Unraveling a Concerted Proton-Coupled Electron Transfer Pathway in Atomically Precise Gold Nanoclusters.

Metal nanoclusters (MNCs) represent a promising class of materials for catalytic carbon dioxide and proton reduction as well as dihydrogen oxidation. In such reactions, multiple proton-coupled electron transfer (PCET) processes are typically involved, and the current understanding of PCET mechanisms in MNCs has primarily focused on the sequential transfer mode. However, a concerted transfer pathway, i.e., concerted electron-proton transfer (CEPT), despite its potential for a higher catalytic rate and lower reaction barrier, still lacks comprehensive elucidation. Herein, we introduce an experimental paradigm to test the feasibility of the CEPT process in MNCs, by employing Au18(SR)14 (SR denotes thiolate ligand), Au22(SR)18, and Au25(SR)18- as model clusters. Detailed investigations indicate that the photoinduced PCET reactions in the designed system proceed via an CEPT pathway. Furthermore, the rate constants of gold nanoclusters (AuNCs) have been found to be correlated with both the size of the cluster and the flexibility of the Au-S framework. This newly identified PCET behavior in AuNCs is prominently different from that observed in semiconductor quantum dots and plasmonic metal nanoparticles. Our findings are of crucial importance for unveiling the catalytic mechanisms of quantum-confined metal nanomaterials and for the future rational design of more efficient catalysts.

A colorimetric sensing strategy based on chitosan-stabilized platinum nanoparticles for quick detection of α-glucosidase activity and inhibitor screening.

α-Glucosidase (α-Glu) is implicated in the progression and pathogenesis of type II diabetes (T2D). In this study, we developed a rapid colorimetric technique using platinum nanoparticles stabilized by chitosan (Ch-PtNPs) to detect α-Glu activity and its inhibitor. The Ch-PtNPs facilitate the conversion of 3,3',5,5'-tetramethylbenzidine (TMB) into oxidized TMB (oxTMB) in the presence of dissolved O2. The catalytic hydrolysis of 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) by α-Glu produces ascorbic acid (AA), which reduces oxTMB to TMB, leading to the fading of the blue color. However, the presence of α-Glu inhibitors (AGIs) hinders the generation of AA, allowing Ch-PtNPs to re-oxidize colorless TMB back to blue oxTMB. This unique phenomenon enables the colorimetric detection of α-Glu activity and AGIs. The linear range for α-Glu was found to be 0.1-1.0 U mL-1 and the detection limit was 0.026 U mL-1. Additionally, the half-maximal inhibition value (IC50) for acarbose, an α-Glu inhibitor, was calculated to be 0.4769 mM. Excitingly, this sensing platform successfully detected α-Glu activity in human serum samples and effectively screened AGIs. These promising findings highlight the potential application of the proposed strategy in clinical diabetes diagnosis and drug discovery.

Stepwise reduction of bone mineral density increases the risk of cage subsidence in oblique lumbar interbody fusion patients biomechanically: an in-silico study.

BACKGROUND: Cage subsidence causes poor prognoses in patients treated by oblique lumbar interbody fusion (OLIF). Deterioration of the biomechanical environment initially triggers cage subsidence, and patients with low bone mineral density (BMD) suffer a higher risk of cage subsidence. However, whether low BMD increases the risk of cage subsidence by deteriorating the local biomechanical environment has not been clearly identified. METHODS: OLIF without additional fixation (stand-alone, S-A) and with different additional fixation devices (AFDs), including anterolateral single rod screws (ALSRs) and bilateral pedicle screws (BPSs) fixation, was simulated in the L4-L5 segment of a well-validated finite element model. The biomechanical effects of different BMDs were investigated by adjusting the material properties of bony structures. Biomechanical indicators related to cage subsidence were computed and recorded under different directional moments. RESULTS: Overall, low BMD triggers stress concentration in surgical segment, the highest equivalent stress can be observed in osteoporosis models under most loading conditions. Compared with the flexion-extension loading condition, this variation tendency was more pronounced under bending and rotation loading conditions. In addition, AFDs obviously reduced the stress concentration on both bony endplates and the OLIF cage, and the maximum stress on ALSRs was evidently higher than that on BPSs under almost all loading conditions. CONCLUSIONS: Stepwise reduction of BMD increases the risk of a poor local biomechanical environment in OLIF patients, and regular anti-osteoporosis therapy should be considered an effective method to biomechanically optimize the prognosis of OLIF patients.

