic industry, the clinical trial projects of in vitro diagnostic reagents conducted by medical laboratory have been increasing day by day. However, there are currently few discussions on the clinical trial of in vitro diagnostic reagents from the perspective of researchers. Therefore, this article summarizes the characteristics of clinical trials of in vitro diagnostic reagents, analyzes the problems and difficulties in conducting clinical trials of in vitro diagnostic reagents in current medical laboratories, and introduces the laboratory's experience in management; to provide reference for medical testing laboratories that have not yet conducted or have already conducted clinical trials of in vitro diagnostic reagents, in order to improve the quality and efficiency of clinical trials.

Semi-diurnal distribution of polycyclic aromatic hydrocarbons bound to PM2.5 and PM0.1 during pollution episode in the urban area of Hanoi.

Every year, Hanoi suffers from several episodes (periods with daily concentration of PM2.5 higher than 50 µg m-3 during at least two consecutive days). These episodes are of health concern because of the high concentration of PM2.5 and/or PM0.1 and the presence of PM-bound toxic components, such as, PAHs. In this study, the concentrations of PAHs bound to PM2.5 and PM0.1 in night-time and day-time samples during episode and non-episode periods in December 2021 were determined. The concentrations of PAHs bound to PM2.5 were found to increase significantly from day-time samples of 3.24 ± 0.83 ng m-3 to night-time samples of 10.8 ± 4.45 ng m-3 in episode periods. However, PAHs bound to PM0.1 increased slightly from day-time samples of 0.58 ± 0.12 ng m-3 to night-time samples of 0.89 ± 0.30 ng m-3 in episode periods. Diagnostic ratios of PAHs indicate that biomass/coal combustion and vehicular emission are the primary sources of PAHs. The incremental lifetime cancer risk was estimated to vary from 8.7E-09 to 2.5E-08 for children and 6.7E-08 to 2.2E-07 for adults, respectively. Accordingly, loss of life expectancy was estimated at 0.11 min and 0.82 min for children and adults, respectively. These findings imply that the carcinogenic impact induced by PAHs via inhalation is negligible during the episode period.

A high resolution reaction microscope with universal two-region time-focusing method.

This paper presents a novel reaction microscope designed for ion-atom collision investigations, established at the Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China. Its time-of-flight (TOF) spectrometer employs an innovative flight-time focusing method consisting of two acceleration regions, providing optimal time focusing conditions for charged fragments with diverse initial velocities. The TOF spectrometer's axis intentionally tilts by 12° relative to the ion beam direction, preventing potential obstructions from the TOF grid electrodes. The introduced focusing method allows for a flexible time-focusing TOF spectrometer design without restricting the length ratio of the two regions. In addition, this configuration in our case significantly suppresses noise on the recoil ion detector produced by residual gas in the ion beam trajectory, which is a considerable challenge in longitudinal spectrometers. In a test experiment on the single electron capture reaction involving 62.5 keV/u He2+ ions and a helium atomic beam, the recoil longitudinal momentum resolution achieved 0.068 atomic units. This novel configuration and successful test run show excellent precision for ion-atom collision studies.

[Effect and mechanism of human adipose-derived stem cell exosomes on diabetic peripheral neuropathy].

