The Suprascapular Artery as a Reference for the Evaluation of Supraspinatus Fatty Infiltration on Magnetic Resonance Imaging.

Background: Fatty infiltration (FI) of the supraspinatus is commonly seen in chronic large-to-massive rotator cuff tears. Evaluating FI in patients with severe muscle atrophy can be confusing. Purpose/Hypothesis: The purpose of this study was to investigate the anatomic relationship between the suprascapular artery and supraspinatus muscle on magnetic resonance imaging (MRI) to provide a method for defining the border of the supraspinatus muscle on Y-view MRI. It was hypothesized that the branches of the suprascapular artery would encircle the supraspinatus muscle on Y-view and adjacent MRI slices and could be used for defining the supraspinatus outline on oblique sagittal images. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A total of 172 shoulders that had undergone arthroscopic repair for large-to-massive rotator cuff tears were retrospectively included. Two methods, one based on the supraspinous fossa and trapezius (SF method) and the other based on the region bounded by the branches of the suprascapular artery (SA method), were used for defining the supraspinatus outline on Y-view MRI for the assessment of FI. Preoperative supraspinatus FI grade and tangent sign and postoperative tendon integrity were evaluated. Shoulder function was assessed using the American Shoulder and Elbow Surgeons (ASES) score and active range of motion. Results: The branches of the suprascapular artery encircled the supraspinatus in all shoulders, with the diameter of the branches ranging from 0.5 to 3 mm. The agreement in supraspinatus FI grading between the SF and SA methods was 65.12%. When limited to the 61 shoulders with a positive tangent sign, the agreement dropped to 22.95% (κ = 0.032). The group (FI grade 2 by SA method and ≥3 by SF method) showed no significant difference in postoperative outcomes compared with the 2-vs-2 group but had significantly better postoperative ASES scores (P = .001) and active range of motion in forward elevation (P = .020) compared with the ≥3-vs-≥3 group. The tangent sign was positive in 92.16% of the 2-vs-≥3 group. Conclusion: The suprascapular artery is a reliable reference for the evaluation of supraspinatus FI. When a positive tangent sign presents, supraspinatus FI is likely to be overestimated if the hyperintensity outside the region bounded by the branches of the suprascapular artery is mistaken as FI.

Comparative study on the antioxidant efficacy of Adinandra nitida extracts in inhibiting lipid oxidation in edible oils.

Exploring natural antioxidants is essential to delay lipid oxidation. This study investigated the inhibitory effect of Adinandra nitida (AN) extract in six edible oils, compared to TP and TBHQ. Methods included extract preparation, bioactive compounds analysis, in vitro antioxidant activities by FRAP, DPPH, and ABTS assays, fatty acid composition detection, and POV determination. The results showed that AN was rich in total flavonoids, total phenols and had better iron ion reduction ability than TBHQ. In oleic and linoleic acid-rich oils, AN significantly delayed early-stage lipid oxidation, outperforming TP and TBHQ. In linolenic acid-rich oils, AN maintained a stable effect. Molecular docking studies revealed strong binding interactions between main compounds and fatty acids, with Camelliaside A in (7.83) showing higher binding energy to linolenic acid than TBHQ (7.64), supporting the antioxidant effects. These findings suggest AN as a promising natural alternative to synthetic antioxidants, enhancing oil stability and shelf life.

Analysis of sediment re-formation factors after ginseng beverage clarification based on XGBoost machine learning algorithm.

The aim of this study was to explore the sediment re-formation factors of ginseng beverages subjected to four clarification ways (11 subgroups) including the ethanol precipitation, enzymatic treatment, clarifier clarification, and Hollow Fiber Column (HFC) methods, based on the Extreme Gradient Boosting (XGBoost) model. The results showed that the clarity of the ginseng beverages was significantly improved by all the clarification treatments, but still formed sediment after storage. HFC method exhibited the highest transmittance, the least sediment, and stronger antioxidant activity in the clarification treatment groups. According to the results of chemical composition analyses and partition coefficients, carbohydrates, saponins, proteins and metal elements were involved in varying degrees in the re-formation of the sediments in ginseng beverage after clarification. Based on the above data, the XGBoost model predicted that protein, Rd, Na, K, and total saponins were the five most important chemical components affecting the sediment re-formation in ginseng beverages.