Preoperative systemic immune-inflammation index predicts prognosis of patients with non-metastatic renal cell carcinoma: a propensity score-matched analysis.

BACKGROUND: A novel systemic immune-inflammation index (SII), based on the neutrophils, lymphocytes and platelet counts, is associated with the prognosis of several cancers. The present study evaluates the prognostic significance of SII in non-metastatic renal cell carcinoma (RCC). METHOD: The present study retrospectively reviewed the medical record of patients with non-metastatic RCC who underwent nephrectomy between 2010 and 2013. Receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cut-off value. In addition, the propensity score matching (PSM) was performed with a matching ratio of 1:1. Univariate and multivariate Cox proportional hazards models were used to identify the prognostic factors. The results were reported by hazard ratio (HR) with 95% confidence interval (95% CI). RESULTS: A total of 646 patients were included in the final analysis. High SII group (> 529) was significantly associated with older age (P = 0.014), larger tumor (P < 0.001), higher pathological T stage (P < 0.001), higher tumor grade (P < 0.001) and more tumor necrosis (P < 0.001). Multivariate Cox regression analysis demonstrated that the higher preoperative SII was significantly associated with worse overall survival (OS) (HR = 2.26; 95% CI 1.44-3.54; P < 0.001) and cancer-specific survival (CSS) (HR = 2.17; 95% CI 1.33-3.55; P = 0.002). After PSM, elevated preoperative SII was an independent predictor of poor OS (HR = 1.78; 95% CI 1.1-2.87; P = 0.018) and CSS (HR = 1.8; 95% CI 1.07-3.03; P = 0.027). CONCLUSION: In conclusion, preoperative SII is associated with adverse factors for RCC. Furthermore, higher preoperative SII is an independent predictor of poor OS and CSS in surgically treated patients with non-metastatic RCC. More prospective and large scale studies are warranted to validate our findings.

An Integrated Microarray Analysis Reveals Significant Diagnostic and Prognostic Biomarkers in Pancreatic Cancer.

BACKGROUND Pancreatic cancer (PAC) is a lethal cancer and it is essential to develop accurate diagnostic and prognostic biomarkers for PAC. MATERIAL AND METHODS An integrated microarray analysis of PAC was conducted to identify differentially expressed genes (DEGs) between PAC and non-tumor controls. Expression of DEGs were further confirmed by The Cancer Genome Atlas and the Genotype-Tissue Expression. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and protein-protein integration network construction were performed to further research the biological functions of DEGs. Receiver-operating characteristic analysis and survival analysis were used to evaluate the diagnostic and prognostic value of DEGs for PAC. RESULTS Seventeen microarray datasets were downloaded from Gene Expression Omnibus to conduct the integrated microarray analysis. A total of 1136 DEGs (596 upregulated and 540 downregulated DEGs) in PAC tissues compared with non-tumor controls were identified. Pancreatic secretion (Kegg: 04972), insulin signaling pathway (Kegg: 04910), and several cancer-related pathways including pathways in cancer (Kegg: 05200), MAPK signaling pathway (Kegg: 04010), and pancreatic cancer (Kegg: 05212) were enriched for DEGs in PAC. Seven DEGs (AHNAK2, CDH3, IFI27, ITGA2, LAMB3, SLC6A14, and TMPRSS4) were found to have both great diagnostic and prognostic value for PAC. High expression of these 7 DEGs were significantly associated with poor prognosis of patients with PAC. CONCLUSIONS These 7 DEGs might be potential diagnostic and prognostic biomarkers for PAC and help uncovering the mechanism of PAC.

Comparison of Two Numerical Parameters to Assess Detrusor Contractility in Prognosing Short-Term Outcome after Transurethral Resection of the Prostate.

