OBJECTIVE: To explore the effect and mechanism of DNA methyltransferase 1 (DNMT1) knockout on the inhibition of acute myeloid leukemia (AML) by natural killer (NK) cells. METHODS: The peripheral blood NK cells of AML patients and controls were collected, and the mRNA and protein level of DNMT1 were measured by PCR and Western blot, respectively. The DNMT1 knockout mice were constructed to obtain NK^DNMT1-/- cells. The NK cells were stimulated with interleukin (IL)-12, IL-15, and IL-18 to construct memory NK cells, and then the interferon-γ (IFN-γ) levels were measured by ELISA. After co-culturing with memory NK cells and HL60 cells, the killing effect of NK^DNMT1-/- cells on HL60 cells was detected by LDH assay. Then, the HL60 cell apoptosis and NK cell NKG2D level were measured by flow cytometry. The perforin and granzyme B protein levels of NK cells were measured by Western blot. The AML model mice were constructed by injecting HL60 cells into the tail vein, meanwhile, memory NK cells were also injected, and then the mouse weights, CD33 positive rates, and survival time were detected. RESULTS: The mRNA and protein levels of DNMT1 in NK cells of AML patients were significantly higher than those in the control group (both P < 0.01), while the IFN-γ level induced by interleukin was significantly lower than that in the control group (P < 0.05). Compared with NK^DNMT1+/+ cells, the ability of NK^DNMT1-/- cells to secrete IFN-γ after interleukin stimulation was significantly increased (P < 0.05). The killing and apoptosis-inducing effects of NK^DNMT1-/- cells on HL60 cells were significantly stronger than those of NK^DNMT1+/+ cells (both P < 0.05). The NKG2D level and expression of perforin and granzyme B of NK^DNMT1-/- cells were significantly increased compared with NK^DNMT1+/+ cells (all P < 0.05). Compared with AML mice injected with NK^DNMT1+/+ cells, AML mice injected with NK^DNMT1-/- cells showed significantly increased body weight, decreased CD33 positive rate, and prolonged survival time (all P < 0.05). CONCLUSION Knocking out DNMT1 can enhance the inhibitory effect of NK cells on AML, which may be related to enhancing NK cell memory function.
Killer Cells, Natural/metabolism* ; Animals ; Leukemia, Myeloid, Acute ; Humans ; DNA (Cytosine-5-)-Methyltransferase 1 ; Mice ; Mice, Knockout ; HL-60 Cells ; Apoptosis ; Interferon-gamma/metabolism* ; Granzymes/metabolism* ; Perforin/metabolism* ; NK Cell Lectin-Like Receptor Subfamily K/metabolism*

As a physical treatment technique, modified electro-convulsive therapy (MECT) is used to treat mental and certain neurological disorders by causing seizures with short, suitable electrical currents applied to the brain while the patient is under general anesthesia and muscle relaxants. MECT is recognized for its therapeutic efficacy and clinical safety, rendering it one of the most prevalent interventions in psychiatric care. To enhance clinical outcomes and minimize adverse effects, this consensus document delineates the indications, therapeutic parameters, therapeutic procedures, potential adverse effects, and associated management strategies for MECT. These guidelines are informed by the latest clinical research and expert consensus, integrating evidence-based medicine methodologies. The objective is to furnish clinicians with precise operational guidelines and to advance the standardization of MECT practices in clinical settings.