TMEM106B Knockdown Exhibits a Neuroprotective Effect in Parkinson's Disease via Decreasing Inflammation and Iron Deposition.

Parkinson's disease (PD) is closely related to iron accumulation and inflammation. Emerging evidence indicates that TMEM106B plays an essential role in PD. But whether TMEM106B could act on neuroinflammation and iron metabolism in PD has not yet been investigated. The aim of this study was to investigate the pathological mechanisms of inflammation and iron metabolism of TMEM106B in PD. 1-methyl-4-phenylpyridinium (MPP+)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SH-SY5Y cells and mice were treated with LV-shTMEM106B and AAV-shTMEM106B to construct PD cellular and mouse models. Pole tests and open-field test (OFT) were performed to evaluate the locomotion of the mice. Immunohistochemistry and iron staining were used to detect TH expression and iron deposition in the SN. Iron staining was used to measure the levels of iron. Western blotting was used to detect the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)), NOD-like receptor protein 3 (NLRP3) inflammasome, divalent metal transporter 1 (DMT1), and Ferroportin1 (FPN1)). Knockdown of TMEM106B improved motor ability and rescued dopaminergic (DA) neuron loss. TMEM106B knockdown attenuated the increases of TNF-α, IL-6, NLRP3 inflammasome, and DMT1 expression in the MPP+ and MPTP-induced PD models. Furthermore, TMEM106B knockdown also increases the expression of FPN1. This study provides the first evidence that knockdown of TMEM106B prevents dopaminergic neurodegeneration by modulating neuroinflammation and iron metabolism.

The synergy of morphokinetic parameters and sHLA-G in cleavage embryo enhancing implantation rates.

Objective: This study aimed to assess the relationship between implantation and soluble HLA-G (sHLA-G) expression in cleavage embryo culture medium (ECM) in conjunction with early developmental kinetics determined by time-lapse imaging (TLI). Methods: A retrospective, single-center study was conducted involving 238 embryos from 165 patients who underwent Frozen-thawed embryo transfer (FET) using autologous oocytes, with either single or double embryo transfer. TLI morphokinetic parameters (t2, t3, t4, t5, t6, t7, t8, cc2, s2, cc3, s3) of embryos were analyzed, and sHLA-G levels in D3 ECM were measured using an enzyme-linked immunosorbent assay (ELISA). A hierarchical classification model was developed to categorize embryos into five groups (A, B, C, D, E). The correlation between sHLA-G levels, TLI classification of embryos, and embryo implantation was investigated to establish a non-invasive method for evaluating implantation potential. Multivariate logistic regression analysis was performed to identify potential influencing factors, and receiver operating characteristic (ROC) curves were used to evaluate the predictive value for implantation. Results: Multivariate unconditional logistic regression analysis indicated that TLI parameters t5 and s3 and sHLA-G level in ECM were independent risk factors affecting embryo implantation. The implantation rate decreased from TLI classification A to E. The proposed classification model effectively assessed the implantation potential of embryos. The implantation rate was higher in the sHLA-G positive group compared to the sHLA-G negative group (p < 0.001). The expression of sHLA-G in D3 ECM, combined with the TLI classification model, accurately evaluated the implantation potential of embryos with an AUC of 0.876. Conclusion: The integration of cleavage kinetics and embryonic sHLA-G expression could reliably identify embryos with a high likelihood of successful implantation.

Trim31 deficiency exacerbates airway inflammation in asthma by enhancing the activation of the NLRP3 inflammasome.

Tripartite motif (Trim) 31 is important for numerous inflammatory diseases. However, whether Trim31 regulates airway inflammation in asthma remains undetermined. The present work explored the role of Trim31 in airway inflammation in asthmatic mice established by ovalbumin (OVA) stimulation. Trim31 expression was markedly downregulated in the lungs of asthmatic mice. Compared with wild-type (WT) mice, Trim31-/- mice showed more severe pathological changes accompanied by increased inflammatory cell infiltration after OVA induction. House dust mite (HDM) stimulation evoked airway epithelial cell injury and inflammation, which were exacerbated by Trim31 silencing or attenuated by Trim31 overexpression. Further examination revealed that Trim31 deficiency exacerbated the activation of the NLRP3 inflammasome in OVA-induced asthmatic mice and HDM-stimulated airway epithelial cells. The inhibition of NLRP3 markedly diminished the Trim31 silencing-mediated enhancement of HDM-induced injury and inflammation in airway epithelial cells. In conclusion, this work demonstrates that Trim31 acts as a crucial mediator of airway inflammation in asthma. Trim31 deficiency may contribute to the progression of asthma by increasing NLRP3 inflammasome activation, suggesting that Trim31 is a potential therapeutic target for asthma.