OBJECTIVE: To investigate and compare the influence of two numerical detrusor contractility parameters, the bladder contractility index (BCI) and the maximum Watts factor (WFmax), on transurethral resection of the prostate (TURP) outcome. METHODS: A retrospective study was conducted on 236 patients who had undergone urodynamic assessment preoperatively and TURP for benign prostatic obstruction. They were evaluated by International Prostate Symptom Score (IPSS) and uroflowmetry preoperatively and 3 months postoperatively. Related criteria were established to determine the overall efficacy of TURP. Logistic regression analysis and receiver operating characteristic curves were made to investigate the influence of the BCI and WFmax on TURP efficacy. RESULTS: Among the 236 patients, 195 treatments were effective and 41 ineffective. Multivariate analysis showed that both the BCI (OR 1.038) and the WFmax (OR 1.291) could influence TURP efficacy. For predicting TURP efficacy, the optimal cut-off values of the BCI and WFmax were 98.7 and 10.27 W/m2, respectively. The AUC, sensitivity and specificity of the BCI were 0.722, 78.5% and 61.0%; those of the WFmax were 0.761, 73.9% and 73.2%, with no significant difference (p > 0.05). CONCLUSIONS: To some extent, the BCI and the WFmax can predict TURP efficacy equally well. A discrimination level of 10.27 W/m2 may be a threshold value for detrusor underactivity (DU); as regards the BCI, the current threshold value is appropriate to diagnose DU.

Sarcopenia predicts prognosis of patients with renal cell carcinoma: A systematic review and meta-analysis.

Sarcopenia, a concept reflecting the loss of skeletal muscle mass, was reported to be associated with the prognosis of several tumors. However, the prognostic value of sarcopenia in patients with renal cancer remains unclear. We carried out this meta-analysis and systematic review to evaluate the prognostic value of sarcopenia in patients with renal cell carcinomas. We comprehensively searched PubMed, Embase, and Cochrane Library from inception to December 2018. Hazard ratio (HR) and 95% confidence interval (CI) were pooled together. A total of 5 studies consisting of 771 patients were enrolled in this quantitative analysis, 347 (45.0%) of which had sarcopenia. Patients with sarcopenia had a worse OS compared with those without sarcopenia (HR=1.76; 95%CI, 1.35-2.31; P<0.001). In the subgroup of patients with localized and advanced/metastatic diseases, sarcopenia was also associated with poor OS (HR=1.48, P=0.039; HR=2.14, P<0.001; respectively). With a limited sample size, we did not observe difference of PFS between two groups (HR=1.56, 95% CI, 0.69-3.50, P=0.282). In the present meta-analysis, we observed that patients with sarcopenia had a worse OS compared with those without sarcopenia in RCC. Larger, preferably prospective studies, are needed to confirm and update our findings.

Image quality and diagnostic value of ultra low-voltage, ultra low-contrast coronary CT angiography.

OBJECTIVE: To explore the image quality (IQ) and diagnostic value of 70 kVp turbo high-pitch coronary CT angiography (THP-CCTA) using automated tube voltage selection (ATVS) and 30 mL of low-concentration contrast agent. METHODS: Patients who underwent 70 kVp THP-CCTA using ATVS with 30 mL of contrast agent (group A) were prospectively enrolled, and those who underwent conventional CCTA (100/120 kVp, prospective sequential mode with 65-75 mL of contrast agent) (group B) were retrospectively selected for study. IQ was assessed subjectively on a 5-point scale, and diagnostic value was assessed based on invasive coronary angiography as the gold standard. Heart rate (HR), HR fluctuation (HRF), body mass index (BMI), effective radiation dose (ED), and iodine uptake (IU) were recorded. RESULTS: A total of 796 patients (398/398 in groups A/B) were included. Between-group differences in age, gender, BMI, HR, HRF, and IQ values were not significant. The ED/IU values were 0.3 ± 0.1 mSv/9.0 ± 0.0 g and 5.8 ± 1.8 mSv/22.9 ± 1.0 g in groups A and B, respectively (p < 0.01). The sensitivity, specificity, positive and negative predictive values, and accuracy of THP-CCTA for the diagnosis of ≥ 50% stenosis were 94.8%, 97.5%, 92.0%, 98.4%, and 96.9% respectively. The mean HR and coronary calcium score were independent predictors of diagnostic image quality, and the best cutoff values were 71.5 bpm and 444.1 respectively. CONCLUSION: This third-generation dual-source CT imaging modality, a 70-kVp THP-CCTA system using ATVS with 30 mL of low-concentration contrast agent, produces high-quality images with high diagnostic accuracy for significant stenosis, with ultra low ED and IU. This technique was most promising in individuals with an HR < 71.5 bpm and coronary calcium score < 444.1. KEY POINTS: • Turbo high-pitch CCTA using 70 kVp via automated tube voltage selection and 30 mL of low-concentration contrast agent is feasible. • This protocol provides high diagnostic accuracy for significant coronary stenosis and reduces radiation doses and iodine uptake significantly. • This protocol was most promising in individuals with an HR < 71.5 bpm and coronary calcium score < 444.1.