Objective: To investigate the changes of artemin protein expression in diabetic peripheral neuropathy (DPN) and to explore the regulatory effect of human adipose-derived stem cell (ADSC) exosomes on the change of artemin protein expression. Methods: This research was a prospective observational clinical research combined with experimental research. Thirteen DPN patients (9 males and 4 females, aged 32 to 68 years) who were admitted to the First Affiliated Hospital of Air Force Medical University (hereinafter referred to as our hospital) from May 2022 to October 2023 and met the inclusion criteria were selected as DPN group, and 5 non-diabetes patients (4 males and 1 female, aged 29 to 61 years) who were admitted to our hospital in the same period of time and met the inclusion criteria were selected as control group. The toe nerve or sural nerve tissue in the abandoned tissue after debridement or amputation of patients in the two groups was collected. The pathological changes of nerve tissue were observed after hematoxylin-eosin staining; the protein expressions of S100ß and artemin in nerve tissue were observed after immunofluorescence staining, and the artemin protein expression was quantified; the protein and mRNA expressions of artemin were detected by Western blotting and real-time fluorescent quantitative reverse transcription polymerase chain reaction, respectively (the sample number in DPN group and control group was 13 and 5, respectively). Twelve male C57BL/6 mice aged 3 to 5 days were collected to isolate Schwann cells, and the cells were divided into conventional culture group cultured routinely, high glucose alone group (cultured with high concentration of glucose solution only), and high glucose+exosome group (cultured with high concentration of glucose solution and extracted human ADSC exosomes). After 24 hours of culture, the cell proliferation activity was detected by cell counting kit 8 (n=6). After 48 hours of culture, the protein expression of artemin was detected by Western blotting (n=3). Results: Compared with those in control group, the neural supporting cells decreased and the inflammatory cells increased in the nerve tissue of patients in DPN group, showing typical manifestations of nerve injury. Immunofluorescence staining showed that compared with those in control group, the nuclei was more, and the protein expression of S100ß was lower in nerve tissue of patients in DPN group. The protein expression of artemin in nerve tissue of patients in DPN group was 71±31, which was significantly lower than 1 729±62 in control group (t=76.92, P<0.05). Western blotting detection showed that the protein expression of artemin in nerve tissue of patients in DPN group was 0.74±0.08, which was significantly lower than 0.97±0.06 in control group (t=5.49, P<0.05). The artemin mRNA expression in nerve tissue of patients in DPN group was significantly lower than that in control group (t=7.65, P<0.05). After 24 hours of culture, compared with that in conventional culture group, the proliferation activities of Schwann cells in high glucose alone group and high glucose+exosome group were significantly decreased (P<0.05); compared with that in high glucose alone group, the proliferation activity of Schwann cells in high glucose+exosome group was significantly increased (P<0.05). After 48 hours of culture, compared with those in conventional culture group, the protein expressions of artemin of Schwann cells in high glucose alone group and high glucose+exosome group were significantly decreased (P<0.05); compared with that in high glucose alone group, the protein expression of artemin of Schwann cells in high glucose+exosome group was significantly increased (P<0.05). Conclusions: The protein expression of artemin in nerve tissue of DPN patients is lower than that in normal nerve tissue, which may be related to the reduction of proliferation activity of Schwann cells by high glucose. Human ADSC exosomes may improve the proliferation activity of Schwann cells by increasing artemin protein expression, thereby delaying the progression of DPN.

Validation of an automated dispensing system for subsequent dose dispensing of different radionuclides.

BACKGROUND: Automated dispensing systems (ADSs) for radiopharmaceuticals have been developed to reduce the radiation exposure of personnel, to improve the accuracy of the dispensed dose and to limit the microbiological contamination. However, before implementing such systems, validation according to various applicable guidelines is necessary to ensure safety and quality. Here we present the selection, validation and implementation of the PT459R2 from manufacturer Lynax s.r.o. as a guidance protocol for validation according to GMP and GRPP guidelines. Validation included linearity accuracy and precision of the internal scintillation detector for different isotopes and microbiological validation for aseptic procedures. RESULTS: The ADS can dispense accurate doses in the following linear range: 1000-10,000 MBq for lutetium-177, 20-74 MBq for zirconium-89, 100-1000 MBq for gallium-68 and 100-2000 MBq for fluorine-18. The maximum bias is 2.35% and the maximum coefficient of variation is 3.03% which meets the acceptance criteria of < 5%. Furthermore, the ADS does not affects the GMP class A environment in a laminar airflow cabinet and can dispense aseptically. In addition, radiation exposure is acceptable and data integrity is preserved. CONCLUSION: The PT459R2 ADS met all the requirements from our performance qualification and is therefore suitable for daily routine use in our center. Our approach can be used as a guidance for PQ of an ADS in a Radiopharmacy according to GMP and GRPP guidelines.

[Research advances on the role of Schwann cells in diabetic peripheral neuropathy].

