Contrast-enhanced ultrasound LI-RADS 2017: comparison with CT/MRI LI-RADS.

OBJECTIVE: To compare the classification based on contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) with that of contrast-enhanced CT and MRI (CECT/MRI) LI-RADS for liver nodules in patients at high risk of hepatocellular carcinoma. METHODS: Two hundred thirty-nine patients with 273 nodules were enrolled in this retrospective study. Each nodule was categorized according to the CEUS LI-RADS version 2017 and CECT/MRI LI-RADS version 2017. The diagnostic performance of CEUS and CECT/MRI was compared. The reference standard was histopathology diagnosis. Inter-modality agreement was assessed with Cohen's kappa. RESULTS: The inter-modality agreement for CEUS LI-RADS and CECT/MRI LI-RADS was fair with a kappa value of 0.319 (p < 0.001). The positive predictive values (PPVs) of hepatocellular carcinoma (HCC) in LR-5, LR-4, and LR-3 were 98.3%, 60.0%, and 25.0% in CEUS, and 95.9%, 65.7%, and 48.1% in CECT/MRI, respectively. The sensitivities and specificities of LR-5 for diagnosing HCC were 75.6% and 93.8% in CEUS, and 83.6% and 83.3% in CECT/MRI, respectively. The positive predictive values of non-HCC malignancy in CEUS LR-M and CECT/MRI LR-M were 33.9% and 93.3%, respectively. The sensitivity, specificity, and accuracy for diagnosing non-HCC malignancy were 90.9%, 84.5%, and 85.0% in CEUS LR-M and 63.6%, 99.6%, and 96.7% in CECT/MRI LR-M, respectively. CONCLUSIONS: The inter-modality agreement of the LI-RADS category between CEUS and CECT/MRI is fair. The positive predictive values of HCCs in LR-5 of the CEUS and CECT/MRI LI-RADS are comparable. CECT/MRI LR-M has better diagnostic performance for non-HCC malignancy than CEUS LR-M. KEY POINTS: • The inter-modality agreement for the final LI-RADS category between CEUS and CECT/MRI is fair. • The LR-5 of CEUS and CECT/MRI LI-RADS corresponds to comparable positive predictive values (PPVs) of HCC. For LR-3 and LR-4 nodules categorized by CECT/MRI, CEUS examination should be performed, at least if they can be detected on plain ultrasound. • CECT/MRI LR-M has better diagnostic performance for non-HCC malignancy than CEUS LR-M. For LR-M nodules categorized by CEUS, re-evaluation by CECT/MRI is necessary.

Transcriptional positive cofactor 4 promotes breast cancer proliferation and metastasis through c-Myc mediated Warburg effect.

BACKGROUND: The human positive cofactor 4 (PC4) is initially identified as a transcriptional cofactor and has an important role in embryonic development and malignant transformation. However, the clinical significance and the molecular mechanisms of PC4 in breast cancer development and progression are still unknown. METHODS: We investigated PC4 expression in 114 cases of primary breast cancer and matched normal breast tissue specimens, and studied the impact of PC4 expression as well as the molecular mechanisms of this altered expression on breast cancer growth and metastasis both in vitro and in vivo. RESULTS: PC4 was significantly upregulated in breast cancer and high PC4 expression was positively correlated with metastasis and poor prognosis of patients. Gene set enrichment analysis (GSEA) demonstrated that the gene sets of cell proliferation and Epithelial-Mesenchymal Transition (EMT) were positively correlated with elevated PC4 expression. Consistently, loss of PC4 markedly inhibited the growth and metastasis of breast cancer both in vitro and in vivo. Mechanistically, PC4 exerted its oncogenic functions by directly binding to c-Myc promoters and inducing Warburg effect. CONCLUSIONS: Our study reveals for the first time that PC4 promotes breast cancer progression by directly regulating c-Myc transcription to promote Warburg effect, implying a novel therapeutic target for breast cancer.

SERPINA3 Silencing Inhibits the Migration, Invasion, and Liver Metastasis of Colon Cancer Cells.