Taste Mechanism of Umami Molecules from Fermented Broad Bean Paste Based on In Silico Analysis and Peptidomics.

In this study, in silico analysis and peptidomics were performed to examine the generation mechanism of the umami taste of fermented broad bean paste (FBBP). Based on the information from peptidomics, a total of 470 free peptides were identified from FBBP, most of which were increased after fermentation. Additionally, the increase of the content of umami peptides, organic acids, and amino acids during fermentation contributed to the perception of umami taste in FBBP. Molecule docking results inferred that these umami molecules were easy to connect with Ser, Glu, His, and Gln in the T1R3 subunit through hydrogen bonds and electrostatic interaction force. The binding sites His145, Gln389, and Glu301 particularly contributed to the formation of the ligand-receptor complexes. The aromatic interaction, hydrogen bond, hydrophilicity, and solvent-accessible surface (SAS) played key roles in the receptor-peptide interaction. Sensory evaluation and electronic tongue results showed that EDEDE, DLSESV, SNGDDE, DETL, CDLSD, and TDEE screened from FBBP had umami characteristics and umami-enhancing effects (umami threshold values ranging from 0.131 to 0.394 mmol/L). This work provides new insight into the rapid and efficient screening of novel umami peptides and a deeper understanding of the taste mechanisms of umami molecules from FBBP.

Exploring the antioxidant potential of nekemias species extracts on edible oils: In vitro assessment and lipid oxidation inhibition.

Synthetic antioxidants have long been used to protect edible oils from oxidation. However, concerns about their potential health risks and environmental impact have led to a growing interest in natural antioxidants. In this study, we explore the antioxidant properties of extracts from four Nekemias plant species: Nekemias grossedentata (AGR), Nekemias megalophylla (AME), Nekemias chaffanjonii (ACH), and Nekemias cantoniensis (ACA) by obtaining the values for different tests. We investigate their bioactive compound content and evaluate their antioxidant capabilities on six edible oils categorized into three lipid systems based on their fatty acid compositions: oleic acid, linoleic acid, and linolenic acid. Our findings demonstrate that AGR and AME extracts, rich in bioactive compounds, exhibit strong antioxidant activities in vitro, effectively inhibiting lipid oxidation, especially in oleic acid-rich oils like camellia oil. The antioxidant effects of these extracts are comparable to synthetic antioxidants such as TBHQ and superior to natural antioxidant Tea Polyphenols (TP). While the extracts also show antioxidant potential in linoleic and linolenic acid systems, the stability of their effects in these oils is lower than in oleic acid system. These results suggest that Nekemias species extracts have the potential to serve as natural additives for extending the shelf life of edible oils, contributing to the exploration of natural antioxidants.

A CT-based radiomics nomogram involving the cystic fluid area for differentiating appendiceal mucinous neoplasms from appendicitis with intraluminal fluid.

