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.

Objective To explore the risk factors affecting the prognosis of sepsis patients progressing to chronic critical illness (CCI), and to construct and validate a Nomogram model for predicting in-hospital mortality risk. Methods Patients who met the criteria for sepsis progressing to CCI were selected from the Medical Information Mart for Intensive Care Ⅳ (MIMIC-Ⅳ) database in the United States as the research objects. Clinical materials of patients were collected retrospectively, and a total of 928 patients were included. The patients were randomly divided into modeling group (n=649) and validation group (n=279) at a ratio of 7 to 3; the patients were also divided into survival group and mortality group based on in-hospital mortality. Univariate and multivariate Logistic regression analyses were performed on the modeling group based on the outcomes; a Nomogram model for predicting in-hospital mortality in sepsis patients progressing to CCI was constructed based on independent risk factors; the discrimination and calibration of the Nomogram model were evaluated by the concordance index and calibration curve, and then validated by the validation group. Results Among the 928 sepsis patients progressing to CCI, 723 cases were in survival group and 205 cases in mortality group, with an in-hospital mortality rate of 22.1%. Age (OR=1.021, 95%CI, 1.007 to 1.036, P=0.004), body mass (OR=0.988, 95%CI, 0.979 to 0.997, P=0.016), the Acute Physiological Score Ⅲ (APS Ⅲ) score (OR=1.013, 95%CI, 1.004 to 1.023, P=0.004), blood alkaline phosphatase (OR=1.002, 95%CI, 1.000 to 1.003, P=0.023), continuous renal replacement therapy (CRRT) duration (OR=1.065, 95%CI, 1.023 to 1.108, P=0.002), and mechanical ventilation duration (OR=1.117, 95%CI, 1.056 to 1.184, P < 0.001) were identified as independent influencing factors for in-hospital mortality in sepsis patients progressing to CCI. A prediction model was constructed based on these risk factors, and the concordance index analysis showed that the concordance index was 0.75 (95%CI, 0.70 to 0.80) in the modeling group and 0.74 (95%CI, 0.68 to 0.81) in the validation group. The calibration curves of both themodeling group and the validation group were close to the standard curve. Conclusion Nomogram model constructed based on the 6 indicators including age, body mass, blood alkaline phosphatase, APS Ⅲ score, CRRT, and mechanical ventilation duration has good discrimination and calibration for predicting the mortality risk of sepsis patients progressing to CCI, which is helpful for clinicians to assess patient's prognosis.

Objective:To investigate the characteristics of anorectal dynamics in elderly patients with functional defecation disorders(FDD), and to provide a basis for their diagnosis, treatment and prevention.Methods:In this retrospective study, 226 patients with FDD receiving 3D high-resolution anorectal manometry were divided into an elderly group(93 cases)and a non-elderly group(133 cases). Results from anorectal manometry parameters were compared and analysis of patterns of anorectal pressure changes in elderly participants based on sex, the Bristol stool classification and clinical symptoms was conducted.Results:The resting anal pressure, rectal pressure and anal relaxation rate were lower( t=-3.407, -2.051, Z=2.548, P=0.001, 0.040, 0.011)and the volume of first sensation was higher( t=1.998, P=0.047)in the elderly group than in the non-elderly group.The maximum anal squeezing pressure, residual anal pressure and maximum tolerated volume were higher( t=4.589, 4.730, 2.025, all P<0.05), whereas the anal relaxation rate and anorectal pressure gradient were lower in elderly men than in elderly women( Z=4.059, t=-3.714, P<0.001 for both). Regarding the types of FDD, both the elderly group and the non-elderly group were dominated with type Ⅱ defecation disorder, with more men than women having type Ⅱ defecation disorder in the elderly group( χ2=10.343, P=0.001). In cases of paradoxical sphincter contraction during simulated defecation, the incidence in the elderly group was 80.65%(75/93), which was higher than 68.42%(91/133)in the non-elderly group( χ2=4.194, P=0.041). The volume of first sensation, volume of first defecation sensation, and maximum tolerated volume of patients in the elderly group without the urge to defecate were(59.86±23.84)ml, (96.76±34.61)ml, and(144.32±30.57)ml, respectively, higher than those of patients with the urge to defecate(46.79±17.20)ml, (75.26±28.75)ml, and(120.00±40.28)ml( t=-2.241, -2.493, -2.891, P=0.027, 0.014, 0.005). The rectal pressure(26.52±16.08)mmHg of patients with defecation dyssynergia was lower than that of patients without defecation dyssynergia(39.91±8.82)mmHg(1 mmHg=0.133 kPa)( t=-3.128, P=0.002), while the resting anal pressure of patients with defecation dyssynergia(90.60±28.44)mmHg was higher than that of patients without defecation dyssynergia(73.65±27.10)mmHg( t=-2.201, P=0.030). The resting anal pressure and maximum anal squeezing pressure in patients with anal blockage sensation[(87.11±24.64)mmHg, (149.28±48.29)mmHg]were higher than those in patients without anal blockage sensation[(72.43±20.02)mmHg, (121.76±26.35)mmHg]( t=2.954、3.066, P=0.004、0.003). There was no significant difference in values from parameters of anorectal dynamics between patients with different Bristol stool types, with and without incomplete defecation or with different degrees of abdominal distension(all P>0.05). Conclusions:Anorectal dynamics in patients with FDD are characterized by paradoxical anal sphincter movements, but older patients with FDD are mainly characterized by inadequate rectal propulsion, pelvic floor muscle dysfunction and reduced rectal sensitivity.