OBJECTIVE: To investigate the impact of SERPINA3 on the migration, invasion, and liver metastasis of colon cancer cells. METHODS: Immunohistochemical staining was conducted to determine SERPINA3 expression in the cancer and adjacent normal tissues of 131 patients suffering from colon cancer. In vitro experiment, colon cancer cells with low (HT-29P), intermediate (KM-12C), and high (HT-29LMM, KM-12L4) metastatic potential were obtained to examine SERPINA3 expression levels. Besides, quantitative real-time PCR (qRT-PCR) and Western Blot were performed to detect SERPINA3 expression in HT-29LMM and KM-12L4 cells transfected with SERPINA3 siRNA; Wound-healing and Transwell assays to measure cell migration and invasion, respectively; and ELISA to detect MMP-2 and MMP-9 levels. In vivo experiment, mice with liver metastasis of colon cancer were established to observe the effect of SERPINA3 silencing on liver metastasis. Immunohistochemical assay was applied to evaluate the expressions of Serpina3, Mmp-2, Mmp-9, and proliferating cell nuclear antigen (Pcna) in liver metastasis tissues. RESULTS: SERPINA3 in colon cancer tissues was higher than in adjacent normal tissues, which was associated with patients' clinicopathological features. Besides, SERPINA3 expression showed a rising trend in low, intermediate, and high metastatic potential colon cancer cells. After KM-12L4 and HT-29LMM cells transfected with SERPINA3 siRNA, the migration and invasive ability of cells, as well as the expression levels of MMP-2 and MMP-9 were all decreased. Moreover, SERPINA3 siRNA could not only reduce live metastasis of mice, but also down-regulate the expression of Mmp-2 and Mmp-9 in liver metastasis tissues. CONCLUSION: SERPINA3 silencing could inhibit the migration, invasion, and liver metastasis of colon cancer cells.

Effects of Octacosanol Extracted from Rice Bran on the Laying Performance, Egg Quality and Blood Metabolites of Laying Hens.

A 42-d study with 384 Hy-line brown laying hens was conducted to assess the effects of dietary octacosanol supplementation on laying performance, egg quality and blood metabolites of laying hens. Hens were randomly allocated into 4 dietary groups of 8 cages each, which were fed basal diet supplemented with 0 (Control), 9 (OCT9), 18 (OCT18), and 27 (OCT27) mg/kg diet of octacosanol isolated from rice bran, respectively. The experiment was conducted in an environmental controlled house and hens were fed twice daily for ad libitum intake. Laying performance was determined over the 42-d period, and egg quality as well as blood metabolites were estimated on d 21 and d 42. Diets in OCT18 and OCT27 increased (p<0.05) laying rate, egg weight, egg mass, egg albumen height, Haugh unit and eggshell strength on d 42, but decreased (p<0.05) feed conversion rate and levels of total cholesterol, triglyceride and low density lipoprotein cholesterol in the serum as compared to those of Control. Feed intake, yolk color, yolk diameter, eggshell thickness and high density lipoprotein cholesterol were similar (p>0.05) among treatments. Results demonstrate that supplementing 18 to 27 mg/kg diet of rice bran octacosanol can improve laying rate and egg quality and reduce blood lipid of laying hens.

Percutaneous first annular pulley release for trigger digits: a systematic review and meta-analysis of current evidence.

PURPOSE: To determine the overall success rate and potential influencing factors within the current evidence for percutaneous first annular pulley release. METHODS: We searched PubMed, EMBASE, and the Cochrane Library for all clinical studies of percutaneous release. The rates of successful procedure and complication were extracted and analyzed. We charted the overall success rate on a forest plot with 95% confidence intervals. Data of success rates were analyzed in 5- and 10-year intervals to determine whether the rate of success had increased chronologically. We then performed 3 subgroup analyses according to instrument type (needles vs knife blades), cortisone use (cortisone vs noncortisone), and sonography guidance (sonography vs non-sonography guidance). Pooled success rates were calculated in the subgroups and compared using chi-square test. RESULTS: A total of 34 studies involving 2,114 percutaneous procedures were included in this systematic review and meta-analysis. The total success rate was 94%. There was a trend toward increasing number of publications in the past 20 years. We found a statistically significant trend showing that overall success rates had increased over time. Chi-square test revealed that percutaneous release with sonography guidance had a significantly higher success rate than non-sonography guidance. There were no significant differences in other subgroup analyses including instrument type and cortisone use. CONCLUSIONS: Percutaneous release is an effective and safe procedure for the treatment of trigger digit. It has become progressively popular in recent years, with a trend toward increased overall success. Sonography might be a helpful tool for maximizing success. The success rates were not affected by instruments and cortisone use. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

[Observation on the efficacy of continuous veno-venous hemodia-filtration combined with hemoperfusion HA380 in the treatment of 15 cases of heat stroke with multiple organ dysfunction syndrome].