Diabetic peripheral neuropathy (DPN) is one of the common chronic complications of diabetes, resulting in neuropathy of spinal nerve, cranial nerve, and vegetative nerve. Diabetic distal symmetric multiple neuropathy is the most representative lesion of DPN, including symptoms of bilateral limbs pain, numbness, and paresthesia, etc. DPN is one of the main reasons causing diabetic foot ulcer (DFU). Schwann cells (SCs) are the primary glia cells of the peripheral nervous system, which play very important role in repairing after nerve injury. As the target cells of chronic hyperglycemia, SCs' functions, including the formation of myelin sheath, the secretion of neurotrophic factors, energy supplying for the axon, and the guidance of axon regeneration, etc., are damaged under the action of high glucose. The destroyed functions of SCs can inhibit the repair of damaged nerves and accelerate the progress of DPN. Therefore, if the damage of high glucose to SCs can be effectively reduced, it will provide a new way for the treatment of DPN and DFU and reduce the morbidity of DFU. This review focuses on the function of SCs and its relationship with DPN.

Class III Antiarrhythmics and Periprocedural Torsades de Pointes.

This case series describes 2 women on prolonged therapy with class III antiarrhythmics who developed torsades de pointes polymorphic ventricular tachycardia in the setting of catheter ablation for atrial fibrillation as a result of QTc prolonging factors. Clinicians must exercise increased vigilance in the perioperative period in patients on QTc-prolonging medications. (Level of Difficulty: Intermediate.).

[A prospective randomized controlled study of antibiotic bone cement in the treatment of diabetic foot ulcer].

Objective: To investigate the clinical effects and related mechanism of antibiotic bone cement in treating diabetic foot ulcer (DFU). Methods: A prospective randomized controlled study was conducted. From August 2020 to August 2022, 24 patients with DFU who met the inclusion criteria were admitted to the First Affiliated Hospital of Air Force Medical University. According to the block randomization, the patients were divided into 2 groups, with 12 patients in each group. In antibiotic bone cement group, there were 7 male and 5 female patients, aged (64±8) years, with the ulcer area of (41±21) cm2. In silver sulfadiazine group, there were 8 male and 4 female patients, aged (62±8) years, with the ulcer area of (38±19) cm2. Under the condition of ensuring the patency of at least one main inferior genicular artery in each patient, the continuous vacuum sealing drainage was performed for 3-5 days after thorough debridement. Thereafter, the wounds in antibiotic bone cement group were treated with gentamicin-laden bone cement, and the wounds in silver sulfadiazine group were treated with silver sulfadiazine cream for dressing change. After 3 weeks of dressing change, the wound was covered with split-thickness skin graft from the lateral thigh on the affected side. Before debridement and after 3 weeks of dressing change, the blood flow intensities of wound tissue and normal skin tissue in foot were measured using laser Doppler flowmeter, and then, the percentage of relative blood flow intensity of wound and the change rate of blood flow intensity were calculated. After 3 weeks of dressing change, the wound margin tissue was taken, the number of CD31-positive neovascular and the vascular morphology were observed and detected by immunohistochemical staining, the morphology of blood vessels surrounded by CD31 and α-smooth muscle actin (α-SMA) double-positive cells was observed by immunofluorescence staining, the cell proliferation activity was evaluated by immunofluorescence staining (denoted as the ratio of Ki67 positive cells), and the protein expression of vascular endothelial growth factor receptor 2 (VEGFR2) was detected by Western blotting. The skin graft survival was observed 3-5 days after skin grafting, and the wound healing time was recorded. Data were statistically analyzed with independent sample t test and Fisher's exact probability test. Results: The percentages of relative blood flow intensity of wounds of patients before debridement were similar between the two groups (P>0.05). After 3 weeks of dressing change, the percentage of relative blood flow intensity of wounds and the change rate of blood flow intensity of patients in antibiotic bone cement group were (44.7±2.0)% and (129±12)%, respectively, which were significantly higher than (28.3±1.2)% and (41±8)% in silver sulfadiazine group (with t values of 24.15 and 20.97, respectively, P<0.05). After 3 weeks of dressing change, compared with those in silver sulfadiazine group, the number of CD31-positive neovascular in the wound margin tissue of patients in antibiotic bone cement group was significantly increased (t=33.81, P<0.05) with larger diameter and more regular arrangement, the vascular wall continuity surrounded by CD31 and α-SMA double-positive cells was better, and the ratio of Ki67 positive cells and protein expression of VEGFR2 were significantly increased (with t values of 40.97 and 47.38, respectively, P<0.05). On post skin grafting day 3-5, all the patients in antibiotic bone cement group and 8 patients in silver sulfadiazine group had good skin graft survival, while 4 patients in silver sulfadiazine group showed spotted/patchy skin graft necrosis, which were cured after corresponding treatment. The wound healing time of patients in antibiotic bone cement group was (47.1±2.9) d, which was significantly shorter than (58.8±2.3) d in silver sulfadiazine group (t=10.86, P<0.05). Conclusions: Compared with silver sulfadiazine, clinical application of antibiotic bone cement for treating DFU has the characteristics of accelerating wound healing and better reconstruction of local blood flow, which may be closely related to the fact that antibiotic bone cement promoted the local angiogenesis effectively in the wound through enhancing the expression of VEGFR2.