Objective:To evaluate the clinical equivalence between a domestic calcipotriol/betamethasone dipropionate ointment and the originator product in the treatment of stable plaque psoriasis.Methods:A multicenter, randomized, double-blind, three-arm, parallel-group, active- and placebo-controlled study was conducted, and 449 patients aged 18 - 65 years with stable plaque psoriasis were enrolled from 25 hospitals (such as the First Affiliated Hospital of China Medical University). Eligible patients had a baseline physician's global assessment (PGA) score of ≥ 3 points, baseline body surface area (BSA) involvement of 5% - 30%, and a target lesion psoriasis area and severity index (TL-PASI) for plaque elevation of ≥ 3 points. Participants were randomly assigned in a 2:2:1 ratio to the test group ( n = 179), reference group ( n = 180), and placebo group ( n = 90), and applied the domestic calcipotriol/betamethasone dipropionate ointment, originator product, and ointment base respectively, once daily in the evening for 4 weeks. Efficacy and safety were assessed at weeks 1, 2, and 4. The primary efficacy endpoints were the treatment success rates and clinical success rates in each group at week 4. The per-protocol set (PPS) was used for the primary efficacy analysis, and the intention-to-treat (ITT) set for supplementary efficacy analysis. Equivalence between the test and reference preparations was tested using the Cochran-Mantel-Haenszel method adjusted for randomization strata. Superiority of the test and reference preparations over the placebo was also tested. Measurement data were compared among the 3 groups using analysis of variance or non-parametric tests, while treatment success rates, clinical success rates, and incidence rates of adverse reactions were compared using the chi-square test. Results:The ITT, PPS, and safety sets included 447, 420, and 448 patients, respectively. In the ITT set, patients were aged 43.6 ± 12.8 years, including 320 (71.6%) males and 127 (28.4%) females, and the disease duration was 11.21 ± 9.05 years; 316 (70.7%) had a PGA score of 3 points and 131 (29.3%) had a PGA score of 4 - 5 points. No significant differences in the baseline characteristics (including age, sex, disease duration and disease severity) were observed among the 3 groups (all P > 0.05). Based on the PPS analysis, the treatment success rates were 57.9% (99/171) in the test group, 50.3% (86/171) in the reference group, and 7.7% (6/78) in the placebo group, and the clinical success rates were 57.9% (99/171), 50.3% (86/171), and 10.3% (8/78), respectively; both the test and reference groups were superior to the placebo group in both treatment and clinical success rates (all P < 0.001) ; the rate differences for treatment success (90% confidence interval [ CI]: -1.3% - 16.4%) and clinical success (90% CI: -1.3% - 16.3%) between the test and reference groups were entirely within the pre-defined equivalence margin (-20% - 20%). Subgroup analyses by baseline PGA scores: for patients with a baseline PGA score of 3 points, the treatment success rates in the test, reference, and placebo groups were 60.8% (73/120), 52.1% (62/119), and 11.1% (6/54), respectively, and the corresponding clinical success rates were 61.7% (74/120), 53.8% (64/119), and 13% (7/54), respectively; the test and reference groups did not differ significantly in treatment or clinical success rates (both P > 0.05), but both showed higher success rates than the placebo group (all P < 0.001) ; the results of statistical comparisons among the 3 groups in patients with a baseline PGA score of 4 - 5 points were consistent with those observed in patients with a baseline PGA score of 3 points. The percentage reductions in PGA and TL-PASI scores from baseline to weeks 1, 2, and 4 showed significant differences among the 3 groups, which were significantly higher in the test and reference groups than in the placebo group (all P < 0.001), but did not differ between the test and reference groups (all P > 0.05). The primary adverse reactions were local skin reactions, such as pruritus, pain, and erythema. The incidence rates of adverse reactions were 8.9% (16/179) in the test group, 7.3% (13/179) in the reference group, and 7.8% (7/90) in the placebo group, with no significant difference among the 3 groups ( P > 0.05) . Conclusions:The domestic calcipotriol/betamethasone dipropionate ointment demonstrated clinical equivalence to the originator product in the treatment of stable plaque psoriasis, and the two agents exhibited comparable efficacy for patients with varying degrees of disease severity, and were comparable in the speed and degree of clinical improvement, with similar favorable safety profiles.

