BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T regs ), an increase in the cluster of differentiation 8 positive (CD8 + ) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8 + T cells, and induced the proportion of T regs . Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.
G-Protein-Coupled Receptor Kinase 2/metabolism* ; Arthritis, Rheumatoid/immunology* ; Animals ; Dendritic Cells/metabolism* ; Paroxetine/therapeutic use* ; Proto-Oncogene Proteins c-akt/metabolism* ; Mice ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Male ; Phosphatidylinositol 3-Kinases/metabolism* ; Lymphocyte Activation/drug effects* ; Female ; T-Lymphocytes/metabolism* ; Middle Aged

OBJECTIVES: Verrucous epidermal nevus (VEN), seborrheic keratosis (SK), verruca plana (VP), verruca vulgaris (VV), and nevus sebaceous (NS) are common verrucous proliferative skin diseases with similar clinical appearances, often posing diagnostic challenges. Dermoscopy and reflectance confocal microscopy (RCM) can aid in their differentiation, yet their specific features under these tools have not been systematically described. This study aims to summarize and analyze the dermoscopic and RCM features of VEN, SK, VP, VV, and NS. METHODS: A total of 121 patients with histopathologically confirmed verrucous proliferative skin diseases were enrolled. Dermoscopy and RCM imaging was used to observe and analyze the microscopic features of these conditions. RESULTS: Under dermoscopy, the 5 diseases displayed distinct characteristics: VEN typically showed gyriform structures; SK was characterized by gyriform structures, comedo-like openings, and milia-like cysts; VP and VV featured dotted vessels and frogspawn-like structures; NS presented as brownish-yellow globules. RCM revealed shared features such as hyperkeratosis and acanthosis across all 5 diseases. Specific features included gyriform structures and elongated rete ridges in VEN; pseudocysts and gyriform structures in SK; evenly distributed ring-like structures in VP; vacuolated cells and papillomatous proliferation in VV; and frogspawn-like structures in NS. CONCLUSIONS These 5 verrucous proliferative skin conditions exhibit distinguishable features under both dermoscopy and RCM. The combination of these 2 noninvasive imaging modalities holds significant clinical value for the differential diagnosis of verrucous proliferative skin diseases.
Humans ; Dermoscopy/methods* ; Diagnosis, Differential ; Microscopy, Confocal/methods* ; Male ; Female ; Adult ; Middle Aged ; Adolescent ; Keratosis, Seborrheic/pathology* ; Young Adult ; Warts/diagnosis* ; Child ; Aged ; Skin Diseases/pathology* ; Nevus, Sebaceous of Jadassohn/diagnosis* ; Skin Neoplasms/diagnosis* ; Child, Preschool

Objective: For patients with elevated hematocrit (Hct), platelet-rich plasma (PRP) apheresis is prone to red blood cell contamination—commonly referred to as “flushing” or erythrocyte carryover—which compromises product quality and therapeutic efficacy. This study reports two clinicaly derived measures to mitigate this issue. Methods: For 21 patients with Hct ≥53%, intravenous 0.9% sodium chloride infusion before apheresis process (replacement method, n=13) or 0.9% sodium chloride fluids hemodilution within the centrifuge bowl during PRP apheresis process (dilution method, n=8) were given, respectively. The collection time, adverse reactions, and the celluar composition of PRP—including white blood cells, red blood cells, and platelet counts—were recorded and compared. Results: Neither method resulted in visible RBC contamination (“flushing”). The red blood cell counts [(0.021±0.014)×10 /L vs (0.019±0.011)×10 /L, P>0.05], white blood cell counts [(2.258±3.288) ×10 /L vs (0.557 5±1.203) ×10 /L, P>0.05], and platelet counts [(1 140±308.2)×10 /L vs (1 105±309.9)×10 /L, P>0.05] in the PRP products obtained by two methods all met the control standards of PRP. There was no significant difference [(2.268±0.927) vs (2.438±0.762) mL/min, P=0.669 2] between the two methods in terms of the speed of PRP collection. One case of adverse reaction occurred with the fluid replacement method, while no adverse reaction occurred with the dilution method. Conclusion: For patients with elevated Hct, both fluid replacement and dilution methods can effectively prevent RBC contamination during PRP collection, yielding products that meet clinical quality standards.

