Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Psoriasis is a chronic inflammatory skin disease, and its pathogenesis is largely modulated by abnormal angiogenesis. Previous research has indicated that AlkB homolog 5 (ALKBH5), an important demethylase affecting N⁶-methyladenosine (m⁶A) modification, plays a role in regulating angiogenesis in cardiovascular and eye diseases. Our present study found that ALKBH5 was upregulated and co-localized with cluster of differentiation 31 (CD31) in the skin of IMQ group compared with control group. ALKBH5-deficient mice decreased IMQ-induced psoriatic dermatitis and exhibited histological improvements, including decreased epidermal thickness, hyperkeratosis, numbers of dermal capillary vessels and inflammatory cell infiltration. ALKBH5-KO mice alleviated angiogenesis in psoriatic lesions by downregulating the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Additionally, the expression of ALKBH5 was significantly upregulated in IL-17A-induced human umbilical vein endothelial cells (HUVECs), which further promoted the expression of angiogenesis-related cytokines and endothelial cell proliferation. Cell proliferation and angiogenesis were suppressed in ALKBH5 knockdown group, whereas ALKBH5 overexpression promoted these processes. The regulation of angiogenesis in HUVECs by ALKBH5 was facilitated through the AKT-mTOR pathway. Collectively, ALKBH5 plays a pivotal role in psoriatic dermatitis and angiogenesis, which may offer a new potential targets for treating psoriasis.
Animals ; Psoriasis/chemically induced* ; Mice ; Humans ; Neovascularization, Pathologic/genetics* ; Human Umbilical Vein Endothelial Cells/metabolism* ; AlkB Homolog 5, RNA Demethylase/genetics* ; Proto-Oncogene Proteins c-akt/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Cell Proliferation ; Mice, Knockout ; Disease Models, Animal ; Signal Transduction ; Male ; Skin/blood supply* ; Mice, Inbred C57BL ; Angiogenesis

Objective:To investigate the risk factors of moderate to severe pain in patients with non-small cell lung cancer within 3 days after lobectomy.Methods:The clinical data of 297 patients with non-small cell lung cancer who underwent lobectomy in the Department of Thoracic Surgery, Sun Yat-sen University Cancer Center from December 2020 to June 2021 were retrospectively analyzed. A numerical rating scale was used to score the most severe pain within 3 days after surgery. Pain score ≥ 4 was defined as moderate to severe pain. The risk factors for moderate to severe pain were analyzed by binary Logistic regression. General linear model repeated measures and linear mixed models were used to analyze the trend of risk factors influencing postoperative pain with time.Results:The incidence of moderate to severe pain was 34.2% (102/297), 59.8% (178/297), 66.4% (198/297), and 28.2% (84/297) on days 0, 1, 2, and 3 after surgery respectively. The risk for moderate to severe pain was significantly higher in patients undergoing thoracotomy than patients undergoing thoracoscopic surgery on days 1 ( OR = 1.99, P = 0.009), 2 ( OR = 3.08, P < 0.001), and 3 ( OR = 3.88, P < 0.001) after surgery. However, the risk for moderate to severe pain in patients undergoing thoracotomy was slightly, but not significantly, higher than that in patients undergoing thoracoscopic surgery ( OR = 1.53, P = 0.087). The risk for moderate to severe pain was higher in female patients than male patients on day 2 ( OR = 1.62, P = 0.077), and in particular on day 3 after surgery ( OR = 2.39, P = 0.002). Prophylactic use of parecoxib significantly reduced the risk of moderate to severe pain on day 0 ( OR = 0.32, P = 0.004), 1 ( OR = 0.20, P < 0.001), 2 ( OR = 0.36, P < 0.001) and 3 ( OR = 0.56, P = 0.047). Conclusion:The incidence of moderate to severe pain on days 1 and 2 after lobectomy was relatively high in patients with non-small cell lung cancer. Patients undergoing thoracotomy have a higher risk of moderate to severe pain than those who underwent thoracoscopic surgery. Female patients have a higher risk for moderate to severe pain on days 2 and 3 after surgery than male patients. Prophylactic use of parecoxib can decrease the risk for moderate to severe pain in patients with non-small cell lung cancer.