Objective To screen the targets related to the metabolic enzymes involved in the cholesterol synthesis pathway that inhibits the polarization of macrophages towards M1 phenotype,and verify the intervention effects and underlying mechanisms in colorectal cancer cells.Methods Mouse colorectal cancer MC38 cells were divided into control group(si-NC)and experimental groups(the expression of enzymes in cholesterol synthesis pathway was interfered with siRNA for corresponding targets).RT-qPCR was used to detect the mRNA levels of corresponding targets in MC38 cells after transfection.After peritoneal macrophages were extracted from male C57BL/6 mice(6 weeks old,weighing 13～18 g),the macrophages were then treated with the conditioned media of MC38 cells transfected with different siRNAs for 48 h.RT-qPCR was employed to detect the mRNA levels of IL-1β,IL-6 and TNF-α in the macrophages so as to evaluate the effect of the culture media on the M1 polarization.MC38 cells were divided into control groups(OE-NC and sh-NC),farnesyl-diphosphate farnesyltransferase 1(FDFT1)overexpression group(OE-FDFT1)and FDFT1 knockdown group(sh-FDFT1).RT-qPCR was applied to detect the mRNA expression of FDFT1,and Western blotting was conducted to measure the protein level of FDFT1.C57BL/6 mice were subjected randomly to construct a subcutaneous tumor-bearing model and a model of intraperitoneal metastatic tumor(n=5)respectively.The growth of tumor mass was then measured.Flow cytometry was used to observe the proliferation and apoptosis of MC38 cells,and Trans well assay to detect migration ability of MC38 cells.Five C57BL/6 macrophage-depleted mice(established with injection of clodronate liposome suspension through tail vein)received intraperitoneal implantation to construct a metastasis model,and then the obtained tumor masses were then weighted.Results Compared with MC38 cells after si-NC transfection,the mRNA levels of corresponding targets in MC38 cells in the experimental groups were significantly reduced(P＜0.05).Significant increases were found in the mRNA levels of IL-1β,IL-6 and TNF-α of the macrophages with FDFT1 interference than the control cells(P＜0.05).There were no statistical differences in the proliferation,apoptosis and migration of MC38 cells in the control group(OE-NC and sh-NC)and the cells of the FDFT1 overexpression group and FDFT1 knockdown group(P＞0.05).In both the subcutaneous tumor-bearing model and the model of intraperitoneal metastatic tumor,the mass weight was significantly heavier in the OE-FDFT1 group than the OE-NC group(P＜0.01),and was notably smaller in the sh-FDFT1 group than the sh-NC group(P＜0.01).For the macrophage-depleted mouse tumor model,no remarkable change was observed in the tumor weight between the OE-FDFT1 group and the OE-NC group as well as the sh-FDFT1 group and the sh-NC group.Conclusion FDFT1,the metabolic enzyme in the cholesterol synthesis pathway of colorectal cancer tumor cells,is a potential target for tumor immunotherapy targeting macrophages,which promotes tumor progression by regulating macrophages.

Objective:To investigate the value of nomogram model based on CT features in differentiating ectopic pancreas (EP) from gastrointestinal stromal tumors (GIST) with a long diameter less than 3 cm.Methods:This study was a case-control study. The clinical and imaging data of 43 patients with EP and 90 patients with GIST confirmed by pathology in the Affiliated Hospital of Guizhou Medical University from August 2013 to March 2024 were retrospectively analyzed. Preoperative CT images were analyzed to obtain qualitative features (number of lesions, location, morphology, growth pattern, borders, cystic degeneration, calcification, ulceration, catheter sign, central umbilication) and quantitative features (lesion long diameter, short diameter, long/short diameter, lesion and normal pancreas arterial-phase and venous-phase CT values, and enhancement ratio). Statistical analyses, including independent sample t-tests, Mann-Whitney U tests, χ2 tests, and Fisher exact tests, were performed to compare CT characteristics between the two groups. Binary logistic regression analysis was used to obtain independent predictors to identify the two groups, to establish a joint model, and to draw a nomogram. The discriminative performance of the independent predictors and the combined model was assessed using receiver operating characteristic (ROC) curves, while calibration curves were used to evaluate model fit. Results:The differences in age, location, morphology, border, catheter sign, central umbilication, short diameter, long/short diameter, arteriovenous phase enhancement CT value and arteriovenous phase enhancement ratio were statistically significant between the EP group and the GIST group (all P<0.05). The logistic analysis showed that the differences in age ( OR=0.920, 95% CI 0.885-0.956, P<0.001), border ( OR=5.994, 95% CI 2.111-17.022, P=0.001), long/short diameter ( OR=7.820, 95% CI 1.841-33.224, P=0.005), and venous phase enhancement ratio ( OR=8.847, 95% CI 1.103-70.972, P=0.040) were the independent predictors for distinguishing EP from GIST, and the area under the ROC curve (AUC) were 0.782 (95% CI 0.698-0.866), 0.684 (95% CI 0.600-0.767), 0.705 (95% CI 0.607-0.803), and 0.693 (95% CI 0.605-0.781), respectively. Combined age, border, long diameter/short diameter and venous phase enhancement ratio were plotted in a nomogram with an AUC of 0.881 (95% CI 0.817-0.945), sensitivity and specificity of 74.4% and 93.3%, respectively. The calibration curve demonstrated a strong agreement between predicted and actual probabilities (Hosmer-Lemeschow test, P=0.267). Conclusions:CT imaging reveals significant differences between EP and small GISTs (<3 cm). EP is more likely when patients are younger and lesions exhibit indistinct borders, a higher long-to-short diameter ratio, and greater venous-phase enhancement. The nomogram derived from CT features provides a valuable tool for differentiating EP from GIST.

