Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Ferroptosis (FPT), a novel form of programmed cell death, is characterized by overwhelming iron/reactive oxygen species (ROS)-dependent accumulation of lipid peroxidation (LPO). However, the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent. To overcome this obstacle, the bromodomain-containing protein 4 (BRD₄)-inhibitor (+)-JQ1 (JQ1) and iron-supplement ferric ammonium citrate (FAC)-loaded gold nanorods (GNRs) are encapsulated into the zeolitic imidazolate framework-8 (ZIF-8) to form matchbox-like GNRs@JF/ZIF-8 for the amplified FPT therapy. The existence of matchbox (ZIF-8) is stable in physiologically neutral conditions but degradable in acidic environment, which could prevent the loaded agents from prematurely reacting. Moreover, GNRs as the drug-carriers induce the photothermal therapy (PTT) effect under the irradiation of near-infrared II (NIR-II) light owing to the absorption by localized surface plasmon resonance (LSPR), while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment (TME). On one hand, the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron (Fe³⁺/Fe²⁺) and ROS to initiate the FPT treatment by LPO elevation. On the other hand, JQ1 as a small molecule inhibitor of BRD₄ protein can amplify FPT through downregulating the expression of glutathione peroxidase 4 (GPX4), thus inhibiting the ROS elimination and leading to the LPO accumulation. Both in vitro and in vivo studies reveal that this pH-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility. As a result, our study points out a PTT combined iron-based/BRD₄-downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.

Background: Subclinical hypothyroidism (SCH) is the most common thyroid dysfunction, and its relationship with blood pressure (BP) has been controversial. The aim of the study was to analyze the association between SCH and newly-diagnosed hypertension. Methods: Based on data from the Thyroid disease, Iodine nutrition and Diabetes Epidemiology (TIDE) study, 49,433 euthyroid individuals and 7,719 SCH patients aged ≥18 years were enrolled. Patients with a history of hypertension or thyroid disease were excluded. SCH was determined by manufacturer reference range. Overall hypertension and stage 1 and 2 hypertension were diagnosed according to the guidelines issued by the American College of Cardiology/American Heart Association in 2017. Results: The prevalence of overall hypertension (48.7%), including stage 1 (28.9%) and 2 (19.8%) hypertension, increased significantly in SCH patients compared with euthyroid subjects. With elevated serum thyroid stimulating hormone (TSH) level, the hypertension prevalence also increased significantly from the euthyroid to different SCH subgroups, which was more profound in females or subjects aged <65 years. The age- and sex-specific regression analysis further demonstrated the same trends in the general population and in the 1:1 propensity matched population. Similarly, several BP components (i.e., systolic, diastolic, and mean arterial BP) were positively associated with TSH elevation, and regression analysis also confirmed that all BP components were closely related with SCH in female subjects aged <65 years. Conclusion The prevalence of hypertension increases for patients with SCH. SCH tends to be associated with hypertension and BP components in females younger than 65 years.

Background: Subclinical hypothyroidism (SCH) is the most common thyroid dysfunction, and its relationship with blood pressure (BP) has been controversial. The aim of the study was to analyze the association between SCH and newly-diagnosed hypertension. Methods: Based on data from the Thyroid disease, Iodine nutrition and Diabetes Epidemiology (TIDE) study, 49,433 euthyroid individuals and 7,719 SCH patients aged ≥18 years were enrolled. Patients with a history of hypertension or thyroid disease were excluded. SCH was determined by manufacturer reference range. Overall hypertension and stage 1 and 2 hypertension were diagnosed according to the guidelines issued by the American College of Cardiology/American Heart Association in 2017. Results: The prevalence of overall hypertension (48.7%), including stage 1 (28.9%) and 2 (19.8%) hypertension, increased significantly in SCH patients compared with euthyroid subjects. With elevated serum thyroid stimulating hormone (TSH) level, the hypertension prevalence also increased significantly from the euthyroid to different SCH subgroups, which was more profound in females or subjects aged <65 years. The age- and sex-specific regression analysis further demonstrated the same trends in the general population and in the 1:1 propensity matched population. Similarly, several BP components (i.e., systolic, diastolic, and mean arterial BP) were positively associated with TSH elevation, and regression analysis also confirmed that all BP components were closely related with SCH in female subjects aged <65 years. Conclusion The prevalence of hypertension increases for patients with SCH. SCH tends to be associated with hypertension and BP components in females younger than 65 years.

