HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

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Objective:To investigate the association between the Doppler variables of the ophthalmic artery with the severity of preeclampsia(PE).Methods:Systematic literature was searched between January 1995 and March 2023 in PubMed,Web of Science,Embase,and the Cochrane Library.Studies comparing ophthalmic artery Doppler variables,including peak systolic velocity(PSV),end-diastolic velocity(EDV),resistive index(Rl),pulsa-tility index(PI),and peak ratio(PR,the ratio of the flow velocity of the second peak to that of the initial peak)in patients with PE,severe preeclampsia(sPE),and healthy pregnant women were included.The random-effects model was adopted as the method of pooled analysis,and the I2value was used to assess heterogeneity.The pooled standardized mean difference(SMD)with 95％confidence interval(CI)was used to estimate the associa-tion between ophthalmic artery Doppler variables and PE patient's characteristics.Results:Eight retrospective studies were eventually included in this Meta-analysis.Our pooled results suggested that compared with PE ca-ses,sPE patients had lower PI levels(SMD-0.56,95％CI-0.92～-0.20,P=0.000),higher EDV levels(SMD 0.47,95％CI 0.12～0.83,P=0.028)and higher PR levels(SMD0.96,95％CI 0.13～1.78,P=0.023).Howev-er,there was no significant difference between PE and sPE patients about the PSV and RI(P=0.361,P=0.626).Conclusions:This review demonstrates that ophthalmic artery Doppler variables(PI,EDV and PR)could be useful for predicting PE and PE development(especially in identifying sPE),which in turn may help the practitioner in the management of these complicated cases and in taking early necessary precautions.

OBJECTIVE To investigate the intervention effect and potential mechanism of breviscapine on hepatic fibrosis （HF） in rats based on the transforming growth factor-β（1 TGF-β1）/Smad2/extracellular signal-regulated protein kinase 1（ERK1） and Kelch-like epichlorohydrin-associated protein 1（Keap1）/nuclear factor-erythroid 2-related factor 2（Nrf2）/heme oxygenase-1（HO-1） pathways. METHODS Totally 60 rats were randomly divided into normal control group， model group， breviscapine low-dose， medium-dose and high-dose groups （5.4， 10.8， 21.6 mg/kg）， and colchicine group （positive control， 0.45 mg/kg）， with 10 rats in each group， half male and half female. Except for the normal control group， HF model of the other groups was induced by carbon tetrachloride. Subsequently， each drug group was given corresponding medicine by gavage once a day for 28 days. The liver appearance of rats in each group was observed and their liver coefficients were calculated. The levels of alanineaminotransferase （ALT） and aspartate aminotransferase （AST）in serum， those of ALT， AST， superoxide dismutase （SOD），malondialdehyde （MDA） and glutathione peroxidase （GSH- Px） in liver tissue were detected. The liver tissue inflammatory and fibrotic changes were observed. The protein and mRNA expressions of TGF-β1， Smad2， ERK1， Nrf2， Keap1 and HO-in liver tissue were detected. RESULTS Compared with the normal control group， the model group showed large areas of white nodular lesions in the liver， obvious inflammatory cell infiltration and collagen fiber deposition. The body weight， the levels of SOD and GSH-Px in liver tissue， the protein and mRNA expressions of Nrf2 and HO-1 were significantly lowered in the model group （P＜0.05）； the liver coefficient， the percentage of Masson staining positive area， ALT and AST levels of serum and liver tissue， MDA level of liver tissue， the protein and mRNA expressions of TGF-β1， Smad2， ERK1 and Keap1 were significantly increased （P＜0.05）. Compared with the model group， the liver lesions of rats in each drug group were improved， and the above quantitative indexes were generally reversed （P＜0.05）. CONCLUSIONS Breviscapine has a good intervention effect on HF rats， which may be related to inhibiting TGF-β1/Smad2/ERK1 pathway for anti-fibrosis and regulating Keap1/Nrf2/HO-1 pathway to inhibit oxidative stress.

Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy in vivo, improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives' inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.