Objective:To evaluate the clinical equivalence between a domestic calcipotriol/betamethasone dipropionate ointment and the originator product in the treatment of stable plaque psoriasis.Methods:A multicenter, randomized, double-blind, three-arm, parallel-group, active- and placebo-controlled study was conducted, and 449 patients aged 18 - 65 years with stable plaque psoriasis were enrolled from 25 hospitals (such as the First Affiliated Hospital of China Medical University). Eligible patients had a baseline physician's global assessment (PGA) score of ≥ 3 points, baseline body surface area (BSA) involvement of 5% - 30%, and a target lesion psoriasis area and severity index (TL-PASI) for plaque elevation of ≥ 3 points. Participants were randomly assigned in a 2:2:1 ratio to the test group ( n = 179), reference group ( n = 180), and placebo group ( n = 90), and applied the domestic calcipotriol/betamethasone dipropionate ointment, originator product, and ointment base respectively, once daily in the evening for 4 weeks. Efficacy and safety were assessed at weeks 1, 2, and 4. The primary efficacy endpoints were the treatment success rates and clinical success rates in each group at week 4. The per-protocol set (PPS) was used for the primary efficacy analysis, and the intention-to-treat (ITT) set for supplementary efficacy analysis. Equivalence between the test and reference preparations was tested using the Cochran-Mantel-Haenszel method adjusted for randomization strata. Superiority of the test and reference preparations over the placebo was also tested. Measurement data were compared among the 3 groups using analysis of variance or non-parametric tests, while treatment success rates, clinical success rates, and incidence rates of adverse reactions were compared using the chi-square test. Results:The ITT, PPS, and safety sets included 447, 420, and 448 patients, respectively. In the ITT set, patients were aged 43.6 ± 12.8 years, including 320 (71.6%) males and 127 (28.4%) females, and the disease duration was 11.21 ± 9.05 years; 316 (70.7%) had a PGA score of 3 points and 131 (29.3%) had a PGA score of 4 - 5 points. No significant differences in the baseline characteristics (including age, sex, disease duration and disease severity) were observed among the 3 groups (all P > 0.05). Based on the PPS analysis, the treatment success rates were 57.9% (99/171) in the test group, 50.3% (86/171) in the reference group, and 7.7% (6/78) in the placebo group, and the clinical success rates were 57.9% (99/171), 50.3% (86/171), and 10.3% (8/78), respectively; both the test and reference groups were superior to the placebo group in both treatment and clinical success rates (all P < 0.001) ; the rate differences for treatment success (90% confidence interval [ CI]: -1.3% - 16.4%) and clinical success (90% CI: -1.3% - 16.3%) between the test and reference groups were entirely within the pre-defined equivalence margin (-20% - 20%). Subgroup analyses by baseline PGA scores: for patients with a baseline PGA score of 3 points, the treatment success rates in the test, reference, and placebo groups were 60.8% (73/120), 52.1% (62/119), and 11.1% (6/54), respectively, and the corresponding clinical success rates were 61.7% (74/120), 53.8% (64/119), and 13% (7/54), respectively; the test and reference groups did not differ significantly in treatment or clinical success rates (both P > 0.05), but both showed higher success rates than the placebo group (all P < 0.001) ; the results of statistical comparisons among the 3 groups in patients with a baseline PGA score of 4 - 5 points were consistent with those observed in patients with a baseline PGA score of 3 points. The percentage reductions in PGA and TL-PASI scores from baseline to weeks 1, 2, and 4 showed significant differences among the 3 groups, which were significantly higher in the test and reference groups than in the placebo group (all P < 0.001), but did not differ between the test and reference groups (all P > 0.05). The primary adverse reactions were local skin reactions, such as pruritus, pain, and erythema. The incidence rates of adverse reactions were 8.9% (16/179) in the test group, 7.3% (13/179) in the reference group, and 7.8% (7/90) in the placebo group, with no significant difference among the 3 groups ( P > 0.05) . Conclusions:The domestic calcipotriol/betamethasone dipropionate ointment demonstrated clinical equivalence to the originator product in the treatment of stable plaque psoriasis, and the two agents exhibited comparable efficacy for patients with varying degrees of disease severity, and were comparable in the speed and degree of clinical improvement, with similar favorable safety profiles.