OBJECTIVE: To develop and validate a radiomics nomogram based on computed tomography (CT) to distinguish appendiceal mucinous neoplasms (AMNs) from appendicitis with intraluminal fluid (AWIF). METHOD: A total of 211 patients from two medical institutions were retrospectively analysed, of which 109 were pathologically confirmed as having appendicitis with concomitant CT signs of intraluminal fluid and 102 as having AMN. All patients were randomly assigned to a training (147 patients) or validation cohort (64 patients) at a 7:3 ratio. Radiomics features of the cystic fluid area of the appendiceal lesions were extracted from nonenhanced CT images using 3D Slicer software. Minimum redundancy maximum relevance and least absolute shrinkage and selection operator regression methods were employed to screen the radiomics features and develop a radiomics model. Combined radiomics nomogram and clinical-CT models were further developed based on the corresponding features selected after multivariate analysis. Lastly, receiver operating characteristic curves, and decision curve analysis (DCA) were used to assess the models' performances in the training and validation cohorts. RESULTS: A total of 851 radiomics features were acquired from the nonenhanced CT images. Subsequently, a radiomics model consisting of eight selected features was developed. The combined radiomics nomogram model comprised rad-score, age, and mural calcification, while the clinical-CT model contained age and mural calcification. The combined model achieved area under the curves (AUCs) of 0.945 (95% confidence interval [CI]: 0.895, 0.976) and 0.933 (95% CI: 0.841, 0.980) in the training and validation cohorts, respectively, which were larger than those obtained by the radiomics (training cohort: AUC, 0.915 [95% CI: 0.865, 0.964]; validation cohort: AUC, 0.912 [95% CI: 0.843, 0.981]) and clinical-CT models (training cohort: AUC, 0.884 [95% CI: 0.820, 0.931]; validation cohort: AUC, 0.767 [95% CI: 0.644, 0.863]). Finally, DCA showed that the clinical utility of the combined model was superior to that of the clinical CT and radiomics models. CONCLUSION: Our combined radiomics nomogram model constituting radiomics, clinical, and CT features exhibited good performance for differentiating AMN from AWIF, indicating its potential application in clinical decision-making.

Quantitative assessments of retinal macular structure among rural-dwelling older adults in China: a population-based, cross-sectional, optical coherence tomography study.

OBJECTIVES: To quantitatively assess and compare retinal macular structures of rural-dwelling older adults in China using two different optical coherence tomography (OCT) scanners and to examine their associations with demographic, lifestyle, clinical and ocular factors. DESIGN, SETTING AND PARTICIPANTS: This population-based, cross-sectional study included 971 participants (age ≥60 years) derived from the Multimodal Interventions to Delay Dementia and Disability in Rural China study. We collected data on demographics, lifestyle factors, clinical conditions (eg, cardiovascular disease (CVD)) and ocular factors (eg, visual acuity and spherical equivalent). We used two models of spectral-domain OCT to measure macular parameters in nine Early Treatment Diabetic Retinopathy Study subfields. Data were analysed using the multiple general linear models. RESULTS: Spectralis OCT demonstrated higher macular thickness but a lower macular volume than Primus 200 OCT (p<0.05). Nasal quadrant of the inner and outer subfields was the thickest, followed by superior quadrant. Adjusting for multiple potential confounding variables, older age was significantly correlated with lower average inner and outer macular thicknesses and overall macular volume. Men had higher macular parameters than women. The presence of CVD was correlated with lower central macular thickness (ß=-6.83; 95% CI: -13.08 to -0.58; p=0.032). Middle school or above was associated with higher average inner macular thickness (ß=7.85; 95% CI: 1.14 to 14.55; p=0.022) and higher spherical equivalent was correlated with lower average inner macular thickness (ß=-1.78; 95% CI: -3.50 to -0.07; p=0.042). CONCLUSIONS: Macular thickness and volume assessed by Spectralis and Primus 200 OCT scanners differ. Older age and female sex are associated with lower macular thickness and volume. Macular parameters are associated with education, CVD and spherical equivalent. TRIAL REGISTERATION NUMBER: MIND-China study (ChiCTR1800017758).

Revealing the formation mechanisms of key flavors in fermented broad bean paste.

Pixian Douban (PXDB) is a popular Chinese condiment for its distinctive flavor. Broad bean fermentation (Meju) is the most important process in the formation of flavor substances. Key flavors were analyzed qualitatively and quantitatively, and metagenomic technology was applied to study the microbial diversity during broad bean fermentation. In addition, the main metabolic pathways of key flavors were explored. Results indicated that Staphylococcus_gallinarum was the main microorganism in the microbial community, accounting for 39.13%, followed by Lactobacillus_agilis, accounting for 13.76%. Aspergillus_flavus was the fungus with the highest species abundance, accounting for 3.02%. The KEGG Pathway enrichment analysis showed that carbohydrate metabolism and amino acid metabolism were the main metabolic pathways. Glycoside hydrolase and glycosyltransferase genes were the most abundant, accounting for more than 70% of the total number of active enzyme genes. A total of 113 enzymes related to key flavors and 39 microorganisms corresponding to enzymes were annotated. And Staphylococcus_gallinarum, Lactobacillus_agilis, Weissella_confusa, Pediococcus_acidilactici, Staphylococcus_kloosii, Aspergillus_oryzae, and Aspergillus_flavus played a key role in the metabolic pathway. This study reveals the formation mechanism of key flavors in fermented broad bean, it is important for guiding the industrial production of PXDB and improving product quality.