Objective:To detect the mRNA expression and methylation status of leucine rich repeat containing 55(LRRC55) gene in pancreatic carcinoma tissues, and discuss the clinical value.Methods:Resected pancreatic ductal adenocarcinoma and normal adjacent specimens from 37 patients admitted in General Surgery of First Affiliated Hospital of Naval Medical University were collected from May 2019 to May 2021. Another two normal pancreas specimens and two blood samples from healthy adults were also collected. All patients′ age, gender, tumor location, tumor size, tumor differentiation, TNM staging, lymphatic metastasis, CEA and CA19-9 level were recorded. Bisulfite treatment of genomic DNA and sequencing analysis was used to study methylation patterns in CpG islands of the promoter for LRRC55 gene in fresh tissues from 2 pancreatic adenocarcinoma and adjacent tissues, 2 normal pancreatic tissues, 2 pancreatic cancer cell lines (PaTu8988 and ASPC1). LRRC55 mRNA in 35 pancreatic adenocarcinoma and adjacent tissues was detected by real-time quantitative PCR and the correlations with clinical parameters were analyzed.Results:CpG islands of LRRC55 in pancreatic adenocarcinoma tissues and pancreatic cancer cell lines was highly methylated and the mean methylation rate was 53% and 71%, respectively; while LRRC55 gene in pancreatic adjacent tissues and normal pancreatic tissues was lowly methylated, and the mean methylation rate was 8% and 11%. The relative expression in the pancreatic adenocarcinoma tissues and the paired adjacent normal tissues was 0.21 (0.02, 1.00 ) and 0.98 (0.33, 3.66 ), respectively; the former was significantly lower than the later and the difference was statistically significant ( P=0.003). Correlation analysis showed that LRRC55 mRNA expression level was related to tumor differentiation and CEA, but not correlated with patients′ age, gender, tumor location and size, CA19-9 level, lymphatic metastasis and TNM staging. Conclusions:Pancreatic cancer tissue and cell lines had abnormal methylation of LRRC55 gene; LRRC55 gene hypermethylation was related with its lower mRNA expression level in pancreatic cancer, which was correlated with the tumor differentiation and CEA level. LRRC55 may be a potential suppressor gene for pancreatic cancer.