Negative pressure pulmonary edema after percutaneous endoscopic interlaminar lumbar discectomy-a case report.

BACKGROUND: Negative pressure pulmonary edema (NPPE) is a rare complication that is more prevalent in young patients. NPPE usually results from acute upper airway obstruction, which is most commonly caused by laryngospasm during extubation. NPPE is characterized by the sudden onset of coughing, hemoptysis, tachycardia, tachypnea, and hypoxia, and is dramatically improved with supportive care, which prevents severe sequelae. To our knowledge, there is no report of a patient developing NPPE after percutaneous endoscopic interlaminar lumbar discectomy. CASE PRESENTATION: Herein, we report the case of a 22-year-old amateur basketball player with L5/S1 disc herniation who developed NPPE during extubation after general anesthesia for a minimally invasive spinal surgery (percutaneous endoscopic interlaminar lumbar discectomy). The NPPE was treated by maintaining the airway patency, applying positive-pressure ventilation, administering dexamethasone and antibiotics, and limiting the volume of fluid infused. The patient had an uneventful postoperative course, and was discharged to his home on postoperative day 3. CONCLUSIONS: Although NPPE is an infrequent complication, especially in patients undergoing percutaneous endoscopic interlaminar lumbar discectomy, this case report highlights the importance of early diagnosis and prompt treatment of NPPE to prevent the development of potentially fatal complications.

Differential proteomic profiling of endometrium and plasma indicate the importance of hydrolysis in bovine endometritis.

Endometritis is an important disease of dairy cows that leads to significant economic losses in the dairy cattle industry. To investigate the alteration of proteins associated with endometritis in the dairy cow, the isobaric tags for relative and absolute quantification (iTRAQ) technique was applied to quantitatively identify differentially expressed proteins (DEP) in the endometrium and peripheral plasma of Chinese Holstein cows with endometritis. Compared with the normal (control) group, 159 DEP in the endometrium and 137 DEP in the plasma were identified in cows with endometritis. Gene ontology analysis demonstrated that the predominant endometrial DEP were primarily involved in responses to stimulus and stress processes and mainly played a role in hydrolysis in the extracellular region. The predominant plasma DEP were mainly components of the cytosol and non-membrane-bound organelles, and they were involved in the response to stress and regulation of enzyme activity. Protein-protein interaction of tissue DEP revealed that some core seed proteins, such as RAC2, ITGB2, and CDH1 in the same network as CD14, MMP3, and MMP9, had important functions in the cross-talk of pathways related to extracellular proteolysis. In summary, significant enzymatic hydrolase activity in the extracellular region is proposed as a molecular mechanism by which altered proteins may promote inflammation and hence endometritis.

A new formula to calculate activity of superoxide dismutase in indirect assays.

To calculate superoxide dismutase (SOD) activity rapidly and accurately by indirect SOD assays, a formula based on the ratio of the catalytic speed of SOD to the reaction speed of the indicator with superoxide anion was deduced. The accuracy of this formula was compared with the conventional formula based on inhibition in five indirect SOD assays. The new formula was validated in nearly the entire SOD activity range, whereas the conventional formula was validated only during inhibition of 40-60%. This formula might also be used for the assays of other enzymes.

Comparative proteomics analysis provide novel insight into laminitis in Chinese Holstein cows.