Tumor-associated Macrophages Mediate Gefitinib Resistance in Lung Cancer through HGF/c-met Signaling Pathway.

BACKGROUND: The biological behavior of cells changes after they develop drug resistance, and the degree of resistance will be affected by the tumor microenvironment. In this study, we aimed to study the effects of M2 macrophages on gefitinib resistance. METHODS: We polarized THP-1 cells into M0 and M2 macrophages, and conducted various experiments to investigate the effects of M2 macrophages on gefitinib resistance in lung cancer. RESULTS: We found that M2 macrophages promote gefitinib resistance in HCC827 and PC9 cells. In addition, we used ELISA to measure the secretion level of HGF. HGF secretion levels were significantly increased in M2 macrophages. Exogenous HGF remarkably increased the proliferation and invasion in HCC827 and PC9 cells. However, the addition of anti-HGF antibodies abolished the proliferation and invasion of both HCC827 and PC9 cells promoted by M2 macrophages. Furthermore, M2 macrophages or exogenous HGF significantly increased the expression of p-met and p-ERK in HCC827 and PC9 cells, while anti-HGF antibodies diminished the expression of p-met and p-ERK by neutralizing HGF in M2 macrophages. CONCLUSION: Our results revealed that M2 macrophages promote gefitinib resistance by activating ERK and HGF/c-met signaling pathways in HCC827 and PC9 cells. Our findings provide a new therapeutic strategy for gefitinib resistance in lung cancer.

Does age affect patient outcomes after humeral head replacement in the treatment of acute proximal humeral fractures? A comparative cohort study with a minimum 10 years long-term follow-up.

BACKGROUND: Humeral head replacement (HHR) is now rarely recommended for complex proximal humeral fractures (PHFs) in older patients. However, in relatively young and active patients with unreconstructable complex PHFs, controversy still exists regarding the treatment options of reverse shoulder arthroplasty and HHR. The goal of this study was to compare the survival, functional, and radiographic outcomes of HHR in patients aged <70 years and those aged ≥70 years after a minimum 10 years follow-up. METHODS: Eighty-seven out of 135 patients undergoing primary HHR were enrolled and then divided into 2 groups based on age: <70 years and ≥70 years. Clinical and radiographic evaluations were performed with a minimum follow-up of 10 years. RESULTS: There were 64 patients (mean, 54.9 years) in the younger group and 23 patients (mean, 73.5 years) in the older group. The younger and older groups had comparable 10-year implant survivorship (98.4% vs. 91.3%). Patients aged ≥70 years had worse American Shoulder and Elbow Surgeons scores (74.2 vs. 81.0, P = .042) and lower satisfaction rates (12% vs. 64%, P < .001) than younger patients. At the final follow-up, older patients had worse forward flexion (117° vs. 129°, P = .047) and internal rotation (17 vs. 15, P = .036). More greater tuberosity complications (39% vs. 16%, P = .019), glenoid erosion (100% vs. 59%, P = .077), and humeral head superior migration (80% vs. 31%, P = .037) were also identified in patients aged ≥70 years. CONCLUSIONS: Unlike the increased risk for revision and functional deterioration over time after reverse shoulder arthroplasty for PHFs in younger patients, a high implant survival rate with lasting pain relief and stable functional outcomes could be observed in younger patients after HHR during long-term follow-up. Patients aged ≥70 years had worse clinical outcomes, lower patient satisfaction, more greater tuberosity complications, and more glenoid erosion and humeral head superior migration than those aged <70 years. HHR should not be recommended for the treatment of unreconstructable complex acute PHFs in older patient populations.

The Posterosuperior Tetralogy Scoring System as a Practical Tool to Predict Shoulder Function After Posterosuperior Large-to-Massive Rotator Cuff Repairs.