[Effects of the anterolateral thigh chimeric perforator flaps in repairing complex wounds of foot and ankle].

Objective: To investigate the effects of anterolateral thigh chimeric perforator flap in repairing complex wounds of foot and ankle. Methods: A retrospective observational study was conducted. From May 2018 to June 2022, 23 patients who met the inclusion criteria were admitted to the First Affiliated Hospital of Air Force Medical University to repair complex wounds of foot and ankle with anterolateral thigh chimeric perforator flaps, including 15 males and 8 females, aged from 20 to 66 years. The wounds were all accompanied by bone exposure and defects, and were complicated with varying degrees of infection. All patients underwent debridement and continuous vacuum sealing drainage treatment for 1 week in stage Ⅰ, with the skin and soft tissue defect area after debridement being 10 cm×5 cm to 22 cm×7 cm. In stage Ⅱ, the anterolateral thigh chimeric perforator flap was used to cover the defective wound, of which the muscle flap was used to fill the deep invalid cavity of the ankle joint or cover bone and internal fixation exposures, and the skin flap was used to cover the superficial wound, with the area of the skin flap ranging from 11 cm×6 cm to 23 cm×8 cm, and the area of the muscle flap ranging from 4.0 cm×2.5 cm to 8.0 cm×5.0 cm. The survival of the flap was observed after operation. During follow-up, the color, texture, appearance, and complications of the flap were observed, the function of ankle joint and its range of dorsiflexion motion and plantar flexion motion were measured, and the scar hyperplasia and muscular hernia in donor area were observed. Results: Ecchymosis and epidermal necrosis occurred at the tip of the flap in 1 patient on 5 days after operation and healed after dressing change for 1 week; the other flaps of patients survived successfully. After 6 to 40 months of follow-up, the color, texture, and shape of flaps were good, but 1 patient was not satisfied with the shape of the flap because of flap swelling; the ankle joint movement was basically normal, the dorsiflexion motion was 15-30°, and the plantar flexion motion was 20-45°; the scar hyperplasia in the donor area of the flap was not obvious, and no muscular hernia occurred. Conclusions: The anterolateral thigh chimeric perforator flap can effectively fill the deep invalid cavity of ankle joint and cover the superficial wound at the same time, with minimal damage to the donor site. So it is an ideal flap for repairing the complex wounds of foot and ankle.

Clinical evaluation of hysterectomy for the treatment of invasive mole in Southern Vietnam.

OBJECTIVE: This study aimed to determine the rate of salvage chemotherapy and review associated factors in invasive mole patients treated by primary or delayed hysterectomy. PATIENTS AND METHODS: This study was carried out at the Tu Du Hospital, where a total of 189 patients were diagnosed with invasive mole based on histologic examination by hysterectomy between 01/2016 to 12/2020. We used the life table method to estimate the cumulative rate. We applied the Cox proportional hazard model to determine the factors associated with the need for salvage chemotherapy. RESULTS: At 12-month follow-up, 47 patients had required salvage chemotherapy. The incidence was 24.87% (95% CI: 18.88-31.66). Applying the multivariate model, prophylactic chemotherapy (HR = 2.75, 95% Cl: 1.20-6.30) and two weeks postoperative hCG value greater than 1,900 mIU/mL (HR = 4.30, 95% Cl: 2.08-8.87) increased the risk of requiring salvage chemotherapy. Postoperative chemotherapy decreased the risk of requiring salvage chemotherapy (HR = 0.43, 95% Cl: 0.22-0.83). CONCLUSIONS: Hysterectomy can be considered safe and effective in treating invasive mole patients. Although patients were treated by hysterectomy, 24.87% of patients needed salvage chemotherapy to achieve remission. This study affirms the malignant nature of invasive mole, a subtype of gestational trophoblastic neoplasia (GTN). It is not purely a local invasion of molar villi. Postoperative chemotherapy plays an essential role in reducing the risk of requiring salvage chemotherapy.