Objective:To study the risk factors of adverse pregnancy outcomes for the diagnosis and treatment of pregnancy after cesarean section complicated with placenta previa.Methods:A national multicenter retrospective study was conducted to select a total of 747 pregnant women with the third trimester singleton pregnancy after cesarean section complicated with placenta previa from 12 tertiary hospitals in January 1st to December 31st, 2018. The risk factors of severe adverse outcomes [hysterectomy, intraoperative blood loss ≥1 000 ml, intraoperative diagnosis of placenta accreta spectrum disorders (PAS)] in pregnant women with second pregnancy complicated with placenta previa after cesarean section were investigated by logistic regression analysis. The roles of prenatal ultrasonography and magnetic resonance imaging (MRI) in the prediction of PAS and severe adverse outcomes were observed. According to whether vascular intervention was performed (uterine artery embolization or abdominal aortic balloon occlusion), the pregnant women were divided into the blocked group and the unblocked group, and the maternal and infant perinatal outcomes between the two groups were compared.Results:(1) General information: the hysterectomy rate of 747 pregnant women with second pregnancy complicated with placenta previa after cesarean section was 10.4% (78/747), the intraoperative blood loss ≥1 000 ml in 55.8% (417/747), and PAS was confirmed in 47.5% (355/747). The incidence of uterine rupture was 0.8% (6/747). (2) Analysis of risk factors for severe adverse outcomes: based on binary unconditioned logistic regression univariate and multivariate analysis, the risk factors for hysterectomy were the mode of vascular embolization and intraoperative blood loss. The probability of hysterectomy with uterine artery embolization was 5.319 times higher than that with abdominal aortic balloon occlusion (95% CI: 1.346-21.018). The risk factors of intraoperative blood loss ≥1 000 ml were the number of cesarean section delivery, ultrasonography indicated PAS and suspected PAS, intraoperative PAS and complete placenta previa. The risk factors for intraoperative PAS were uterine scar thickness, ultrasonography indicated PAS and suspected PAS, MRI indicated PAS and suspected PAS, and complete placenta previa. (3) The roles of ultrasonography and MRI in predicting PAS: the sensitivity and specificity of ultrasonography in predicting PAS were 47.5% and 88.4%; the kappa value was 0.279 ( P<0.001), with fair agreement. The sensitivity and specificity of MRI to predict PAS were 79.2% and 97.8%, respectively. The kappa value was 0.702 ( P<0.001), indicating a good agreement. The intraoperative blood loss and hysterectomy rate of pregnant women with PAS indicated by ultrasonography and MRI were significantly higher than those with PAS only by ultrasonography or MRI. (4) Influence of vascular occlusion on pregnancy outcome: there were no significant differences in intraoperative blood loss and incidence of intraoperative bleeding ≥1 000 ml between the blocked group and the unblocked group (all P>0.05). There was no significant difference in intraoperative blood loss between the pregnant women with abdominal aortic balloon occlusion, uterine artery embolization and those without occlusion ( P=0.409). The hysterectomy rate of pregnant women with uterine artery embolization was significantly higher than those with abdominal aortic balloon occlusion [39.3% (22/56) vs 10.0% (5/50), P=0.001]. Conclusions:In the third trimester of pregnancy with placenta previa after cesarean section, MRI examination has better consistency in predicting PAS than ultrasonography examination. Ultrasonography examination combined with MRI examination could effectively predict the hysterectomy rate and intraoperative blood loss. Vascular occlusion could not reduce the amount of intraoperative blood loss. The hysterectomy rate of pregnant women with uterine artery embolization is higher than those with abdominal aortic balloon occlusion.