Objective To explore the risk signals of niraparib and provide references for rational and safe clinical medication.Methods Niraparib-related adverse drug events(ADEs)reports from Q1 2017 to Q2 2023 were extracted from the US FDA Adverse Event Reporting System(FAERS)database.Risk signals were identified using the reporting odds ratio(ROR),proportional reporting ratio(PRR),Bayesian confidence propagation neural network(BCPNN),and multi-item gamma Poisson shrinker(MGPS)methods.The Risk signals were described and classified by preferred system organ classes(SOCs)and preferred terms(PTs)from the Medical Dictionary for Regulatory Activities(MedDRA)version 26.1,and the occurrence of niraparib-related ADEs was also analyzed.Results A total of 16,961 ADE reports with niraparib as the primary suspected drug were extracted.Through screening and analysis,32 PTs were identified involving 11 SOCs,which were largely consistent with the information in the drug label.However,suspicious signals not mentioned in the label,including neuropathy peripheral,decreased red blood cell count,reduced hematocrit,dehydration,and hot flashes,require further attention.The median occurrence time was 22 days(IQR 2-98 days),and the Weibull distribution test indicated an early failure-type curve.Conclusion When using niraparib,particularly in early stages of treatment,it is essential to monitor not only the ADEs mentioned in the drug instructions,such as decreased platelet count,nausea and fatigue,but also to pay close attention to the ADEs not included in the instructions,such as peripheral neuropathy and decreased red blood cell count,which exhibit strong signal values,to ensure patient medication safety.

ObjectivesTo observe the clinical effectiveness， safety， and potential mechanism of Yisui Shengxue Pills （益髓生血丸） as adjuvant treatment for myelosuppression after chemotherapy for malignant tumours with qi and yin deficiency syndrome. MethodsEighty patients of myelosuppression after chemotherapy for malignant tumours with qi and yin deficiency syndrome were randomly divided into trial group and control group， with 40 cases in each group. Both groups received conventional western medicine treatment， while the control group added placebo taken orally， and the trial group received Yisui Shengxue Pills orally， and both groups were treated for 21 consecutive days. Granulocyte colony stimulating factor （G-CSF）， granulocyte-macrophage colony stimulating factor （GM-CSF）， soluble intercellular cell adhesion molecule-1 （sICAM-1）， Jagged 1 （Jagl）， Notch homolog 2 （Notch2）， cell fate determinant membrane associated protein 1 （Numb1）， neutrophils， platelet count， white blood cell count， hemoglobin， cluster of differentiation 4⁺ （CD4⁺）， and cluster of differentiation 8⁺ （CD8⁺） were detected before and after treatment； myelosuppression grade and TCM syndrome scores of the two groups were evaluated before and after treatment， and clinical effectiveness and adverse events of the two groups were compared. ResultsThe difference in myelosuppression grading between the two groups after treatment was statistically significant （P＜0.05）. Compared with this group before treatment， plasma G-CSF， GM-CSF， sICAM-1， Numb1 expression， platelet count， neutrophil count， leukocyte count， haemoglobin， CD4⁺ level decreased， Jagl， Notch2 expression and CD8⁺ level increased， and fatigue， spontaneous sweating， palpitation， night sweating， insomnia， scanty complexion， mouth erosion， vexing heat in chest， palms and soles scores all reduced （P＜0.05）. Compared with the control group after treatment， plasma G-CSF， GM-CSF， sICAM-1， Numb1 expression， platelet count， neutrophil count， leukocyte count， haemoglobin， CD4+ levels increased， Jagl， Notch2 expression and CD8⁺ levels decreased， and fatigue， spontaneous sweating， palpitations， night sweating， insomnia， pale face， mouth erosion， and vexing heat in chest， palms and soles scores decreased in trial group （P＜0.05）. The total effective rate of the trial group was 95.00%， which was significantly higher than that of the control group， which was 80.00% （P＜0.05）. Comparison of the incidence of liver function damage and renal function damage between the two groups showed no statistically significant difference （P＞0.05）， and the incidence of gastrointestinal damage in the trial group was lower than that in the control group （P = 0.02）. ConclusionYisui Shengxue Pills as adjuvant treatment for myelosuppression after chemotherapy for malignant tumours with qi and yin deficiency syndrome can improve the myelosuppression and clinical symptoms， improve the clinical effectiveness， and has a good synergistic and toxicity-reducing effect， and its mechanism of action may be related to the regulation of the Notch signalling pathway and the reduction of immune function impairment.