[Comparison of efficacy and safety of transurethral thulium laser vapoenucleation of prostate and transurethral thulium laser enucleation of prostate in the treatment of benign prostatic hyperplasia].

Objective: To compare early outcomes between transurethral thulium laser vapoenucleation of prostate and transurethral thulium laser enucleation of prostate for the treatment of benign prostatic hyperplasia (BPH). Methods: Retrospective analysis was conducted on the clinical data of 1 638 BPH patients admitted to the Department of Urology of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from January 2018 to December 2021. There were 916 patients underwent transurethral thulium laser vapoenucleation of prostate (ThuVEP group) and 722 patients underwent transurethral thulium laser enucleation of prostate (ThuLEP group). The operation time, eliminated tissue weight, surgical complications, duration of post-operative catheter implantation were compared between the two groups. The improvement of International Prostate Symptom Score (IPSS), Quality of Life Index (QoL), maximum uroflow rate (Qmax) and post-void residual urine volume (PVR) at 1 month after operation was compared between the two groups. Results: There were no significant differences in age, preoperative and 1-month postoperative prostate volume, IPSS score, QoL score, Qmax, and PVR between the ThuVEP and ThuLEP group (all P>0.05). There were no significant differences in perioperative indicators such as operation time, cutting or enucleation time, tissue crushing time, tissue weight, hemoglobin change, catheter indwelling time, and postoperative hospital stay between ThuVEP group and ThuLEP group (all P>0.05). The incidence of minor gross hematuria after extubation in the ThuVEP group was 7.8% (56/916), which was lower than 9.4% (65/722) in the ThuLEP group (P=0.026); the incidence of temporary incontinence at 1 month after surgery was 5.2% (38/916) in ThuVEP group, lower than 11.9% (86/722) in ThuLEP group (P<0.001). A total of 3 patients (0.4%) in ThuLEP group required operative intervention for severe post-operation bleeding, but none of ThuVEP group suffered from this kind of surgical complications. Conclusions: ThuVEP has similar efficacy with ThuLEP for the treatment of BPH. ThuVEP can significantly reduce the incidence of post-operation temporary urine incontinence, and has much superiority in stanching bleeding.

The Mediator complex regulates enhancer-promoter interactions.

Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target gene promoters. However, the molecular mechanisms by which interactions between enhancers and promoters are formed are not well understood. Here, we investigate the function of the Mediator complex in the regulation of enhancer-promoter interactions, by combining rapid protein depletion and high-resolution MNase-based chromosome conformation capture approaches. We show that depletion of Mediator leads to reduced enhancer-promoter interaction frequencies, which are associated with a strong decrease in gene expression. In addition, we find increased interactions between CTCF-binding sites upon Mediator depletion. These changes in chromatin architecture are associated with a redistribution of the Cohesin complex on chromatin and a reduction in Cohesin occupancy at enhancers. Together, our results indicate that the Mediator and Cohesin complexes contribute to enhancer-promoter interactions and provide insights into the molecular mechanisms by which communication between enhancers and promoters is regulated.

First CLAS12 Measurement of Deeply Virtual Compton Scattering Beam-Spin Asymmetries in the Extended Valence Region.

Deeply virtual Compton scattering (DVCS) allows one to probe generalized parton distributions describing the 3D structure of the nucleon. We report the first measurement of the DVCS beam-spin asymmetry using the CLAS12 spectrometer with a 10.2 and 10.6 GeV electron beam scattering from unpolarized protons. The results greatly extend the Q^{2} and Bjorken-x phase space beyond the existing data in the valence region and provide 1600 new data points measured with unprecedented statistical uncertainty, setting new, tight constraints for future phenomenological studies.