Objective: To observe and compare the effects of two standards on the overweight trend in urban Shanghai infants and young children. Methods: A cluster randomized controlled trial was conducted in 19 communities in two districts of Shanghai, and the subjects (n=15 019) were divided into S-group and W-group by sealed envelope randomization. The subjects were newborns born between November 2013 and December 2014. The 2005 Shanghai growth standard was applied in the S-group and the 2006 WHO growth standard was used in the W-group. At each follow-up time point age of 1, 2, 4, 6, 9, 12 and 18 months, the outpatient physician assessed the length and weight of the infants according to the standard adopted by each group and provided feeding guidance. The weight-for-age Z scores (WAZ), length-for-age Z scores (LAZ) and weight-for-length Z scores (WLZ) were calculated according to the WHO standard. Weight, length, WAZ, LAZ, WLZ and overweight ratio (WLZ≥2) were compared between the two groups using t test, Wilcoxon test and χ² test. Results: A total of 6 509 infants (3 391 were boys, 3 118 were girls) were in the W-group, and 8 510 infants (4 374 were boys, 4 136 were girls) were in the S-group. Among the boys, the weight values at the age of 4, 6, 9, 12, 18 months in the W-group were all lower than those in the S-group ((7.5±0.8) vs. (7.7±0.8) kg, (8.6±0.8) vs. (8.7±0.8) kg, (9.6±0.9) vs. (9.7±0.9) kg, (10.4±1.0) vs. (10.5±1.0) kg, (11.5±1.1) vs.(11.7±1.1) kg; t=4.329, 2.422, 3.739, 2.451, 2.736; P<0.01, 0.015,<0.01, 0.014, 0.009). The length had no significant difference between two groups at all months of age(all P>0.05). The overweight ratio in the W-group was lower than that in the S-group at the age of 9, 12, 18 months(3.3% (71/2 170) vs. 4.9% (143/2 927), 2.5% (51/2 037) vs. 4.5% (126/2 818), 0.8% (7/832) vs. 3.1% (39/1 266); χ²=6.520, 14.209, 12.350; P=0.011,<0.01,<0.01).Among the girls, except at the age of 2 months (W-group (5.6±0.6) vs. S-group (5.7±0.6), t=2.935, P=0.003), weight values had no significant difference between the two groups at other age months (all P>0.05).The length in the W-group was higher than that in the S-group at 12 and 18 months of age ((75.6±2.4) vs.(75.5±2.3)cm, (82.4±2.9) vs.(82.2±2.7) cm; t=2.351, 2.197; P=0.019, 0.028). The ratio of overweight in the W-group was lower than that of S-group at the age of 12 and 18 months (1.8% (33/1 871) vs.3.0% (80/2 658), 0.6% (5/790) vs.1.7% (20/1 178); χ²=6.764,4.276; P=0.009, 0.039). Conclusions The application of WHO growth standard can help to reduce the weight gain rate of boys, promote the linear growth of girls, and thus alleviate the overweight trend of infants within 18 months. It suggested that 2006 WHO growth standard should be applied to infants within 1 year of age in Shanghai.

Objective:3D hydrogel cell model was established,and cyclic compressive loading on MC3T3-E1 cell with different intensities,frequencies and durations was applied,in order to research the suitable solution about promoting the osteoblast differentiation with cyclic compression.Methods:Cyclic compressive loading on MC3T3-E1 cell was applied with different intensity,frequency and time.After compressive loading finished,the total RNA extraction from cell-gel constructs were performed and quantified ATF4,ALP,Runx2,Osteocalcin,RANKL and RANK mRNA.Results:RANKL and RANK mRNA expression significantly with different frequencies cyclic compressive loading (P ＜ 0.05),and ALP mRNA (P ＜ 0.05) and Runx2 mRNA (P ＜ 0.01) expression significantly with different intensities and frequencies cyclic compressive loading (P ＜ 0.05).Meanwhile,Runx2 mRNA expression with 4h significant higher than 12h (P ＜ 0.05),and RANKL mRNA expression with 4h significant lower than 12h (P ＜ 0.05).Conclusion:Determine the stress intensity and frequency,1％ intensity,frequency of 0.5 Hz,4 h of cyclic compression intervention could promote the growth of osteoblasts-like cells in the 3D hydrogel model.