Objective:To investigate the value of nomogram model based on CT features in differentiating ectopic pancreas (EP) from gastrointestinal stromal tumors (GIST) with a long diameter less than 3 cm.Methods:This study was a case-control study. The clinical and imaging data of 43 patients with EP and 90 patients with GIST confirmed by pathology in the Affiliated Hospital of Guizhou Medical University from August 2013 to March 2024 were retrospectively analyzed. Preoperative CT images were analyzed to obtain qualitative features (number of lesions, location, morphology, growth pattern, borders, cystic degeneration, calcification, ulceration, catheter sign, central umbilication) and quantitative features (lesion long diameter, short diameter, long/short diameter, lesion and normal pancreas arterial-phase and venous-phase CT values, and enhancement ratio). Statistical analyses, including independent sample t-tests, Mann-Whitney U tests, χ2 tests, and Fisher exact tests, were performed to compare CT characteristics between the two groups. Binary logistic regression analysis was used to obtain independent predictors to identify the two groups, to establish a joint model, and to draw a nomogram. The discriminative performance of the independent predictors and the combined model was assessed using receiver operating characteristic (ROC) curves, while calibration curves were used to evaluate model fit. Results:The differences in age, location, morphology, border, catheter sign, central umbilication, short diameter, long/short diameter, arteriovenous phase enhancement CT value and arteriovenous phase enhancement ratio were statistically significant between the EP group and the GIST group (all P<0.05). The logistic analysis showed that the differences in age ( OR=0.920, 95% CI 0.885-0.956, P<0.001), border ( OR=5.994, 95% CI 2.111-17.022, P=0.001), long/short diameter ( OR=7.820, 95% CI 1.841-33.224, P=0.005), and venous phase enhancement ratio ( OR=8.847, 95% CI 1.103-70.972, P=0.040) were the independent predictors for distinguishing EP from GIST, and the area under the ROC curve (AUC) were 0.782 (95% CI 0.698-0.866), 0.684 (95% CI 0.600-0.767), 0.705 (95% CI 0.607-0.803), and 0.693 (95% CI 0.605-0.781), respectively. Combined age, border, long diameter/short diameter and venous phase enhancement ratio were plotted in a nomogram with an AUC of 0.881 (95% CI 0.817-0.945), sensitivity and specificity of 74.4% and 93.3%, respectively. The calibration curve demonstrated a strong agreement between predicted and actual probabilities (Hosmer-Lemeschow test, P=0.267). Conclusions:CT imaging reveals significant differences between EP and small GISTs (<3 cm). EP is more likely when patients are younger and lesions exhibit indistinct borders, a higher long-to-short diameter ratio, and greater venous-phase enhancement. The nomogram derived from CT features provides a valuable tool for differentiating EP from GIST.

As a physical treatment technique, modified electro-convulsive therapy (MECT) is used to treat mental and certain neurological disorders by causing seizures with short, suitable electrical currents applied to the brain while the patient is under general anesthesia and muscle relaxants. MECT is recognized for its therapeutic efficacy and clinical safety, rendering it one of the most prevalent interventions in psychiatric care. To enhance clinical outcomes and minimize adverse effects, this consensus document delineates the indications, therapeutic parameters, therapeutic procedures, potential adverse effects, and associated management strategies for MECT. These guidelines are informed by the latest clinical research and expert consensus, integrating evidence-based medicine methodologies. The objective is to furnish clinicians with precise operational guidelines and to advance the standardization of MECT practices in clinical settings.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Periarticular fracture of the shoulder is a common type of fractures in the elderly. Postoperative adverse events such as internal fixation failure, humeral head ischemic necrosis and upper limb dysfunction occur frequently, which seriously endangers the exercise and health of the elderly. Compared with the fracture with normal bone mass, the osteoporotic periarticular fracture of the shoulder is complicated with slow healing and poor rehabilitation, so the clinical management becomes more difficult. At present, there is no targeted guideline or consensus for this type of fracture in China. In such context, experts from Youth Osteoporosis Group of Chinese Orthopedic Association, Orthopedic Expert Committee of Geriatrics Branch of Chinese Association of Gerontology and Geriatrics, Osteoporosis Group of Youth Committee of Chinese Association of Orthopedic Surgeons and Osteoporosis Committee of Shanghai Association of Chinese Integrative Medicine developed the Chinese expert consensus on the diagnosis and treatment of osteoporotic periarticular fracture of the shoulder in the elderly ( version 2023). Nine recommendations were put forward from the aspects of diagnosis, treatment strategies and rehabilitation of osteoporotic periarticular fracture of the shoulder, hoping to promote the standardized, systematic and personalized diagnosis and treatment concept and improve functional outcomes and quality of life in elderly patients with osteoporotic periarticular fracture of the shoulder.