Objective:To study the risk factors of adverse pregnancy outcomes for induced abortion of cesarean scar pregnancy in midtrimester.Methods:A national multicenter retrospective study was conducted. A total of 154 singletons pregnant women with cesarean scar pregnancy during the second trimester induced abortion by various reasons in 12 tertiary A hospitals were selected, their pregnant outcomes were observed and the risk factors of serious adverse outcomes were analyzed with univariate and multivariate logstic regression; the role of ultrasound and MRI in predicting placenta accreta and severe adverse outcomes was evaluated, the effectiveness of uterine artery embolization (UAE) in preventing hemorrhage in pregnant women with and without placenta accreta was compared.Results:Among 154 subjects, the rate of placenta accreta was 42.2% (65/154), the rate of postpartum hemorrhage≥1 000 ml was 39.0% (60/154), the rate of hysterectomy was 14.9% (23/154), the rate of uterine rupture was 0.6% (1/154). The risk factor of postpartum hemorrhage≥1 000 ml and hysterectomy was placenta accreta ( P<0.01). For each increase in the number of parity, the risk of placenta accreta increased 2.385 times (95% CI: 1.046-5.439; P=0.039); and the risk of placenta accreta decreased with increasing ultrasound measurement of scar myometrium thickness ( OR=0.033, 95% CI: 0.001-0.762; P=0.033). The amount of postpartum hemorrhage and hysterectomy rate in the group with placenta accreta diagnosed by ultrasound combined with MRI were not significantly different from those in the group with placenta accreta diagnosed by ultrasound only or MRI only (all P>0.05). For pregnant women with placenta accreta, there were no significant difference in the amount of bleeding and hysterectomy rate between the UAE group [median: 1 300 ml; 34% (16/47)] and the non-embolization group (all P>0.05); in pregnant women without placenta accreta, the amount of bleeding in the UAE group was lower than that in the non-embolization group (median: 100 vs 600 ml; P<0.01), but there was no significant difference in hysterectomy rate [2% (1/56) vs 9% (3/33); P>0.05]. Conclusions:(1) Placenta accreta is the only risk factor of postpartum hemorrhage≥1 000 ml with hysterectomy for induced abortion of cesarean scar pregnancy in midtrimester; multi-parity and ultrasound measurement of scar myometrium thickness are risk factors for placenta accreta. (2) The technique of using ultrasound and MRI in predicting placenta accreta of cesarean scar pregnancy needs to be improved. (3) It is necessary to discuss of UAE in preventing postpartum hemorrhage for induced abortion of cesarean scar pregnancy in midtrimester.

Objective To observe the clinical effect of the Bushen-Qiangjin capsule and calcium D in the treatment of aromatase inhibitors-associated bone loss (AIBL) in breast cancer patients. Methods A total of 65 patients were randomized into a treatment group and a control group, 32 in the control group taking calcium D, and 33 in the treatment group taking calcium D and Bushen-Qiangjin capsule. After a 3-month treatment, the bone mineral density T (BMD), bone-specific alkaline phosphatase (BALP), bone gla protein (BGP) and tartrate resistant acid phosphatase (TrACP) of two groups were evaluated. Results The BMD increased significantly after treatment in both groups (P<0.05), and the therapeutic efficacy of the treatment group was better than of the control group (P<0.05). After treatment, the level of BALP (308.76 ± 10.99 U/L vs. 280.00 ± 7.44 U/L, t=8.170) and the BGP (42.21 ± 3.04 ng/ml vs. 34.38 ± 2.06 ng/ml, t=6.818) of the treatment group were significantly higher than those of the control group (P<0.01). The level of TrACP decreased significantly after treatment in both groups (P<0.05), and the TrACP (60.12 ± 4.58 U/L vs. 67.25±4.06 U/L, t=1.653) of treatment group was significantly lower than that of the control group (P<0.05). Conclusions The Bushen-Qiangjin capsule can produce a content efficacy in treating AIBL in breast cancer patients, improving the BMD and bone metabolism.

Objective To investigate the physical and magnetic properties and cytotoxity of 5-FAM-dextran-coated superparamagnetic iron oxide nanoparticles ( 5-FAM-dextran-Fe3 O4 ) , and to observe the cell-labeling character of these nanoparticles. Methods 5-FAM-dextran-Fe3 O4 were prepared by ultra-sonic and chemical coprecipitation method and the characteristics were evaluated. The size and distribution of 5-FAM-dextran-Fe3 O4 were measured by transmission electron microscope ( TEM) and Malvern Zetasizer. The organic structure of the coating was characterized by fourier translation infrared spectroscopy. The optical imaging ability was measured by ultraviolet visible spectrometer and the susceptibility was measured by vi-brating sample magnetometer. In vitro cytotoxities of 5-FAM-dextran-Fe3 O4 , dextran-Fe3 O4 and Fe3 O4 were detected by MTT assay. The area of labeled neuronal cells was observed by confocal microscopy after incuba-ted with nanoparticles under different magnetic intensities. One-way analysis of variance was used. Results The size of 5-FAM-dextran-Fe3 O4 was homogeneous under TEM, and the diameter ranged from 15 to 25 nm ( average=22 nm) by Malvern Zetasizer. The organic structure of the coating of Fe3 O4 was confirmed by fou-rier translation infrared spectroscopy. Ultraviolet visible spectrometer observation showed that the nanoparti-cles expressed unanimous green fluorescence under ultraviolet activation. The saturation magnetization, residu-al magnetization and coercivity of the nanoparticles by magnetometer detection were 86. 02 A · m2 · kg-1 , 15. 05 A·m2 ·kg-1 and 5414.01 A/m respectively, showing superparamagnetic character. MTT assay re-sults showed that 5-FAM-dextran-Fe3 O4 had no obvious cytotoxicity. The confocal microscopy observation in-dicated that the cell-labeled area reached the maximum under the magnetic field intensity of 500 mT ((0. 880±0.146) mm2, F=320.298, P<0.05). Conclusions 5-FAM-dextran-Fe3O4 prepared by ultra-sonic coprecipitation method have the advantages of small size, good homogeneity and magnetic property. Therefore, they might be used as the fluorescent magnetic bio-probe in laboratory and clinical studies.