Objective:To investigate the morphological characteristics of coracoid process in different stages of temporomandibular joint osteoarthrosis (TMJOA), and to provide theoretical data for clinical and anatomic study.Methods:A total of 290 patients who were diagnosed with TMJOA in the Department of Temporomandibular Joint, Kunming Medical University School and Hospital of Stomatology from January 2015 to February 2021 were collected, including 69 males and 221 females, with age of (35.1±13.7) years (16-69 years old), 64 cases of unilateral lesions (64 sides), and 226 cases of bilateral lesions (452 sides). According to the TMJOA X-ray staging standard put forward by Ma Xuchen in 2005, the affected joints were divided into stage Ⅰ (227 sides), stage Ⅱ (38 sides), stage Ⅲ (164 sides) and stage Ⅳ (87 sides). Twenty-six patients without clinical and imaging manifestations of temporomandibular disorders in the Department of Radiology, Kunming Medical University School and Hospital of Stomatology from October 2020 to June 2021 were selected as the control group, including 8 males and 18 females. The age was (34.3±13.9) years (17-60 years). The dicom data of each group were imported into Simplant Pro 11.04 software to measure the height of coracoid process, anteversion angle and the ratio of coracoid vertex to mandibular corner to condylar vertex to mandibular angle. R 3.6.1 was used to analyze the difference of the morphological characteristics of coracoid process between in the affected side of TMJOA and in the both sides of the control group, in the healthy side and the affected side of unilateral patients and in different stages of TMJOA.Results:The height of the coracoid process [(16.26±2.81) mm], the ratio of the coracoid process vertex-mandibular angle point and the condyle vertex-mandibular angle point distance [0.96(0.92,1.01)] on the affected side of TMJOA were significantly higher than those in the control group [(15.31±3.03) mm; 0.95(0.89, 0.99)] ( t=2.18, P=0.033; Z=2.87, P=0.004). There was no significant difference between the ante-version angle and the control group ( t=-1.37, P=0.176). The ratio of the distance between the apex of the coracoid process and the apex of the mandibular angle to the apex of the condyle and the angle of the mandible in the affected side of unilateral patients was significantly greater than that in the healthy side ( t=-3.46, P=0.001). There was no significant difference in coracoid height, coracoid anteversion angle and the healthy side ( t=-1.85, P=0.069; t=-0.06, P=0.955) in different periods. The intra-group analysis showed that there was no significant difference in the height of the coracoid process in different stages ( F=0.37, P=0.774). There was no significant difference in the ante-version angle of the coracoid process: stage Ⅰ, stage Ⅱ, and stage Ⅲ ( P>0.008), but all were significantly smaller than stage Ⅳ ( PⅠ-Ⅳ<0.001, PⅡ-Ⅳ=0.009, PⅢ-Ⅳ<0.001). The ratio of the distance between coracoid apex-mandibular angle and condyle apex-mandibular angle: there was no significant difference in stage Ⅰ, stage Ⅱ, and stage Ⅲ ( P>0.008), and stage Ⅰ and stage Ⅲ were significantly smaller than stage Ⅳ ( P<0.001). Conclusions:The coracoid height and the ratio of the coracoid apex-mandibular angle to the condyle apex-mandibular angle distance on the TMJOA side were significantly greater than those without temporomandibular joint disorders. The bone deposition was mainly concentrated in the upper and posterior part of the condyle. TMJOA had a certain correlation with the height of the coracoid process.

Objective:To explore a fast method to identify and confirm suspected clonorchis sinensis infection.Methods:For suspected clonorchis sinensis infection, the clonorchiasis serum antibody was detected first with ELISA. If the antibody was positive, the fecal examination for eggs was performed. If the fecal examination was negative, duodenal drainage under gastroscopy was recommended to detect eggs from the drainage fluid.Results:A total of 126 patients met the requirements and aged 54.14±13.33 (24- 87). There were 83 cases (65.87%, 83/126) with eggs positive in the drainage fluid, of which 53 cases were male, aged 55.91±11.47 (30-86), and 30 cases female, aged 55.87± 13.85(30-87). There was no significant difference in age between males and females( P>0.05). The time of catheterization (T1) of 126 cases was 3.79 ±1.45 min. The time of drainage (T2) of 126 cases was 31.39 ±14.29 min. There was no significant difference in T1 or T2 between the positive group and the negative group( P>0.05). The detection rates of eggs were 91.57% (76 cases) in intrahepatic bile duct drainage, 81.93% (68 cases) in the bile-cyst juice and 75.90% (63 cases) in the common bile duct fluid. No serious adverse reactions occurred during or after the operation. Conclusion:The detection rate of clonorchiosis sinensis can be effectively improved by the combination of clonorchiasis serum antibody test and gastroscopy-guided duodenal drainage.