The process of exercise regulating bone metabolism is complicated, which involves a number of signaling pathways. A large number of studies in vitro have indicated that mechanical stress regulates bone metabolism by Wnt, bone morphogenetic protein (BMP), and osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK) signaling pathways. Both the in-tensity and frequency of mechanical stress have varing impact on bone tissue and cells. Plenty of studies in vivo also have shown that exer-cise regulates bone metabolism by key factors in bone metabolism signaling pathways. This paper reviewed the effects of exercise on bone metabolism pathways and their mechanisms.

Objective To explore the effects of rhubarb navel therapy on fecal continence in rectal cancer patients with colostomy.Methods 60 patients with colostomy were randomly divided into the experimental group and the control group with 30 patients in each group.Patients in the control group received routine therapy and health education whereas the experimental group received 30-day extra rhubarb navel therapy started on the 15th day after the operation.The two groups were compared in postoperative 3 months with the following factors:the functions of colostomy and the formation of bowel regularity.Results The scores of the scale about the functions of permanent abdominal colostomy were improved in both groups.However,the score in the experimental group was much higher than that in the control group.The number of patients forming bowel regularity in the experimental group was more than that in the control group (19 and 4 cases respectively).Conclusions Rhubarb navel therapy is beneficial to rectal cancer patients with colostomy to improve the functions of colostomy and form the bowel regularity.

Action surface electromyography (SEMG) signals can be acquired from human skin surface. Its pattern recognition plays a very important role in practical applications such as human prosthesis and human-computer interface systems. For the purpose of increasing the recognition accuracy, we proposed a new recognition method combining fuzzy entropy (FuzzyEn) with multi-scale analysis. Considering the nonlinear and non-stationary characteristics of the SEMG, a multi-scale fuzzy entropy (MSFuzzyEn) feature was introduced and applied to the pattern recognition of six type action SEMG signals of the forearm. Firstly, multi-scale decomposition was applied to original signal using wavelet decomposition. Then MSFuzzyEn of the decomposed signals were calculated and inputted to support vector machine (SVM) for classification as feature vectors. The mean recognition accuracy reached 97%, which was 3% greater than that when FuzzyEn of original signal is applied to the classification of SEMG signals. The results have proved that the MSFuzzyEn is effective and precise in the classification of action SEMG signals.
Algorithms ; Electromyography ; methods ; Entropy ; Fuzzy Logic ; Humans ; Muscle, Skeletal ; physiology ; Pattern Recognition, Automated ; methods ; Signal Processing, Computer-Assisted ; Wavelet Analysis

Objective To evaluate the sensitivity and specificity of Rome Ⅲ criteria in diagnosis of functional dyspepsia (FD) and assess its value in differentiate FD from other organic diseases in upper gastrointestinal tract. Methods Four thousand nine hundred and sixty-two patients, who underwent gastroscopy from July to August 2006 and March to April 2007, were consecutively enrolled and interviewed face to face with a standard questionnaire. The patients who were diagnosed as FD were according to Rome Ⅲ criteria, and those who were diagnosed as upper gastrointestinal diseases, such as chronic erosive gastritis (CEG), gastric ulcer (GU), duodenal ulcer (DU) and gastric carcinoma (GC), were done by gastroscopy and pathology. The differences of clinical characteristics among these diseases were analyzed. Results The FD patients accounted for 7.58% (376/4962) with female in predominant (P = 0.000). The patient with CEG, GU, DU or GC accounted for 29.99% (1488/4962), 1.89% (94/4962),4.25% (211/4962) or 4.57% (227/4962), respectively, all with male in predominant (P<0.05). Further analysis indicated that the age of onset between patients with FD and DU was no difference, but was younger than those with other three diseases (P<0.05). The incidence of early satiation and postprandial in FD patients were higher than those in other patients (P<0.05). The incidence of belching, nausea and vomiting showed no difference among these patients(P>0.05). According to Rome Ⅲ criteria, the symptoms of epigastric pain, early satiation, postprandial fullness and epigastric burning had higher sensitivity and specificity (except epigastric burning)in diagnosing FD (P<0.05), with highest Youden index in epigastric pain (0.42) and postprandial fullness (0.46). Conclusion Rome Ⅲ criteria has high specificity and sensitivity in diagnosing FD, and also has an important value in differentiate FD from other organic diseases.