Objective To evaluate clinical application value of critical flicker frequency (CFF),psychometric hepatic encephalopathy score (PHES) and Stroop test in the diagnosis of covert hepatic encephalopathy (CHE).Methods A total of 110 patients with decompensated liver cirrhosis and 54 individuals without liver diseases were enrolled as control group.According to PHES＜-4 points as reference threshold for CHE,the threshold of CFF and time of Stroop test for CHE diagnosis was caculated.Positive results of at least two of PHES,CFF and Stroop tests was considered as the gold standard for CHE diagnosis,and then the value of these three methods in CHE diagnosis was evaluated.Student's t test and receiver operating characteristic curve (ROC) were used for statistical analysis.Results Among the 110 patients with liver cirrhosis,40 patients had no hepatic encephalopathy (HE0),52 patients had CHE,and 18 patients had grade 2 hepatic encephalopathy (HE2).The CFF value and total time of Stroop test of control group were (43.70±1.92) Hz and (201.17±20.65) s,respectively.The CFF value of HE0 group was (41.40 ± 1.85) Hz,which was higher than that of CHE group ((38.33 ± 2.32) Hz),and the difference was statistically significant (t=-7.116,P＜0.01).The total time of Stroop test of HE0 group was (197.91±26.68) s,which was shorter than that of CHE group ((253.24± 33.33) s),and the difference was statistically significant (t=8.936,P＜0.01).When PHES＜-4 points was considered as a reference threshold of CHE,the threshold of CFF for CHE diagnosis was 39 Hz,the sensitivity was 94.9％ and the specificity was 73.1％,the area under the curve (AUC) was 0.879.The threshold of the total time of Stroop test for CHE diagnosis was 233.80 s,the sensitivity was 83.3 ％ and the specificity was 71.1％,the AUC was 0.803.The completion time of the number connection test (NCT)-A,NCT-B and digit symbol test (DST),which were there of five subtests of PHES,of CHE group were (80.27±36.05) s,(124.18±55.96) s and (25.03±8.23) s,respectively,compared with those of HE0 patients ((56.68±18.82) s,(80.00±25.58) s and (34.68±8.75) s,respectively),the differences were statistically significant (t =3.691,4.108 and-4.780;all P＜0.01).Compared with the results of combined PHES and Stroop test in the diagnosis of HE0,CHE and HE2,the consistency rates of CFF＜39 Hz as threshold for diagnosis were 95.0％,61.5％ and 100.0％,respectively.Conclusions NCT-A,NCT-B and DST three subtests of PHES have higher efficiency in CHE diagnosis.CFF and Stroop test are also reliable screening methods for CHE,with advantage of objectivity and high specificity.

Non-drug treatment of hypertension has become a research hotspot, which might overcome the heavy economic burden and side effects of drug treatment for the patients. Because of the good treatment effect and convenient operation, a new treatment based on slow breathing training is increasingly becoming a kind of physical therapy for hypertension. This paper explains the principle of hypertension treatment based on slow breathing training method, and introduces the overall structure of the portable blood pressure controlling instrument, including breathing detection circuit, the core control module, audio module, memory module and man-machine interaction module. We give a brief introduction to the instrument and the software in this paper. The prototype testing results showed that the treatment had a significant effect on controlling the blood pressure.
Biofeedback, Psychology ; methods ; Blood Pressure ; Humans ; Hypertension ; therapy ; Physical Therapy Modalities ; instrumentation