OBJECTIVE: To investigate the clinical efficacy of continuous veno-venous hemodia-filtration (CVVHDF) combined with hemoperfusion (HP) HA380 in the treatment of heat stroke patients with multiple organ dysfunction syndrome (MODS). METHODS: A retrospective and observational study was conducted. A total of 15 patients with heat stroke combined with MODS who were admitted to the department of intensive care unit (ICU) of Suizhou Central Hospital/Hubei University of Medicine from July to September 2022 were selected as the study objects. All 15 patients were treated with CVVHDF combined with HA380 based on the comprehensive management strategy for severe illness. Organ function indicators [including total bilirubin (TBil), aspartate aminotransferase (AST), creatine kinase (CK), lactate dehydrogenase (LDH), creatinine (Cr), cardiac troponin T (cTnT), myoglobin (Myo), MB isoenzyme of creatine kinase (CK-MB), sequential organ failure assessment (SOFA)] and inflammatory indicators [including white blood cell count (WBC), neutrophil count (NEU), C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6)] were collected. The improvements of the above indexes at admission, after the first HP, after the second HP, after the third HP, and on the 5th day of treatment were compared. Combined with the clinical outcome of patients, the comprehensive efficacy of CVVHDF combined with HA380 in the treatment of severe heat radiation disease was evaluated. RESULTS: There were 10 males and 5 females among the 15 patients. The average age was (64.5±11.5) years old. There were 6 cases of classical heat stroke and 9 cases of exertional heat stroke. Glasgow coma scale (GCS) was 3-8 at admission; SOFA score was 9-17 within 12 hours after admission; acute physiology and chronic health evaluation II (APACHE II) was 25-45 within 24 hours after admission. After treatment, the IL-6 level and SOFA score gradually decreased, and there were significant differences in the decrease after the second HP compared to admission [IL-6 (ng/L): 48.37 (15.36, 113.03) vs. 221.90 (85.87, 425.90), SOFA: 8.3±3.3 vs. 11.1±2.4, both P < 0.05]. The PCT level reached its peak after the first HP [12.51 (6.07, 41.65) µg/L], and then gradually decreased, and the difference was statistically significant after the third HP [1.26 (0.82, 5.40) µg/L, P < 0.05]. Compared those at admission, Cr level significantly improved after the first HP (µmol/L: 66.94±25.57 vs. 110.80±31.13, P < 0.01), Myo significantly decreased after the second HP [µg/L: 490.90 (164.98, 768.05) vs. 3 000.00 (293.00, 3 000.00), P < 0.05], After the third HP, the CK level also showed significant improvement [U/L: 476.0 (413.0, 922.0) vs. 2 107.0 (729.0, 2 449.0), P < 0.05]. After CVVHDF combined with 3 times HP treatment, the patient's inflammatory response was gradually controlled and organ function gradually recovered. On the 5th day of the disease course, WBC, PCT and IL-6 levels were significantly improved compared to admission, and AST, CK, LDH, Cr, Myo, CK-MB, and SOFA score were significantly corrected compared with those on admission. The 24-hour survival rate of 15 patients was 86.67%, and the 24-hour, 7-day and 28-day survival rates were both as high as 73.33%. The average mechanical ventilation time of 11 surviving patients was (101.8±22.0) hours, the average continuous renal replacement therapy (CRRT) time was (58.8±11.0) hours, the average length of ICU stay was (6.3±1.0) days, and the average total hospitalization was (14.6±5.2) days. CONCLUSIONS: CVVHDF combined with HP HA380 in the treatment of heat stroke patients with MODS can effectively improve organ function and alleviate the inflammatory storm, which is an effective means to improve the rescue rate and reduce the mortality of severe heat stroke patients.

Pharmaceutical Manipulation of Mitochondrial F0F1-ATP Synthase Enables Imaging and Protection of Myocardial Ischemia/Reperfusion Injury Through Stress-induced Selective Enrichment.