BACKGROUND: Laminitis is considered as the most important cause of hoof lameness in dairy cows, which causes abundant economic losses in husbandry. Through intense efforts in past decades, the etiology of laminitis is preliminarily considered to be subacute ruminal acidosis; however, the pathogenesis of laminitis needs further research. The differentially expressed proteins (DEP) were detected in plasma of healthy cows and clinical laminitis cows by two-dimensional gel electrophoresis (2-DE) and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: Nineteen protein spots were differentially expressed, and 16 kinds of proteins were identified after peptide mass fingerprint search and bioinformatics analysis. Of these, 12 proteins were differentially up-regulated and 4 down-regulated. Overall, these differential proteins were involved in carbohydrate metabolism, lipids metabolism, molecular transport, immune regulation, inflammatory response, oxidative stress and so on. CONCLUSIONS: The DEPs were closely related to the occurrence and development of laminitis and the lipid metabolic disturbance may be a new pathway to cause laminitis in dairy cows. The results provide the theory foundation for further revealing the mechanism of laminitis and screening the early diagnostic proteins and therapeutic target.

Use of Dual-Source Computed Tomography to Evaluate Renal Cortical Perfusion in Patients With Essential Hypertension Without Diabetes: Preliminary Results.

OBJECTIVES: To assess renal cortical perfusion parameter changes using computed tomography (CT) renal perfusion examination in patients with essential hypertension (EH), especially those with EH-related target organ damage (TOD), and to correlate renal perfusion parameters with clinical and laboratory data. METHODS: Consecutive patients with EH (without exclusion criteria) and healthy controls underwent 128-slice dual-source CT perfusion imaging. Quantitative perfusion analysis of renal cortex parameters [blood flow (BF), blood volume, time to peak, and mean transit time] was performed. RESULTS: Ninety-one participants (60 patients with EH, 31 healthy controls) underwent renal perfusion CT imaging, and 84 participants (92.3%) were eligible for perfusion analysis. The BF values were lower in patients with EH than that in controls. Blood flow was correlated with age (P < 0.01), duration of hypertension (P < 0.01), estimated glomerular filtration rate (eGFR; P < 0.01), pulse pressure (P < 0.05), and body mass index (BMI; P < 0.05). Duration of hypertension, eGFR, and BMI were independently associated with BF. No parameter differed between control subjects and those with EH but not. Blood flow was lower in patients with TOD than in control subjects (P < 0.01), but no other parameter differed. Blood flow was lower (P < 0.01) and mean transit time and time to peak were higher (P < 0.05) in the TOD than that in the non-TOD group. CONCLUSIONS: Essential hypertension, especially EH-related TOD, alters renal cortical perfusion parameters, especially BF. Four-dimensional spiral CT renal perfusion examination showed that duration of hypertension, eGFR, and BMI were independently associated with decreased BF.

[Application of microwave irradiation technology to the field of pharmaceutics].

Microwaves can be directly transformed into heat inside materials because of their ability of penetrating into any substance. The degree that materials are heated depends on their dielectric properties. Materials with high dielectric loss are more easily to reach a resonant state by microwaves field, then microwaves can be absorbed efficiently. Microwave irradiation technique with the unique heating mechanisms could induce drug-polymer interaction and change the properties of dissolution. Many benefits such as improving product quality, increasing energy efficiency and reducing times can be obtained by microwaves. This paper summarized characteristics of the microwave irradiation technique, new preparation techniques and formulation process in pharmaceutical industry by microwave irradiation technology. The microwave technology provides a new clue for heating and drying in the field of pharmaceutics.

Synthesis, Characterization, and Physicochemical Properties of New [Emim][BF3X] Complex Anion Ionic Liquids.

A new series of complex anion ionic liquids (ILs) [Emim][BF3X] (X = CH3SO3, EtSO4, HSO4, Tosylate) were synthesized and characterized by nuclear magnetic resonance, elemental analysis, differential scanning calorimetry analysis, and thermogravimetry. The physicochemical properties of these ILs, such as density, viscosity, conductivity, and surface tension, were measured and correlated with thermodynamic and empirical equations in the temperature range of 293.15-358.15 K under ambient conditions, and the thermal expansion coefficient, standard molar entropy, lattice potential energy, viscosity activation energy, surface enthalpy, and surface entropy were further calculated from experimental values. According to the temperature-dependent viscosity and conductivity, [Emim][BF3X] ILs follow the Walden rule, and they are classified as "good (or super) ionic liquids".