Objective:To investigate the efficacy and safety of the modified gasless unilateral axillary approach (MGUAA) endoscopic thyroid surgery in treatment of papillary thyroid microcarcinoma (PTMC) .Methods:From Jan. 2019 to Dec. 2019, 90 patients receiving PTMC (cT1N0M0, cI stage, 8th, 2017 AJCC) therapy by modified gasless unilateral axillary approach endoscopic thyroid surgery (MGUAA group, n=41) , and conventional open thyroid surgery (OS group, n=49) were retrospectively analyzed. Ninety patients were enrolled in the study, including 14 males and 76 females,with the mean age (42.1±12.0) years.The effectiveness of central lymph node dissection (CLND) , the operation time, the types of operation, the amount of drainage, the duration of hospital stay, the related complications, the postoperative pain of neck and axillary and the cosmetic satisfaction were compared between the two groups.SPSS 25.0 statistical software was used for statistical analysis, the measurement data was expressed by ±s, paired t test was used to compare the measurement data between groups, and Chi-square test was used to campare the count date between groups. Results:The mean age (35.0±8.6) years and the amount of surgical bleeding (12.3±7.3) ml in the MGUAA group were significantly lower than those (48.1±11.1) years and (16.1±4.3) ml in the OS group ( P<0.01) , while the mean operation time (99.1±19.5) min, the mean amount of drainage (221.4±67.9) ml and the postoperative drainage tube placement time (5.0±0.8) days were significantly higher than those of (70.6±17.8) min, (98.3±63.7) ml and (3.8±1.0) days in the MGUAA ( P<0.01) . There was no significant difference in the number of lymph nodes of CLND or the duration of hospital stay between the two groups ( P>0.05) . In terms of surgical complications, the transient recurrent laryngeal nerve injury, the postoperative hematoma, the postoperative infection, and the lymphatic leakage had no significant difference between the two groups ( P>0.05) . The MGUAA group had significant advantages in avoiding the postoperative dysphagia in front of neck, the postoperative pain of neck, and cosmetic satisfaction over the OS group [ (0.0% vs 28.6%) , (14.6% vs 71.4%) , (1.1±0.3) score vs (2.4±0.5) score ( P<0.01) ]. Whereas in axillary area pain on the surgical side, the MGUAA group was inferior to the OS group ( P<0.01) . Conclusion:The modified gasless unilateral axillary approach endoscopic thyroid surgery is a feasible, safe and cosmetically operation for PTMC (cT1N0M0, cI stage, 8th, 2017 AJCC) .

Objective:To investigate the efficacy, safety and advantages of gasless unilateral axillary approach (GUAA) in endoscopic thyroid surgery.Methods:A total of 334 patients who underwent the GUAA endoscopic thyroid surgery (GUAA group) or conventional open thyroid surgery (OS group) in the Department of Head and Neck Surgery of Zhejiang Cancer Hospital from January 2017 to June 2018 were retrospectively analyzed. There were 45 males and 289 females, aged from 12 to 72 years old, of whom 139 patients were assigned to GUAA group and 195 patients to OS group. Pathological results included papillary thyroid carcinoma (282 cases), nodular goiter (41 cases) and thyroid adenoma (11 cases). Surgical exploration development curve of GUAA group was drawn and was divided into two parts: the technical exploration stage and the technical stable stage. Surgical efficiency, incidences of complications, and incision satisfaction were compared between GUAA group in technical stable stage and OS group. SPSS 25.0 software was adopted for statistical analysis.Results:The mean age in GUAA group was younger than that in OS group, with a significant difference [(35.3±9.5) years vs. (48.1±10.6) years, t=11.31, P<0.01]. The cases in the endoscope group were divided into technical exploration stage for 51 cases and technical stable stage for 88 cases according to the exploration and development curve. In unilateral radical thyroidectomy and unilateral thyroid lobectomy, the mean operation time [(90.6±18.6) min and (93.5±22.0) min] and postoperative drainage volumes [(121.5±87.6) ml and (155.5±69.1) ml] of GUAA group in the stable stage were more than those of OS group [(61.6±15.6) min and (46.5±8.4) min] and [(93.2±42.3) ml and (78.9±48.7) ml]. The difference was statistically significant ( t=12.28, 7.23, 3.35 and 3.05 respectively, all P<0.05), but there were no significant differences in surgical bleeding volumes between two groups [(12.7±6.8) ml vs. (13.5±7.7) ml, t=0.74, P>0.05 and (16.3±14.1) ml vs. (11.9±5.1) ml, t=1.05, P>0.05]. Compared with OS group, GUAA group had the lower incidence of anterior cervical discomfort during swallowing (2.3% vs. 29.2%, P<0.01) and the higher incision satisfaction score (1.1±0.5 vs. 2.8±0.7, t=21.12, P<0.01), however, GUAA group had the higher incidence of supraclavicular (or infraclavicular) numbness after surgery (5.7% vs. 0, P<0.01). And there was no significant difference in the incidences of temporary recurrent laryngeal nerve injury, bleeding, hematoma, infection, lymphatic leakage or chylous leakage after surgery between two groups ( P>0.05). Conclusion:GUAA endoscopic thyroid surgery is a safe method with high cosmetic satisfaction.