To rescue ischemic myocardium from progressing to myocardial infarction, timely identification of the infarct size and reperfusion is crucial. However, fast and accurate identification, as well as the targeted protection of injured cardiomyocytes following ischemia/reperfusion (I/R) injury, remain significantly challenging. Here, a near infrared heptamethine dye IR-780 is shown that has the potential to quickly monitor the area at risk following I/R injury by selectively entering the cardiomyocytes of the at-risk heart tissues. Preconditioning with IR-780 or timely IR-780 administration before reperfusion significantly protects the heart from ischemia and oxidative stress-induced cell death, myocardial remodeling, and heart failure in both rat and pig models. Furthermore, IR-780 can directly bind to F0F1-ATP synthase of cardiomyocytes, rapidly decrease the mitochondrial membrane potential, and subsequently slow down the mitochondrial energy metabolism, which induces the mitochondria into a "quiescent state" and results in mitochondrial permeability transition pore inhibition by preventing mitochondrial calcium overload. Collectively, the findings show the feasibility of IR-780-based imaging and protection strategy for I/R injury in a preclinical context and indicate that moderate mitochondrial function depression is a mode of action that can be targeted in the development of cardioprotective reagents.

A small-molecule inhibitor of Keap1-Nrf2 interaction attenuates sepsis by selectively augmenting the antibacterial defence of macrophages at infection sites.

BACKGROUND: Macrophages at infection sites are considered as the promising therapeutic targets to prevent sepsis development. The Nrf2/Keap1 system acts as a critical modulator of the antibacterial activity of macrophages. Recently, Keap1-Nrf2 protein-protein interaction (PPI) inhibitors have emerged as safer and stronger Nrf2 activators; however, their therapeutic potential in sepsis remains unclear. Herein, we report a unique heptamethine dye, IR-61, as a Keap1-Nrf2 PPI inhibitor that preferentially accumulates in macrophages at infection sites. METHODS: A mouse model of acute lung bacterial infection was used to investigate the biodistribution of IR-61. SPR study and CESTA were used to detect the Keap1 binding behaviour of IR-61 in vitro and in cells. Established models of sepsis in mice were used to determine the therapeutic effect of IR-61. The relationship between Nrf2 levels and sepsis outcomes was preliminarily investigated using monocytes from human patients. FINDINGS: Our data showed that IR-61 preferentially accumulated in macrophages at infection sites, enhanced bacterial clearance, and improved outcomes in mice with sepsis. Mechanistic studies indicated that IR-61 potentiated the antibacterial function of macrophages by activating Nrf2 via direct inhibition of the Keap1-Nrf2 interaction. Moreover, we observed that IR-61 enhanced the phagocytic ability of human macrophages, and the expression levels of Nrf2 in monocytes might be associated with the outcomes of sepsis patients. INTERPRETATIONS: Our study demonstrates that the specific activation of Nrf2 in macrophages at infection sites is valuable for sepsis management. IR-61 may prove to be a Keap1-Nrf2 PPI inhibitor for the precise treatment of sepsis. FUNDING: This work was supported by the National Natural Science Foundation of China (Major program 82192884), the Intramural Research Project (Grants: 2018-JCJQ-ZQ-001 and 20QNPY018), and the Chongqing National Science Foundation (CSTB2022NSCQ-MSX1222).

SPECT/CT imaging features of cystic degeneration of the talus and their relation to pathological findings.