Objective:To explore the influencing factors for compliance to colonoscopy screening for colorectal cancer in outpatients.Methods:Patients aged 40-74 years who visited the outpatient gastroenterology department of 7 tertiary hospitals in 7 regions of Xinjiang from January 2022 to June 2022 were enrolled. Recommendations for colonoscopy screening were made according to the patient's medical conditions, and the questionnaire was used to collect information. The Chi-square test was used to compare the differences of compliant and non-compliant patients. Multivariate logistic regression was used to analyze the influencing factors of compliance to colonoscopy screening.Results:A total of 463 valid questionnaires were obtained from 7 centers, in which, 427 outpatients (92.2%) followed the recommendation for colonoscopy screening, and 36 (7.8%) did not. Chi-square test results showed that there were statistically significant differences between the two groups in gender, age, education, subjective cognition of intestinal polyps, personal history of colorectal polyps, family history of colorectal cancer, family history of colorectal polyps, abdominal pain or distension, and defecation habit or stool changes ( P<0.05). The results of multivariate regression analysis showed that the screening compliance of patients aged 40-49 years ( P=0.005, OR=0.141, 95% CI: 0.036-0.549) and 50-59 years ( P=0.039, OR=0.257, 95% CI: 0.071-0.932) was lower than that of patients aged 60-74 years. The screening compliance of patients with high school education ( P=0.011, OR=3.121, 95% CI: 1.304-7.473) and college education or above ( P=0.016, OR=3.544, 95% CI: 1.270-9.890) was higher than those with primary school education and below. Patients with personal history of colorectal polyps ( P=0.015, OR=12.288, 95% CI: 1.629-92.719), family history of colorectal cancer ( P=0.038, OR=8.506, 95% CI: 1.124-64.351) and changes in defecation habit or stool trait ( P=0.039, OR=4.794, 95% CI: 1.085-21.192) also had higher compliance. Conclusion:Age, educational level, personal history of colorectal polyps, and family history of colorectal cancer are related to colonoscopy screening compliance in outpatients of 7 tertiary hospitals in 7 regions of Xinjiang. The independent risk factors affecting compliance to colorectal cancer screening in outpatients are age of 40-59 years, lower educational level, no previous history of polyps or family history of colorectal cancer, and no defecation habit or stool changes.

Objective: QL1604 is a highly selective, humanized monoclonal antibody against programmed death protein 1. We assessed the efficacy and safety of QL1604 plus chemotherapy as first-line treatment in patients with advanced cervical cancer. Methods: This was a multicenter, open-label, single-arm, phase II study. Patients with advanced cervical cancer and not previously treated with systemic chemotherapy were enrolled to receive QL1604 plus paclitaxel and cisplatin/carboplatin on day 1 of each 21-day cycle for up to 6 cycles, followed by QL1604 maintenance treatment. Results: Forty-six patients were enrolled and the median follow-up duration was 16.5 months. An 84.8% of patients had recurrent disease and 13.0% had stage IVB disease. The objective response rate (ORR) per Response Evaluation Criteria in Advanced Solid Tumors (RECIST) v1.1 was 58.7% (27/46). The immune ORR per immune RECIST was 60.9% (28/46).The median duration of response was 9.6 months (95% confidence interval [CI]=5.5–not estimable). The median progression-free survival was 8.1 months (95% CI=5.7–14.0). Fortyfive (97.8%) patients experienced treatment-related adverse events (TRAEs). The most common grade≥3 TRAEs (>30%) were neutrophil count decrease (50.0%), anemia (32.6%), and white blood cell count decrease (30.4%). Conclusion QL1604 plus paclitaxel-cisplatin/carboplatin showed promising antitumor activity and manageable safety profile as first-line treatment in patients with advanced cervical cancer. Programmed cell death protein 1 inhibitor plus chemotherapy may be a potential treatment option for the patient population who have contraindications or can’t tolerate bevacizumab, which needs to be further verified in phase III confirmatory study.

Objective: QL1604 is a highly selective, humanized monoclonal antibody against programmed death protein 1. We assessed the efficacy and safety of QL1604 plus chemotherapy as first-line treatment in patients with advanced cervical cancer. Methods: This was a multicenter, open-label, single-arm, phase II study. Patients with advanced cervical cancer and not previously treated with systemic chemotherapy were enrolled to receive QL1604 plus paclitaxel and cisplatin/carboplatin on day 1 of each 21-day cycle for up to 6 cycles, followed by QL1604 maintenance treatment. Results: Forty-six patients were enrolled and the median follow-up duration was 16.5 months. An 84.8% of patients had recurrent disease and 13.0% had stage IVB disease. The objective response rate (ORR) per Response Evaluation Criteria in Advanced Solid Tumors (RECIST) v1.1 was 58.7% (27/46). The immune ORR per immune RECIST was 60.9% (28/46).The median duration of response was 9.6 months (95% confidence interval [CI]=5.5–not estimable). The median progression-free survival was 8.1 months (95% CI=5.7–14.0). Fortyfive (97.8%) patients experienced treatment-related adverse events (TRAEs). The most common grade≥3 TRAEs (>30%) were neutrophil count decrease (50.0%), anemia (32.6%), and white blood cell count decrease (30.4%). Conclusion QL1604 plus paclitaxel-cisplatin/carboplatin showed promising antitumor activity and manageable safety profile as first-line treatment in patients with advanced cervical cancer. Programmed cell death protein 1 inhibitor plus chemotherapy may be a potential treatment option for the patient population who have contraindications or can’t tolerate bevacizumab, which needs to be further verified in phase III confirmatory study.