Background: Fatty infiltration (FI) or atrophy alone has been found to be inaccurate in predicting shoulder function after repair of large-to-massive rotator cuff tears (L/MRCTs), especially when a diverse extent of FI and atrophy presents in multiple rotator cuff muscles. Purpose/Hypothesis: The Posterosuperior Tetralogy Scoring System (PS-Tetra Score), which integrates FI and atrophy, was proposed to predict shoulder function after surgery. It was hypothesized was that a PS-Tetra Score ≥3 would be a risk factor for poor shoulder function after repair of posterosuperior L/MRCTs and would possess greater diagnostic value than using isolated FI or atrophy of the supraspinatus (SSP) or infraspinatus (ISP). Study Design: Case-control study; Level of evidence, 3. Methods: A total of 187 arthroscopic repairs of posterosuperior L/MRCTs were reviewed. Magnetic resonance imaging evaluations were performed of FI and atrophy of the SSP and ISP, teres minor hypertrophy, tendon retraction, and acromiohumeral distance. A postoperative American Shoulder and Elbow Surgeons (ASES) score of 70 was used to subgroup patients according to shoulder function. Univariate and multivariate analyses were performed to determine the risk factors of poor shoulder function (ASES ≤70). The diagnostic values of different indicators for predicting shoulder function were evaluated. Results: In univariate analysis, female sex, higher Goutallier grade of the SSP and ISP, positive SSP tangent sign, and PS-Tetra Score ≥3 was significantly associated with ASES score ≤70, whereas in binary logistic regression analysis, a PS-Tetra Score ≥3 was the only significant risk factor for poor shoulder function. The occurrence rate of poor function in shoulders with a PS-Tetra Score of 0, 1, 2, 3, and 4 was 0% (0/52), 0% (0/52), 19.57% (9/46), 58.06% (18/31), and 83.33% (5/6), respectively. PS-Tetra Score ≥3 possessed higher crude agreement (87.70%), specificity (90.97%), positive predictive value (62.16%), and area under the receiver operating characteristic curve (0.814) than the other 3 indicators, with relatively high negative predictive value (94.00%) and moderate sensitivity (71.88%). Conclusion: PS-Tetra Score ≥3 was a risk factor of poor shoulder function after repair of posterosuperior L/MRCTs and possessed greater diagnostic value than using isolated FI or atrophy of SSP or ISP alone for predicting shoulder function.

Postoperative Nursing Care of Obese Patients with Aortic Dissection Receiving Modified Prone Position Mechanical Ventilation: A Report of Two Cases.

Background: Aortic dissection is a critical cardiovascular disease, with Stanford Type A aortic dissection (TAAD) posing significant concern due to its high mortality rate, especially in obese patients. Acute respiratory distress syndrome (ARDS) is among the most common postoperative complications. Therefore, preventing ARDS is critically important for TAAD patients. Objective: This study aims to investigate the impact of enhanced prone mechanical ventilation on oxygenation levels, early extubation rates, and length of stay in the intensive care unit (ICU) among obese TAAD patients. The goal is to assess its potential to improve patient clinical outcomes and provide a scientific foundation for clinical practice. Case Presentation: Following evaluation by the attending physician, two hypoxemic patients underwent prone mechanical ventilation on postoperative day 3 for 12 hours daily, consecutively for 3-5 days. Patients' oxygenation significantly improved, and mechanical ventilation was discontinued after respiratory exercises. Successful removal of oral intubation was achieved, followed by individualized nursing care. No complications arose during intensive care, and both patients were transferred out of the ICU and subsequently discharged. Conclusions: The early implementation of modified prone position ventilation effectively mitigates postoperative hypoxemia in obese patients with aortic dissection. It increases the rate of early postoperative oral extubation and reduces the length of stay in the ICU.

Targeting MET endocytosis or degradation to overcome HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma.