BACKGROUND: Osteochondral lesions of the talus (OLTs) are a common orthopedic condition. The image presentation is very similar to that of ischemic necrosis of the talus complicated by a talar neck fracture, but the two are very different lesions. When abnormalities in bone density (or signal) of the talar body (apex of the fornix) with concomitant bone defects and cystic changes are found on X-ray, computed tomography (CT), or magnetic resonance imaging, it is important to accurately determine the nature of the lesion and make a correct diagnosis for the treatment and prognosis of the patient. The purpose of this study was to explore the imaging features of three-phase single-photon emission computed tomography (SPECT)/CT images of cystic lesions of the talus. METHODS: A total of 189 patients with chronic pain in the ankle joint suspected to be caused by cystic degeneration of the talus were enrolled. All patients underwent 99mTc-methyl diphosphonate (99mTc-MDP) three-phase SPECT/CT bone imaging and delayed scans in our hospital. The location, range of involvement, classification, CT value, and radioactivity uptake of the sclerotic areas of cystic lesions on the talus, and the continuity of the articular surface, were recorded. All recorded parameters were analyzed in comparison with pathological results. RESULTS: Eighty-three percent (157/189) of the talar cysts were located on the medial fornix, largely involving the anterior middle part (43.27%), with larger cysts involving the posterior part (9.6%). Sixty-three percent (119/189) of the patients had type I lesions and 37% (70/189) had type II lesions. The articular surface of the medial dome of the talus was intact in all patients, but the subchondral bony articular surface was rough in 88% (166/189) of patients. The coincidence rate for the location, type, and range of involvement of cystic lesions with the pathological results was 87.83% (166/189). The mean CT value of the cystic lesions was 45 ± 15 HU (30-60 HU). The percentages of pathological chondrogenesis in high CT value ≥ 50 HU (19/70) and low CT value < 50 HU (51/70) groups were 89.47% (17/19) and 29.14% (15/51) (χ2 = 20.12, p < 0.001), respectively. The target/background ratio (T/B ratio) of the radioactivity-uptake area of the talus vault was 2.0 ± 0.5 (1.5-2.5). The percentages of pathological new trabecular bone in those with a T/B ratio ≥ 2.0 (157/189) and T/B ratio < 2.0 (32/189) were 82.80% (130/157) and 25.00% (8/32; χ2 = 45.08, p < 0.001), respectively. CONCLUSIONS: Three-phase bone imaging could identify damage of the talus caused by cystic degeneration, while delayed SPECT/CT images showed advantages for displaying bone microstructure, blood supplement, and bone metabolism when examining the location, range of involvement, classification, and repair of cystic lesions of the talus.

Effects of Human Serum Albumin on the Fluorescence Intensity and Tumor Imaging Properties of IR-780 Dye.

IR-780 is a lipophilic dye with excellent optical and tumor imaging properties for early tumor diagnostics. Although the mechanism of tumor targeting has not been fully identified, the view that serum albumin plays an important role in tumor accumulation has been recognized. Here, the mechanism of the interaction between IR-780 and HSA was studied to explore the effect of albumin on its tumor targeting properties. Data demonstrate that IR-780 can be tightly adsorbed by HSA at a ratio of 1:1 to form a noncovalent complex, which exhibits significant improvement in the near-infrared fluorescence imaging and tumor diagnosis capacity. During this process, the endogenous fluorescence and esterase activity of HSA are both partially inhibited by IR-780, and the α-helical content of HSA slightly increases. Molecular docking simulation displays that the binding site of IR-780 on HSA is between subdomains IIA and IIB. These results indicate that HSA is an important factor to mediate the optical performance of IR-780, giving it higher tumor diagnosis capability.

Combination of CT/MRI LI-RADS with CEUS can improve the diagnostic performance for HCCs.

BACKGROUND & AIMS: To compare the classifications for focal liver lesions smaller than 3 cm by the CEUS and CT/MRI LI-RADS and explore the discrepancy between the two classifications strategies. METHODS: Focal liver lesions with a size smaller than 3 cm undergoing CEUS and CT/MRI (MR required on a 3.0 T magnet) within 1 month were enrolled. Each nodule was categorized according to the CEUS LI-RADS v2017 (usLI-RADS) and CT/MRI LI-RADS v2018. Intermodality agreement between the usLI-RADS and LI-RADS for CT/MRI was assessed. The reasons for inconsistent classifications by the CEUS and CT/MRI LI-RADS were clarified. RESULTS: A total of 213 lesions were included. The positive predictive value (PPV) for HCCs of LR-3, 4 and 5 were 57.1% (95% CI: 32.6-78.6), 75.0% (95% CI: 62.3-84.5) and 94.2% (95% CI: 88.9-97.0) for CT/MRI and 37.5% (95% CI: 18.5-61.4), 56.0% (95% CI: 37.1-73.3) and 97.9% (95% CI: 94.1-99.3) for CEUS, respectively. CECT/MRI and CEUS LI-RADS had a poor agreement in classification with a kappa value of 0.254 (P < 0.001). 84 lesions (39.4%) were classified inconsistently in CT/MRI and CEUS LI-RADS. 40 lesions classified as LR-3 or LR-4 by CT/MRI were upgraded by CEUS. 21 lesions classified as LR-4 or LR-5 by CT/MRI were downgraded by CEUS. We reclassified the lesion in CT/MRI LR-3 and LR-4 by CEUS. The PPVs for HCCs in reclassified LR-3, LR-4 and LR-5 were 27.3% (95% CI: 9.7-56.6), 41.7% (95% CI: 26.2-69.0) and 94.2% (95% CI: 89.3-97.0), respectively, which decreased the incidences of HCCs in CT/MRI LR-3 and LR-4. CONCLUSION: Lesions in CT/MRI LR-3 and 4 have a higher probability of being HCCs than those in usLR-3 and 4, respectively. Reclassification of lesions in CT/MRI LR-3 and 4 using CEUS can help the corresponding HCCs get a definite diagnosis.