The association between chronic venous disease and knee osteoarthritis.

OBJECTIVE: Chronic venous disease (CVD) and knee osteoarthritis (KOA) are two common diseases in the elderly. Both share common risk factors, such as age, sex, and obesity, and are believed to be associated with inflammatory conditions and venous stasis. However, studies of the association between CVD and KOA are limited, especially in the elderly. To investigate the association between CVD and KOA and their effects on pain and functional status in the elderly at the Rheumatology Clinic of University Medical Center Ho Chi Minh City (HCMC). PATIENTS AND METHODS: This cross-sectional study included 222 elderly patients (aged ≥60 years) at the Rheumatology Clinic of University Medical Center HCMC from December 2019 to June 2020, including 167 with and 55 without KOA. Patient data were collected for both groups, including demographics, symptoms, clinical signs, and diagnostic tests for KOA and CVD, including knee radiographs and duplex scanning of the lower extremity veins. RESULTS: CVD was a common comorbidity among elderly patients with KOA (73.65% vs. 58.18%; p = 0.030). CVD symptoms did not differ significantly between patients with and without KOA. After adjusting for age, sex, body mass index, and some comorbid conditions, the differences in CVD incidence between the groups remained significant (odds ratio = 2.46, 95% confidence interval: 1.20-5.06; p = 0.014). Visual Analog Scale and Western Ontario and McMaster Universities Osteoarthritis Index pain scores were higher in elderly patients with KOA and CVD. CONCLUSIONS: CVD is common in elderly patients with KOA. While age, sex, and weight are risk factors for both conditions, there is an independent association between them. Patients comorbid with KOA and CVD have more pain and limited functional status.

CTCF, BEAF-32, and CP190 are not required for the establishment of TADs in early Drosophila embryos but have locus-specific roles.

The boundaries of topologically associating domains (TADs) are delimited by insulators and/or active promoters; however, how they are initially established during embryogenesis remains unclear. Here, we examined this during the first hours of Drosophila embryogenesis. DNA-FISH confirms that intra-TAD pairwise proximity is established during zygotic genome activation (ZGA) but with extensive cell-to-cell heterogeneity. Most newly formed boundaries are occupied by combinations of CTCF, BEAF-32, and/or CP190. Depleting each insulator individually from chromatin revealed that TADs can still establish, although with lower insulation, with a subset of boundaries (~10%) being more dependent on specific insulators. Some weakened boundaries have aberrant gene expression due to unconstrained enhancer activity. However, the majority of misexpressed genes have no obvious direct relationship to changes in domain-boundary insulation. Deletion of an active promoter (thereby blocking transcription) at one boundary had a greater impact than deleting the insulator-bound region itself. This suggests that cross-talk between insulators and active promoters and/or transcription might reinforce domain boundary insulation during embryogenesis.

Chimeric Antigen Receptor-Natural Killer Cells: A New Breakthrough in the Treatment of Solid Tumours.

Natural killer (NK) cells can quickly and directly eradicate tumour cells without recognising tumour-specific antigens. NK cells also participate in immune surveillance, which arouses great interest in the development of novel cancer therapies. The chimeric antigen receptor (CAR) family is composed of receptor proteins that give immune cells extra capabilities to target specific antigen proteins or enhance their killing effects. CAR-T cell therapy has achieved initial success in haematological tumours, but is prone to adverse reactions, especially with cytokine release syndrome in clinical applications. Currently, CAR-NK cell therapy has been shown to successfully kill haematological tumour cells with allogeneic NK cells in clinical trials without adverse reactions, proving its potential to become an off-the-shelf product with broad clinical application prospects. Meanwhile, clinical trials of CAR-NK cells for solid tumours are currently underway. Here we will focus on the latest advances in CAR-NK cells, including preclinical and clinical trials in solid tumours, the advantages and challenges of CAR-NK cell therapy and new strategies to improve the safety and efficacy of CAR-NK cell therapy.