The overexpression of hepatic growth factor(HGF) is one of the important reasons for the development of gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma cells. Targeting the HGF receptor MET through endocytosis inhibition or degradation induction has been proposed as a potential strategy to overcome this resistance. However, the effectiveness of this approach remains needs to be evaluated. In this study, we observed that MET receptors undergo persistent endocytosis but rarely enter the degradation pathway in HGF-overexpressing cells. We showed that MET endocytosis can be inhibited by using gene silence method or MET inhibitors. CHC or DNM2 gene silence slightly increases the sensitivity of resistant cells to gefitinib without affecting MET activity, while GRB2 gene silence can simultaneously inhibit MET endocytosis and reduce MET activity, resulting in a significant reversal effect of gefitinib resistance. Similarly, MET inhibitors significantly reverse drug resistance, accompanied by simultaneous inhibition of MET endocytosis and activity, highlighting the importance of both endocytosis and activity in HGF-induced gefitinib resistance. Additionally, we demonstrated that promoting MET degradation through deubiquitinase (USP8 or USP32) gene silence is another effective method for reversing drug resistance. Overall, our findings suggest that targeting MET receptor endocytosis and degradation is an attractive strategy for overcoming HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma.

What Are the Long-term Outcomes of Locking Plates for Nonosteoporotic Three-part and Four-part Proximal Humeral Fractures With a Minimum 10-year Follow-up Period?

BACKGROUND: Proximal humeral fractures (PHFs) often occur in elderly individuals who experience low-energy falls. Open reduction and internal fixation (ORIF) of the proximal humerus is typically performed in young, active patients because of their good bone quality and high functional demands. Although good short-term results have been reported after ORIF in young patients, few studies have specifically evaluated long-term outcomes. QUESTIONS/PURPOSES: (1) What are the long-term clinical outcomes scores and (2) radiologic outcomes of nonosteoporotic three-part and four-part PHFs treated with locking plates? (3) What complications occurred after treatment, and what factors are associated with poor postoperative functional outcomes scores and avascular necrosis (AVN) of the humeral head after ORIF? METHODS: Between June 2005 and December 2012, we surgically treated 774 patients for displaced two-, three-, and four-part PHFs. Approximately 75% (581 of 774) underwent ORIF, 10% (77 of 774) underwent hemiarthroplasty, 7% (54 of 774) underwent intramedullary nailing, 5% (39 of 774) underwent reverse shoulder arthroplasty, and the remaining 3% (23 of 774) underwent other surgical treatments. We considered those who had ORIF as potentially eligible. Based on that criterion, 75% (581) were eligible. However, only patients with nonosteoporotic three- and four-part PHFs (cortical thickness of the proximal humeral diaphysis greater than 6 mm on a preoperative AP radiograph of the affected shoulder) and a minimum of 10 years of follow-up were included. Sixty-four percent (498 of 774) of the patients were excluded because of simple or osteoporotic fractures, 1% (7 of 774) were excluded because of ipsilateral limb multiple fractures, 0.3% (2 of 774) were excluded because of pathologic PHFs, and another 2% (13 of 774) were lost before the minimum study follow-up of 10 years, leaving 8% (61 of 774) for analysis here. The mean age at surgery was 45 ± 12 years, with a mean follow-up of 13 years. Fifty-seven percent (35 of 61) of the patients were men. Patient-reported outcomes were evaluated using the University of California Loas Angeles (UCLA) score (range 0 to 35; higher scores represent better shoulder function) and Constant score (range 0 to 100; higher scores represent better shoulder function) at least 10 years postoperatively. Postoperative radiographs were reviewed to assess the cortical bone thickness of the proximal humerus, neck-shaft angle, head-to-tuberosity distance, and radiologically confirmable complications. Logistic regression analysis was performed to evaluate factors associated with poor postoperative functional scores (UCLA score ≤ 27 or Constant score ≤ 70) and AVN of the humeral head; the association between AVN and postoperative functional outcomes was also assessed. RESULTS: At the most-recent follow-up, these patients had a mean UCLA score of 31 ± 3 and a Constant score of 88 ± 10. The mean neck-shaft angle was 133° ± 10°, and 23% (14 of 61) of patients experienced AVN of the humeral head during follow-up. Twenty-nine complications in 30% (18 of 61) of patients were reported. After controlling for potentially confounding variables such as age and gender, we found that the presence of greater tuberosity malposition (odds ratio 18 [95% confidence interval 2 to 167]; p = 0.01) and immediate postoperative neck-shaft angle less than 130° (OR 19 [95% CI 3 to 127]; p = 0.002) were associated with poor postoperative functional scores. Four-part PHFs (OR 13 [95% CI 2 to 82]; p = 0.008) and metaphyseal extension less than 8 mm (OR 7 [95% CI 1 to 35]; p = 0.03) were associated with AVN of the humeral head. For patients who met the criteria for anatomic reduction (achievement of all of the following three criteria: neck-shaft angle ≥ 130°, head-shaft displacement < 5 mm, and head-to-tuberosity distance greater than or equal to 3 mm and less than or equal to 20 mm), there were no differences in postoperative functional scores between patients with AVN and those without. CONCLUSION: ORIF of nonosteoporotic proximal humeral fractures with locking plates led to favorable functional and radiologic outcomes at a minimum of 10 years of follow-up. When encountering complex PHFs in patients with good bone quality, every effort must be made to achieve an anatomic reduction of the fracture as far as possible, which may not reduce the risk of AVN (this occurred in nearly one-fourth of patients). However, good outcomes can usually be expected, even in patients with AVN. Because this was a retrospective study with a high risk of bias owing to sparse data, the factors associated with poor postoperative functional outcomes must be further investigated in large prospective studies. LEVEL OF EVIDENCE: Level III, therapeutic study.