Objective:To investigate the effects of Satir model group intervention on stress coping style, self-consistency and congruence and subjective well-being of re-employment nurses, in order to provide evidence for nursing managers to take targeted intervention measures.Methods:This was a quasi-experimental study. Convenience sampling was used to select 63 re-employment nurses from Shandong Provincial Third Hospital in 2021 as the research objects. The re-employment nurses were divided into control group (32 cases) and observation group (31 cases) by random number table method. The control group received humanistic care including heart-to-heart talk, group discussion and psychological lecture, and the observation group received Satir model group intervention for 6 weeks. Simplified Coping Style Questionnaire, Self Consistency and Congruence Scale and General Well-Being Scale were used to evaluate the intervention effect before intervention, immediately after intervention, 3 months after intervention, and 6 months after intervention.Results:There was no significant difference in coping style, self-consistency and congruence and subjective well-being between the two groups before intervention ( P>0.05). The positive coping scores of the observation group immediately after intervention, 3 months after intervention and 6 months after intervention were (28.94 ± 2.99), (28.71 ± 4.70) and (29.16 ± 3.23) points, significantly higher than the control group (23.38 ± 5.50), (24.72 ± 5.91), (24.65 ± 5.65) points, the differences were statistically significant ( t=4.96, 2.96, 3.87, all P<0.01); the total self-consistency and congruence scores were (94.52 ± 14.00), (99.87 ± 16.82), (91.84 ± 10.36) points, significantly lower than the control group (105.72 ± 10.75), (114.23 ± 20.10), (107.41 ± 13.39) points, the differences were statistically significant ( t=-3.57, -3.07, -5.15, all P<0.01); the total subjective well-being scores were (84.97 ± 7.37), (84.58 ± 10.33), (91.84 ± 7.01) points, which were higher than the control group (75.69 ± 7.94), (77.28 ± 8.27), (77.00 ± 8.48) points, and the differences were statistically significant ( t=4.80, 3.69, 7.56, all P<0.01). Conclusions:Satir model group intervention can improve the coping style, enhance the level of self-consistency and congruence and subjective well-being among re-employment nurses.

The rapid spread of carbapenemase-producing Klebsiella pneumoniae(cpKP)poses seri-ous threats to public health;however,the underlying genetic basis for its dissemination is still unknown.We conducted a comprehensive genomic epidemiology analysis on 420 cpKP isolates col-lected from 70 hospitals in 24 provinces/autonomous regions/municipalities of China during 2009-2017 by short-/long-read sequencing.The results showed that most cpKP isolates were categorized into clonal group 258(CG258),in which ST11 was the dominant clone.Phylogenetic analysis revealed three major clades including the top one of Clade 3 for CG258 cpKP isolates.Additionally,carbapenemase gene analysis indicated that blaKPC was dominant in the cpKP isolates,and most blaKPC genes were located in five major incompatibility(Inc)groups of blaKPC-harboring plasmids.Importantly,three advantageous combinations of host-blaKPC-carrying plasmid(Clade 3.1+3.2-IncFⅡpHN7A8,Clade 3.1+3.2-IncFⅡpHN7A8:IncR,and Clade 3.3-IncFⅡpHN7A8:InCpA1763-KPC)were identified to confer cpKP isolates the advantages in both genotypes(strong correlation/coevolution)and phenotypes(resistance/growth/competition)to facilitate the nationwide spread of ST11/CG258 cpKP.Intriguingly,Bayesian skyline analysis illustrated that the three advanta-geous combinations might be directly associated with the strong population expansion during 2007-2008 and subsequent maintenance of the population of ST11/CG258 cpKP after 2008.We then examined drug resistance profiles of these cpKP isolates and proposed combination treatment regimens for CG258/non-CG258 cpKP infections.Thus,the findings of our systematical analysis shed light on the molecular epidemiology and genetic basis for the dissemination of ST11/CG258 cpKP in China,and much emphasis should be given to the close monitoring of advantageous cpKP-plasmid combinations.

Objective:To explore the effect of goal-oriented rehabilitation nursing in patients with thoracolumbar fracture.Methods:From April 2019 to April 2021, 109 patients with thoracolumbar fracture admitted to the Shandong Provincial Third Hospital were selected as the study subject by convenience sampling. The patients admitted from April 2019 to April 2020 were set as the control group ( n=57) , and the patients admitted from May 2020 to April 2021 were set as the observation group ( n=52) . The patients in the control group received routine rehabilitation management, while the patients in the observation group received goal-oriented rehabilitation nursing on the basis of the control group. The hospitalization time, the inidence of complications and lower limb motor function before and after intervention were compared between the two groups. Results:The hospitalization time of patients in the observation group was shorter than that in the control group, and the incidence of complications was lower than that in the control group, and the differences were statistically significant ( P<0.05) . After the intervention, the lower limb motor function score of the patients in the observation group was higher than that of the control group, with a statistically significant difference ( P<0.05) . Conclusions:The goal-oriented rehabilitation nursing in patients with thoracolumbar fracture can shorten the rehabilitation time, improve limb function, and reduce the risk of complications.