OBJECTIVE: To investigate the changes in the expression of voltage-gated potassium channel subunit KCNA2 in the dorsal root ganglion (DRG) neurons of rats with osteoarthritis (OA) pain induced by sodium monoiodoacetate and explore the mechanism. METHODS: A total of 156 adult male Sprague-Dawley rats were randomly divided into blank control group, saline group and intra-articular monoiodoacetate injection-induced OA group. The paw withdrawal mechanical threshold (PWMT) was measured before and at 1, 2, 4, and 6 weeks after monoiodoacetate injection. At 4 weeks after the injection, the pathological changes in the knee joints were analyzed using HE staining and Safranin O-Fast Green staining, and the expression of activating transcription factor 3 (ATF-3) and inducible nitric oxide synthase (iNOS) in the DRG neurons were detected by immunofluorescence staining. The expression of mRNA in the DRG neurons was detected by RT-qPCR at 1, 2, 4 and 6 weeks after the injection. The expression of KCNA2 in the DRG was measured by Western blotting, and the methylation level of promoter region was measured by MSPCR at 4 weeks after the injection. RESULTS: The PWMT of the rats in OA group was significantly decreased at 2, 4, and 6 weeks after the injection as compared with the baseline ( < 0.05 or < 0.001) as well as the control group ( < 0.05 or < 0.001). Four weeks after the intra-articular injection, fractures and defects on the surface of the articular cartilage, bone hyperplasia, and blurred tidal line were observed in the rats in OA group, but no obvious pathological changes were detected in the control or saline groups. Compared with those in the control group, the expressions of ATF-3 and iNOS were significantly increased ( < 0.01) at 4 weeks after injection; the expression of mRNA at 2, 4 and 6 weeks and the expression of KCNA2 protein at 4 weeks were all significantly decreased ( < 0.05 or < 0.01), and the methylation level of gene was significantly increased at 4 weeks after the injection in OA group ( < 0.01). CONCLUSIONS The expression of KCNA2 is decreased in the DRG neurons of rats with OA pain likely as a result of enhanced methylation of promoter region.
Animals ; Disease Models, Animal ; Ganglia, Spinal ; Knee Joint ; Kv1.2 Potassium Channel ; metabolism ; Male ; Osteoarthritis ; complications ; metabolism ; Pain ; etiology ; metabolism ; Promoter Regions, Genetic ; Rats ; Rats, Sprague-Dawley

The present study was aimed to evaluate resting-state functional connectivity and topological properties of brain networks in narcolepsy patients compared with healthy controls. Resting-state fMRI was performed in 26 adult narcolepsy patients and 30 matched healthy controls. MRI data were first analyzed by group independent component analysis, then a graph theoretical method was applied to evaluate the topological properties in the whole brain. Small-world network parameters and nodal topological properties were measured. Altered topological properties in brain areas between groups were selected as region-of-interest seeds, then the functional connectivity among these seeds was compared between groups. Partial correlation analysis was performed to evaluate the relationship between the severity of sleepiness and functional connectivity or topological properties in the narcolepsy patients. Twenty-one independent components out of 48 were obtained. Compared with healthy controls, the narcolepsy patients exhibited significantly decreased functional connectivity within the executive and salience networks, along with increased functional connectivity in the bilateral frontal lobes within the executive network. There were no differences in small-world network properties between patients and controls. The altered brain areas in nodal topological properties between groups were mainly in the inferior frontal cortex, basal ganglia, anterior cingulate, sensory cortex, supplementary motor cortex, and visual cortex. In the partial correlation analysis, nodal topological properties in the putamen, anterior cingulate, and sensory cortex as well as functional connectivity between these regions were correlated with the severity of sleepiness (sleep latency, REM sleep latency, and Epworth sleepiness score) among narcolepsy patients. Altered connectivity within the executive and salience networks was found in narcolepsy patients. Functional connection changes between the left frontal cortex and left caudate nucleus may be one of the parameters describing the severity of narcolepsy. Changes in the nodal topological properties in the left putamen and left posterior cingulate, changes in functional connectivity between the left supplementary motor area and right occipital as well as in functional connectivity between the left anterior cingulate gyrus and bilateral postcentral gyrus can be considered as a specific indicator for evaluating the severity of narcolepsy.