Human amnion-derived mesenchymal stem cells improve subclinical hypothyroidism by immunocompetence mediating apoptosis inhibition on thyroid cells in aged mice.

Subclinical hypothyroidism (SCH) affects 10% of the global population, which is most prevalent in women and the elderly. However, it remains debatable whether the elderly with subclinical hypothyroidism needs thyroxine supplement. Human amnion-derived mesenchymal stem cells (hAMSCs) could play important roles in autoimmune diseases, suggesting that hAMSC be a candidate to regulate the thyroid function of female age-related subclinical hypothyroidism. Herein, we established the model of SCH in the aged female mice. This study was designed to investigate whether human amnion-derived mesenchymal stem cells (hAMSC) could effect on immune regulation, apoptosis inhibition of thyroid cells, thyroid function, blood lipid levels, and heart function. In addition, qualified hAMSCs were intravenously injected into aged female SCH mice via the tail vein on day 0 and day 10. The levels of thyroid hormone and blood lipids as well as cardiac function, serum immunological indexes, and apoptosis of thyroid cells were then analyzed on day 5, 10, 15, and 20; meanwhile, the quantity of Th1, Th2, Th17, and Treg immune cells in peripheral blood was evaluated before and on day 20 post-injection. Our study demonstrated that after hAMSC transplantation, the thyroid functions, blood lipid levels, and heart function indexes of age-related SCH (AR-SCH) mice were significantly improved. Consistent with this, Th1 and Treg cells increased significantly, while Th2 and Th17 cells decreased in peripheral blood. Apoptosis was also suppressed in the thyroid cells. In summary, hAMSC delivery can potentially be a safe and effective therapy for treating SCH in the elderly, improving related complications by immunomodulatory and apoptosis inhibition.

Relationship between vancomycin-induced nephrotoxicity and vancomycin trough concentration in older adults: A retrospective observational study.

OBJECTIVES: The objective of the study is to investigate the risk factors of vancomycin-induced renal toxicity in older adults, especially in those with chronic kidney disease (CKD) Stages 3-5. METHODS: In this retrospective observational study, serum vancomycin trough concentrations (VTCs) in patients aged g65 years treated with vancomycin were analyzed, and independent risk factors of vancomycin-induced nephrotoxicity (VIN) were determined by logistic regression analysis. RESULTS: In total, 321 patients were included in this study. Serum VTC was an independent risk factor for vancomycin-induced renal toxicity in total cohort (odds ratio [OR], 1.07; P = 0.004) as well as in the cohort with CKD Stages 3-5 (OR, 1.09; P = 0.010). A daily dose of vancomycin and Charlson comorbidity index was an independent risk factor for vancomycin-induced renal toxicity in total cohort (OR, 3.63; P = 0.006) and in the cohort with CKD Stage 3-5 (OR, 1.83; P = 0.002), respectively. In older adults with CKD Stages 3a and 3b-5, the VTCs associated with higher risk for vancomycin-induced renal toxicity were 21.5 mg/L and 16.5 mg/L, respectively. CONCLUSIONS: In older adults, serum VTC is an independent risk factor for VIN. VTCs over 21.5 mg/L and 16.5 mg/L are associated with increased risk of VIN in this population with CKD Stage 3a and 3b-5, respectively.