Objective To assess the clinical ultrasound value of layer‐specific strain in evaluation of left ventricular systolic myocardial dysfunction of uremia patients after long‐time dialysis at different time . Methods A total of 68 uremia patients accepted maintenance hemodialysis ( M HD ) were enrolled . T he patients were divided into two groups according to the dialysis duration :dialysis time ＜3 years ( group B , n＝31) and dialysis time ≥3 years ( group C , n ＝37) . T he age and sex mached healthy cases were selected as control group ( group A , n ＝ 30 ) . T he standard dynamic two‐dimensional echocardiographic viewes of apical four‐chamber ,three‐chamber ,two‐chamber and the short‐axis view at three levels of mitral valve , papillary muscle and apex were acquired for three cardiac cycles . T he highest value of peak systolic longitudinal strain ( LS ) ,circumferential strain ( CS ) at different levels ,left venrticular global longitudinal strain ( GLS ) and global circumferential strain ( GCS ) were respectively assessed from endocardium ,mid‐myocardium and epicardium using GE EchoPAC workstation . T he comparisons of those parameters were performed among the 3 groups for differences . T he efficacies of GLS and GCS at different myocardial layers in diagdosing the left ventricular systolic function of M HD patients were analyzed by the ROC curve . Results ① Global transmural parameters :compared with those in group A ,the values of GLS at three myocardial layers in both M HD groups were significantly decreased ( all P ＜ 0 .01 ) ,the value of GLS at three myocardial layers in group C was also decreased ,and was statistically different from that in group B ( P＜0 .01) . Compared with those in group A ,the values of GCS at mid‐myocardium in group B and three myocardial layers in group C were also decreased ( all P ＜0 .01) . T here was no significant difference of GCS between group B and C ( P ＞0 .05) . ②Longitudinal transmural parameters at different levels :the values of LS at three myocardial layers of mitral valve ,papillary muscle and apex were decreased in group B and C compared with those in group A ( P ＜0 .05 or P ＜0 .01) ; T he values of LS at three myocardial layers of mitral valve ,papillary muscle and apical levels were also decreased in group C compared with those in group B ( P ＜0 .05 or P ＜0 .001) . ③Short‐axis transmural parameters at different levels :compared with those in group A ,the value of CS at mid‐myocardium of mitral valve level was decreased in group B ( P ＜0 .05) ,the values of CS at three myocardial layers of the mitral valve level and mid‐myocardium of papillary muscle level and apical level were decreased in group C ( P ＜0 .05 or P ＜0 .01) . Besides ,compared with those in group B ,the values of CS at mid‐myocardium and epicardium of mitral valve level were also decreased in group C ( P ＜0 .05) . ④ROC curve showed that determining left ventricular systolic dysfunction in M HD patients using GLS ,GCS at different myocardial layers ,when the area under the curve ( AUC ) of GLS of intima was 0 .851 ,the cut‐off value was －21 .45% ,the sensitivity was 72 .7% ,and the specificity was 93 .3% ; when the AUC of GCS of mid‐myocardium was 0 .683 ,the cut‐off value was －17 .08% , the specificity was 58 .5% , and the specificity was 83 .3% . Conclusions T he left ventricular systolic myocardial function is progressively damaged with the extended dialysis duration time . Ultrasonic layer‐specific strain technology could be used to quantitatively evaluate left ventricular systolic transmural myocardial dysfunction and might contribute to the evaluation of the severity of left ventricular myocardial dysfunction clinically for a more accurate intervention .

Objectives To investigate the ability of T1 mapping and intravoxel incoherent motion imaging (IVIM) parameters for evaluating renal allografts at the early stage after renal transplantation. Methods This prospective study protocol was approved by the local ethics committee, and written informed consent was obtained from all subjects. Sixty two recipients 2 to 4 weeks after kidney transplantation and 20 healthy volunteers (control group) underwent routine MRI, T1 mapping, and IVIM imaging (11 b values, 0 to 700 s/mm2). Recipients were divided into two groups base on their estimated glomerular filtration rate (eGFR):37 recipients with good allograft function (eGFR≥60 ml·min-1·1.73 m-2) and 25 recipients with impaired allograft function (eGFR<60 ml·min-1·1.73 m-2). The ADC, true diffusion coefficient (ADCslow), pseudo-diffusion coefficient (ADCfast), perfusion fraction (f) and T1 values were measured on both cortex and medulla. Differences among groups were compared using the one-way analysis of variance. Correlations between eGFR and the parameters in renal allografts were assessed by using Pearson correlation analysis. ROC was performed to assess the diagnostic utilities of using these parameters to discriminate allografts with impaired function from good function. Results Excepting for cortical T1, ADCfast and medullary T1, f values, allografts with good function showed no differences in other parameters compared with healthy control. Excepting for medullary T1 and ADCfast,the other values showed significantly differences in allografts with impaired function compared to allografts with good function (all P<0.05). Excepting for medullary f and ADCfast values, allografts with impaired function showed significantly differences in the parameters compared with good function group(all P<0.05). In renal allografts, excepting for medullary T1, ADCfast, and f values, cortical T1 exhibited a negative correlation with renal function, and there was a significant positive correlation between eGFR and other parameters. Cortical T1 value showed high sensitivity(91.9%) to discriminate renal allografts with different function, with the threshold of 17.36 × 102 ms, and ADC value showed high specificity(96.0%)with the threshold of 1.98 × 10-3 mm2/s. Conclusion T1 mapping and IVIM technique may be useful for detecting renal allograft dysfunction, and be a reliable imaging for evaluating and monitoring allograft function.