G protein-coupled receptor kinase 2 (GRK2) participates in the phosphorylation and desensitization of G protein-coupled receptor (GPCR), impacting various biological processes such as inflammation and cell proliferation. Dysregulated expression and activity of GRK2 have been reported in multiple cells in rheumatoid arthritis (RA). However, whether and how GRK2 regulates synovial hyperplasia and fibroblast-like synoviocytes (FLSs) proliferation is poorly understood. In this study, we investigated the regulation of GRK2 and its biological function in RA. We found that GRK2 transmembrane activity was increased in FLSs of RA patients and collagen-induced arthritis (CIA) rats. Additionally, we noted a positive correlation between high GRK2 expression on the cell membrane and serological markers associated with RA and CIA. Immunoprecipitation-mass spectrometry and pull-down analyses revealed tumor necrosis factor receptor-associated factor 2 (TRAF2) as a novel substrate of GRK2. Furthermore, surface plasmon resonance (SPR) and molecular docking assays determined that the C-terminus of GRK2 binds to the C-terminus of TRAF2 at the Gln340 residue. GRK2 knockdown and the GRK2 inhibitor CP-25 attenuated synovial hyperplasia and FLS proliferation in CIA both in vitro and in vivo by decreasing GRK2 membrane expression and activity. Mechanistically, increased GRK2 transmembrane activity contributed to the recruitment of TRAF2 on the cell membrane, promoting GRK2-TRAF2 interactions that facilitate the recruitment of the E3 ubiquitin ligase TRIM47 to TRAF2. This enhanced TRAF2 Lys63 polyubiquitylation and induced nuclear factor (NF)-κB activation, leading to synovial hyperplasia and abnormal proliferation of FLSs. Our study provides a mechanistic and preclinical rationale for further evaluation of GRK2 as a therapeutic target for RA.

Objective:To investigate the safety and efficacy of MR-guided focused ultrasound surgery (MRgFUS) in treating localized prostate cancer.Methods:Six patients with localized prostate cancer who underwent MRgFUS treatment from August 2020 to September 2021 in Beijing Hospital were prospectively enrolled in this study. The patients were all over 18 years old, with an average age of (68±10) years, and had not received any prior treatment for prostate cancer. Pretreatment pelvic MR and CT scans were performed to determine the region of treatment (ROT). Different urinary catheterization measures were given based on the location of the lesion. Under general anesthesia, the lesions were treated by MRgFUS using a specialized rectal ultrasound transducer on the treatment bed. The patients were followed up at 1, 3, and 6 months after treatment and annually thereafter. During follow-up, prostate-specific antigen (PSA) levels, pelvic MR scans, International Prostate Symptom Score (IPSS), International Index of Erectile Function-15 (IIEF-15) scores, and adverse events were assessed.Results:(1) All six patients underwent MRgFUS treatment for six lesions, with an average duration of (126±56) minutes, an average number of (7.3±3.2) focal ultrasound pulses per lesion, and an average non-perfusion volume of (3.8±1.1) cm 3, which covered the entire treatment target area. No treatment-related adverse events were reported. (2) The PSA levels at baseline, 1, 3, 6, and 12 months after treatment were (6.6±0.8), (3.6±1.3), (3.4±3.0), (2.5±1.7), and (2.3±1.8) ng/ml, respectively. PSA levels increased in 2 out of 6 patients during follow-up, and pelvic MR scan revealed recurrent lesions, while PSA levels continued to decrease in the remaining 4 patients, and pelvic MR scan were normal. (3) The IPSS scores at baseline, 1, and 3 months after treatment were 13.0 (4.0, 16.0), 10.0 (4.0, 12.0), and 5.0 (3.0, 6.0) points, respectively. For the three sexually active patients, the IIEF-15 scores at baseline were 40, 51, and 14 points, respectively, and IIEF-15 at 1 month after treatment were 9, 8, and 14 points, respectively, and at 3 months after treatment were 9, 66 and 26 points, respectively. (4) One patient was diagnosed with recurrence 10 months after treatment, and another patient was found to have a new lesion 6 months after treatment. Conclusions:MRgFUS might be a safe, non-invasive, and effective treatment for localized prostate cancer, but regular follow-up is vital for detecting tumor recurrence.

We reported a case of polyglandular syndrome induced by programmed death-1(PD-1) inhibitors. The patient was a 51-years-old male with non-small cell lung cancer, treated with PD-1 inhibitor nivolumab/pembrolizumab because of postoperative subcarinal lymph node metastasis indicated by PET-CT. During 14 cycles of PD-1 inhibitor treatment, the patient successively developed primary hypothyroidism, and type 1 diabetes mellitus(T1DM). More than five months after the withdrawal of pembrolizumab, the patient experienced recurrentce. Laboratory examinations showed mild hyponatremia and hypopituitarism including ACTH and growth hormone(GH)/insulin-like growth factor-1(IGF-1) insufficiency. This is the first report of a patient diagnosed as polyglandular syndrome caused by PD-1 inhibitor. In particularly, the hypothyroidism and T1DM did not improve after drug withdrawal, while hypopituitarism was further aggravated. This case reminds us that we should pay more attention to the changes of endocrine function during and after the treatment of PD-1 inhibitor, so that we can make the correct diagnosis and take proper medical measures timely, to avoide missed diagnosis, and improper treatment.