IR-61 Improves Voiding Function via Mitochondrial Protection in Diabetic Rats.

Diabetic bladder dysfunction (DBD) afflicts nearly half of diabetic patients, but effective treatment is lacking. In this study, IR-61, a novel heptamethine cyanine dye with potential antioxidant effects, was investigated to determine whether it can alleviate DBD. Rats were intraperitoneally injected with IR-61 or vehicle after diabetes was induced with streptozotocin. Before evaluating the effects of IR-61 in improving DBD by filling cystometry, we detected its distribution in tissues and subcellular organelles by confocal fluorescence imaging. Near infrared (NIR) imaging showed that IR-61 could accumulate at high levels in the bladders of diabetic rats, and confocal images demonstrated that it was mainly taken up by bladder smooth muscle cells (BSMCs) and localized in mitochondria. Then, filling cystometry illustrated that IR-61 significantly improved the bladder function of diabetic rats. The histomorphometry results showed that IR-61 effectively mitigated the pathological changes in bladder smooth muscle (BSM) in diabetic rats. Furthermore, IR-61 remarkably reduced the number of apoptotic BSMCs and the unfavorable expression of proteins related to the mitochondrial apoptotic pathway (Bcl-2, BAX, Cytochrome C, and cleaved Caspase-9) in diabetic rats. Moreover, the frozen section staining and transmission electron microscopy results proved that IR-61 significantly reduced the reactive oxygen species (ROS) levels and prevented the mitochondrial mass and morphology damage in the BSM of diabetic rats. In addition, IR-61 upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its associated antioxidant proteins in the BSM of diabetic rats. Together, these results indicate that IR-61 can improve the voiding function of rats with DBD by protecting the mitochondria of BSMCs from oxidative stress, which is possibly mediated through the activation of the Nrf2 pathway.

The near-infrared dye IR-61 restores erectile function in a streptozotocin-induced diabetes model via mitochondrial protection.

This study aimed to evaluate the therapeutic effect of IR-61, a novel mitochondrial heptamethine cyanine dye with antioxidant effects, on diabetes mellitus-induced erectile dysfunction (DMED). Eight-week-old male Sprague-Dawley rats were intraperitoneally injected with streptozotocin (STZ) to induce type 1 diabetes. Eight weeks after STZ injection, all rats were divided into three groups: the control group, DM group, and DM + IR-61 group. In the DM + IR-61 group, the rats were administered IR-61 (1.6 mg kg-1) twice a week by intravenous injection. At week 13, erectile function was evaluated by determining the ratio of the maximal intracavernous pressure to mean arterial pressure, and the penises were then harvested for fluorescent imaging, transmission electron microscopy, histological examinations, and Western blot analysis. Whole-body imaging suggested that IR-61 was highly accumulated in the penis after intravenous injection. IR-61 treatment significantly improved the maximal ICP of diabetic rats. Additionally, IR-61 ameliorated diabetes-induced inflammation, apoptosis, and phenotypic transition of corpus cavernosum smooth muscle cells (CCSMCs) in penile tissue. IR-61 also attenuated mitochondrial damage, reduced reactive oxygen species production in the corpus cavernosum and upregulated sirtuin1 (SIRT1), sirtuin3 (SIRT3), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and heme oxygenase expression in penile tissue. In conclusion, IR-61 represents a potential therapeutic option for DMED by protecting the mitochondria of CCSMCs, which may be mediated by activation of the SIRT1, SIRT3, and Nrf2 pathways.

Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-ß1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.

Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages.

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

[Study on the iodine 125 uptake of H460 lung cancer cell line by co-transfection with the human sodium/iodide symporter and the human thyroperoxidase].

BACKGROUND AND OBJECTIVE: Lung cancer harms people's health or even lives severely. Especially, the therapy of non-small cell lung cancer (NSCLC) has not been obviously improved for many years. The aim of this study is to transfer the human sodium/iodide symporter (hNIS) and the human thyroperoxidase (hTPO) genes into H460 lung cancer cell line, and to study the uptake ability of iodide after co-transfected hTPO and hNIS gene in cell lines. METHODS: Through cloning, recombination, packaging and amplifying, the recombinant adenosine virus (AdTPO) was constructed. Then the protein expression of AdTPO was tested by Western blot. After transfected hNIS gene into human lung cancer cell line H460 through liposome, stably expressing hNIS gene cell lines (hNIS-H460) selected by G418 antibiotics was determined as hNIS-H460 group. Using AdTPO, hTPO gene was transducted into hNIS-H460, as AdTPO-hNIS-H460 group. H460 cell without hNIS gene was applied as control group (H460). Then, we investigated the 125I uptake assay of the above cells. RESULTS: We were successful in co-transfecting hNIS and hTPO gene into human lung cell lines H460, and were obtained hNIS and hTPO gene lung cancer cell lines (hNIS-H460 and AdTPO-hNIS-H460). In AdTPO-hNIS-H460, hNIS-H460 and H460, the uptake ability of 125I was (59 637.67 +/- 1 281.13), (48 622.17 +/- 2 242.28) and (1 440.17 +/- 372.86) counts x min(-1). The uptake ability of 125I was 41 fold higher in AdTPO-hNIS-H460 than in blank control H460 (P < 0.01), and 34 fold higher in hNIS-460 than in blank control H460 (P < 0.01), and 1.2 fold higher in AdTPO-hNIS-H460 than in hNIS-H460 (P < 0.01). CONCLUSION: The uptake ability of 125I could increase by co-transfected hNIS and hTPO genes into human lung cancer cell lines H460.

Utility of technetium-99m-methylene diphosphonate single-photon emission computed tomography/computed tomography fusion in detecting post-traumatic chronic-infected nonunion in the lower limb.

BACKGROUND: This study aimed to evaluate fused images of single-photon emission computed tomography/computed tomography (SPECT/CT), stand-alone whole-body scintigraphy (WBS) and stand-alone CT in the diagnosis of post-traumatic chronic-infected nonunion osteomyelitis (OST) of the lower limb. PATIENTS AND METHODS: The imaging data from 144 patients with known/suspected chronic-infected fracture nonunion in the lower limbs following internal/external fixation between June 2015 and December 2017 were reviewed retrospectively. Technetium-99m-methylene diphosphonate SPECT/CT scans were performed on the patients. For each patient, the diagnosis on the basis of each imaging approach was classified as yes (OST), no (no OST), or equivocal by experienced nuclear medicine physicians and radiologists. An intraoperative bacterial culture experiment was conducted as our gold standard. The diagnostic sensitivity, specificity, accuracy, positive predictive value, negative predictive value, κ coefficient, significance level, and agreement level were analyzed. RESULTS: The diagnosis on the basis of SPECT/CT fused images showed a sensitivity of 91.3%, a specificity of 84.6%, and accuracy of 88.9% compared to that based on WBS, with a sensitivity of 52.2%, a specificity of 15.4%, accuracy of 38.9%, and CT, with a sensitivity of 65.2%, a specificity of 23.1%, accuracy of 50.0%. The fused images can show the precise sites of post-traumatic chronic-infected OST. Considerable agreement (κ 0.679) was found between the SPECT/CT diagnosis and an intraoperative bacterial culture test (WBS, κ 0.218; CT, κ = 0.184). CONCLUSION: Technetium-99m-methylene diphosphonate SPECT/CT imaging fusion can improve diagnostic confidence for post-traumatic patients with chronic nonunion OST. This imaging approach can achieve an accurate diagnosis by revealing the precise location and scope of OST with high sensitivity and specificity, which has important implications for surgical guidance by providing the precise location of OST.