Objective To investigate the changes in the structural parameters and mechanical properties of the necrotic femoral head and compare the effects of core decompression and hone grafting with those of bone cement filling on the mechanical properties and pre-vention of articular surface collapse of the necrotic femoral head.Methods Thirty-two fresh human femoral heads were collected from patients who underwent total hip arthroplasty at our hospital between June 2020 and January 2022.The femoral heads were divided into four groups:8 femoral neck fractures(TFF group),8 osteonecrosis of the femoral head(ONFH group),8 osteonecrosis of the femoral head treated with cement percutaneous injection(CPI group),and 8 osteonecrosis of the femoral head treated with core decompression and bone graft(CDBG group).Cement filling or core decompression was performed under radiographic guidance.All samples were scanned and three-dimensionally reconstructed using micro-CT.The spatial heterogeneity of the femoral head was observed,and the bone morphometric parameters of each region of interest were calculated.Mechanical analysis was performed to evaluate the femoral head parameters of dis-placement and stress in vitro.Results Bone microarchitecture and morphometry in necrotic femoral heads were markedly altered.The biomechanical properties of the necrotic zone in the femoral head were markedly weakened.After the necrotic area was filled with bone cement,the biomechanical properties of the necrotic zone of the femoral head increased significantly.In addition,after core decompres-sion and bone grafting in the necrotic area,the biomechanical properties increased significantly in the necrotic zone of the femoral head.Conclusion Bone cement filling or bone grafting in the necrotic area can change the biomechanical mechanism of the femoral head,improve the load-supporting ability,and prevent femoral head collapse.Cement filling may be a practical approach for the treatment of osteonecrosis of the femoral head that can be useful for practicing orthopedists.

Objective To develop a pulmonary rehabilitation training system based on scenario simulation for children with bronchiolitis obliterans,and to explore its application effect.Methods A pulmonary rehabilitation training program for children with bronchiolitis obliterans was constructed,and on the basis of this program,a pul-monary rehabilitation training system based on scenario simulation was developed for children with bronchiolitis obliterans,with real-time monitoring of relevant data.44 children with bronchiolitis obliterans who were hospitalized in the Department of Respiratory Medicine of a tertiary A children's specialized hospital in Hunan Province from January to December 2022 were selected by convenience sampling method,and the subjects were divided into an experimental group and a control group with 22 cases in each group.The experimental group adopted a pulmonary rehabilitation training program based on scenario simulation,and the control group implemented pulmonary rehabili-tation through nurse demonstration and guidance.At pre-intervention,4 weeks,and 12 weeks of intervention,the 2 groups were compared in terms of clinical symptom severity,pulmonary function,adherence to pulmonary rehabilita-tion,and the occurrence of pulmonary rehabilitation-related adverse events.Results There were no shedding cases in the experimental group and a case in the control group,and 22 cases were finally included in the experimental group and 21 cases in the control group.The results of repeated measures ANOVA showed that the comparison of clinical symptom severity and pulmonary function between the 2 groups at different time points was statistically sig-nificant in terms of time,between groups and interaction(P＜0.05).Simple effect analysis showed that after 4 and 12 weeks of intervention,the severity of clinical symptoms in the experimental group was lighter than that in the control group,and the difference was statistically significant(P＜0.001).At 12 weeks of intervention,pulmonary func-tion indexes,such as exertional expiratory volume in the first second,exertional lung volume,and maximum expiratory flow rate,were higher in the experimental group than those in the control group,and the difference was statistically significant(P＜0.001).At 4 and 12 weeks of intervention,the compliance of pulmonary rehabilitation in the experi-mental group was higher than that of the control group,and the difference was statistically significant(P＜0.05).At 12 weeks of intervention,the occurrence of adverse events related to pulmonary rehabilitation in the experimental group was less than that in the control group,and the difference was statistically significant(P=0.026).Conclusion The use of a scenario simulation-based pulmonary rehabilitation training system for children with bronchiolitis obliterans can effectively alleviate the clinical symptoms of children,improve their pulmonary function,increase compliance,and reduce the occurrence of pulmonary rehabilitation-related adverse events.