Objective:To evaluate the feasibility, safety and efficacy of the magnetic resonance imaging guided focused ultrasound surgery (MRgFUS) in the treatment of localized prostate cancer (PCa).Methods:The data of 5 patients treated by MRgFUS from August 2020 to June 2021 in our institution were retrospectively analyzed. The median age was 73 (58-80) years, with the median PSA of 7.34 (5.19-8.40) ng/ml, and a median prostate volume of 27.96 (21.50-37.91) ml. The median pretreatment international prostate symptom score (IPSS) was 13(0-18). Of the 3 patients with intention of erectile function preservation, the pretreatment international index of erectile function-15 (IIEF-15) score was 12, 23 and 3, respectively. All patients had histopathology-proven PCa of grade group ≤ International Society of Urological Pathology (ISUP) 3, pre-operative PSA level <20 ng/ml, and a clinical stage ≤T 2b. A total of 6 lesions was confirmed by biopsy, with 3 of ISUP grade group 3 and 3 of ISUP grade group 1. All 5 patients underwent MRgFUS which was guided by a real-time magnetic resonance imaging (MRI). PSA, MRI and repeated biopsy were conducted to monitor recurrence. Questionnaires consisted of IPSS, IIEF-15, and the International Consultation on Incontinence-questionnaire-Short Form (ICI-Q-SF) were recorded before and after MRgFUS to evaluate the impact on functional preservation. Results:A total of 5 patients received MRgFUS. In total, 5 of the 6 lesions were treated. 1 lesion unvisible on MRI was not clinically significant and was left untreated. The median time in MRI scanner was 190 (140-355) min, and the median sonication time was 64 (35-148) min with the median sonications of 8 (5-13). The median catheter indwelling time was 1 (1-8) days. No other adverse effects were reported. The PSA level of all 5 patients decreased, with the nadir PSA of 1.196 ng/ml, 4.398 ng/ml, 4.135 ng/ml, 1.562ng/ml and 1.350ng/ml, respectively. 4 of the patients had a PSA decrease over 50%. No PCa lesion was seen on MRI at 3-month follow-up visit. As for functional preservation, the post-MRgFUS IPSS declined compared with the baseline score, and the IPSS of last follow-up was 5(0-14). Of the 3 patients with intention to preserve the erectile function, the erectile function score of IIEF-15 were 12, 30 and 9 three months after the treatment, respectively. No incontinence occurred postoperatively.Conclusions:MRgFUS is a feasible and safe way for the treatment of low- to intermediate-risk localized PCa, with satisfactory performance on functional preservation and low incidence of complications. The oncological outcomes still need to be establised with longer follow-up time and larger sample studies.

Objective To compare the efficacy and safety of the long-term intermittent maintenance treatment with tacrolimus 0.03％ ointment versus traditional treatment in reducing relapses and prolonging the recurrence interval in children with moderate to severe atopic dermatitis (AD).Methods A two-phase randomized,open-labelled,controlled clinical trial was conducted from September 2012 to November 2013.In the first phase,a total of 171 children aged 2-15 years with moderate to severe AD were enrolled from 7 hospitals in China,and received conventional treatment with tacrolimus 0.03％ ointment twice a day for 2-6 weeks.At the end of the treatment,the patients who achieved an investigator's global assessment (IGA) score ≤ 2 (n =125) were randomly classified into 2 groups to receive the second-phase treatment:test group (n =62) receiving intermittent maintenance treatment with tacrolimus 0.03％ ointment twice a week (Monday and Thursday),and control group (n =63) receiving no treatment.If the patients in the 2 groups experienced relapse,they received conventional treatment with tacrolimus 0.03％ ointment twice a day.The overall observation period was 6 months.The primary endpoint was the time to the first relapse,which was defined as the number of days from the end of the first-phase treatment to the first relapse.The secondary endpoints included the number of relapses at the second-phase trial,the disease severity at the time of relapse,the duration of relapse,the pruritus score at the time of relapse,the total amount of tacrolimus ointment used,the total response rate at the second-phase trial,and the incidence of adverse events.Results A total of 125 children with AD were enrolled into the second-phase trial,and 121 of them completed the follow-up.Among the 121 patients,the recurrence rate was significantly lower in the test group (25/60,41.7％) than in the control group (46/61,75.4％;x2 =14.20,P ＜ 0.001).The time to the first relapse was significantly longer in the test group (46.9 ± 37.7 d) than in the control group (28.8 ± 32.3 d;Z =1 093.50,P =0.020).The total number of recurrence was 31 and 86 in the test group and control group respectively,and the mean number of recurrence in each patient was significantly lower in the test group (0.52 ± 0.68) than in the control group (1.41 ± 1.23,t =4.96,P ＜ 0.001).There were no significant differences between the two groups regarding disease severity during relapse (eczema area and severity index:Z =971.50,P =0.39),duration of relapse (Z =747.00,P =0.07),and pruritus score during relapse (Z =894.00,P =0.95).The therapeutic drug was tolerated well in all the children,and no tacrolimus-related serious adverse events occurred.Conclusion The intermittent maintenance treatment with tacrolimus 0.03％ ointment twice a week for 6 months can effectively and safely prevent and reduce relapses,and prolong the recurrence interval in children with moderate to severe AD.