Acinetobacter baumannii Ventilator-Associated Pneumonia: Clinical Efficacy of Combined Antimicrobial Therapy and in vitro Drug Sensitivity Test Results.

Objective: To evaluate therapeutic efficacy of different combined antimicrobial treatments against Acinetobacter baumannii ventilator-associated pneumonia (VAP). Methods: Clinical outcomes were retrospectively analyzed to elucidate the efficacy of four combined antimicrobial regimens. The chessboard and micro broth dilution methods determined the minimum inhibitory concentrations (MICs) of four antiseptic drugs singly used and combined two drugs against 36 isolates of multidrug-resistant (MDR) A. baumannii. Results: The incidence of VAP was approximately 6.9% (237/3424) between January 1, 2015 and December 31, and 35.9% (85/237) of the cases were caused by A. baumannii. Among these cases, 60 belonged to AB-VAP, for whom antimicrobial treatment plan was centralized and clinical data was complete. Moreover, all 60 strains of A. baumannii were MDR bacteria from reports microbiological laboratory. Resistance rate was lowest for amikacin (68.3%) and ampicillin sulbactam (71.7%). Resistance rate for imipenem increased from 63.2 to 90.9% during the 3 years. However, in these 60 cases of AB-VAP, the combination between 4 antibiotics was effective in most cases: the effective rate was 75% (18/24) for sulbactam combined with etilmicin, 71.4% (10/14) for sulbactam combined with levofloxacin, 72.7% (8/11) for meropenem combined with etilmicin, and 63.6% (7/11) for meropenem combined with levofloxacin. There was no statistical difference between four regimens (P > 0.05). Sulbactam combined with etilmicin decreased 1/2 of MIC50 and MIC90 of sulbactam while the decreases in etilmicin were more obviously than single drug. When adopting meropenem combined with levofloxacin or etilmicin, the MIC of meropenem reduced to 1/2 of that in applying single drug. As for sulbactam or meropenem combined with levofloxacin, it also lessened the MIC50 of levofloxacin to 1/2 of that for single drug. FIC results suggested that the effects of four combined antimicrobial regimens were additive or unrelated. When sulbactam was combined with etimicin, the additive effect was 63.89%. Conclusion: Drug combination sensitivity test in vitro may be helpful for choosing antimicrobial treatment plans. Sulbactam or meropenem as the basis of treatment regimens can function as the alternatives against AB-VAP. Sulbactam combined with etimicin has been regarded as a recommended regimen in Suizhou, Hubei, China.

Cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents.

The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer.

MMP-1/TIMP-1 expressions in rectal submucosa of females with obstructed defecation syndrome associated with internal rectal prolapse.

OBJECTIVE: To explore the MMP-1/TIMP-1 expressions in rectal submucosa of females with obstructed defecation syndrome (ODS) associated with internal rectal prolapse (IRP). METHODS: Fifty-six female patients with ODS associated with IRP were enrolled as Case group, and 43 female hemorrhoids of stages III-IV without constipation and IRP were enrolled as Control group. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were performed to test the expressions of MMP-1/TIMP-1 in the rectal submucosa. Western blotting was used to examine protein expressions of MMP-1/TIMP-1 and pro-inflammatory cytokines (IL-6 and TNF-α) in the rectal submucosa. EVG staining was conducted to detect collagen and elastic fibers in rectal submucosa. RESULTS: The increased expression of MMP-1 was negatively linked to the decreased TIMP-1 level in the rectal submucosa of patients with ODS associated with IRP. Besides, the expressions of IL-6 and TNF-α were increased in the Case group as compared with the Control group. Additionally, ODS severity and the pro-inflammatory cytokines was positively linked to MMP-1, but negatively related to TIMP-1 in Case group. EVG staining showed that the area ratios of collagen and elastic fibers were lower in Case group than Control group. Through Pearson's correlation analysis, the area ratios of collagen and elastic fibers were positively associated with MMP-1 expression, but negatively correlated with TIMP-1 expression in rectal submucosa of patients with ODS associated with IRP. CONCLUSION: Elevated MMP-1 and reduced TIMP-1 were found in ODS associated with IRP, which was related to the ODS severity, inflammation and contents of collagen and elastic fibers.