[Evaluation of the comprehensive schistosomiasis control measures with emphasis on infection source of replacing cattle with machine].

OBJECTIVE: To evaluate the effect of comprehensive measures with an emphasis on schistosomiasis infection source control by replacing cattle with machine. METHODS: In 2011, 2 villages from each of Jingzhou District, Jianli County and Jiangling County, Hubei Province, were selected as intervention group where the comprehensive measures were implemented, while 2 villages from Shishou City served as control with routine control activities. A cluster random sampling was carried out in the 8 villages with more than 300 people in each village were sampled. Stool examination using modified Kato-Katz was applied for identification of the infected persons and hatching test for cattle survey. The systemic sampling was applied for snail survey, fecal specimens from the field were examined by hatching test. Each sample was examined three times. Data were collected for the analysis of control effect between intervention and control groups in 2007 (baseline), 2009 (before implementation of comprehensive measures) and 2011 (post-intervention). RESULTS: In intervention villages, the overall prevalence in human reduced significantly from 3.6% (135/3 772) in 2007 and 2.0% (63/3 116) in 2009 to 0.9% (21/2 396) in 2011 (chi2 = 43.411, chi2 = 11.840, P < 0.05). Until 2011, there were no cattle in intervention group; the prevalence decreased by 52.6% in human and about 100% in cattle from 2010 to 2011. In control group, the infection rate in residents in 2007, 2009 and 2011 was 4.5% (64/1 410), 2.6% (34/1 294) and 1.8% (24/1,320), respectively (chi2 = 16.178, P < 0.05), and 5.1% (8/158) in 2007, 1.6% (3/187) in 2009 and 1.6% (3/189) in 2011 in cattle, respectively (chi2 = 3.387, P > 0.05). The infection rate in human and cattle fell by 25.0% and 5.9% from 2010 to 2011, respectively. There was a significant difference in human infection rate between the intervention and control groups after intervention (chi2 = 6.309, P < 0.05). No infected snails were detected in intervention and control groups. No positive feces from the field was found in the intervention group, 7.5% positive rate was recorded in the control. CONCLUSION: The comprehensive measures focused on infection source control by replacing cattle with machine can effectively control Schistosoma japonicum transmission, with a significant decrease of the prevalence in human and cattle.

Micropapillary Pattern in Invasive Mucinous Adenocarcinoma of the Lung: Comparison With Invasive Non-Mucinous Adenocarcinoma.

Background. The presence of a micropapillary pattern is associated with poor outcomes in lung adenocarcinoma. This study aimed to assess the clinicopathological features of micropapillary pattern in mucinous adenocarcinoma of the lung. Methods. The patients were stratified into three groups: the invasive mucinous adenocarcinoma group (60 patients), the mixed invasive mucinous adenocarcinoma group (33 patients), and the invasive non-mucinous adenocarcinoma group (237 patients). The presence of micropapillary pattern and its clinicopathological features were analyzed and compared between the three groups. Results. Compared to mixed invasive mucinous adenocarcinoma, invasive mucinous adenocarcinoma had lower frequencies of micropapillary pattern (28.3% vs 87.9%, respectively; P < .001) and lymph node metastasis (00.0% vs 15.1%, respectively; P = .005). The frequency of tumor spread through air space (STAS) in invasive mucinous adenocarcinoma (23.3%) was higher than that in invasive non-mucinous adenocarcinoma (6.3%; P < .001), while lower than that in mixed invasive mucinous adenocarcinoma (60.6%; P < .001). When the three groups were all accompanied by micropapillary pattern, there was no obvious difference in STAS between invasive mucinous adenocarcinoma with micropapillary pattern and mixed mucinous adenocarcinoma with micropapillary pattern (P > .05). No filigree pattern occurred in invasive mucinous adenocarcinoma with micropapillary pattern. Conclusions. The micropapillary pattern is frequently observed in invasive mucinous adenocarcinoma and has a better prognosis compared to mixed invasive mucinous adenocarcinoma and invasive non-mucinous adenocarcinoma. However, the malignancy of the micropapillary pattern in mixed mucinous adenocarcinoma was similar to that in invasive non-mucinous adenocarcinoma, even with the presence of mucus. These findings suggest that the development mechanisms of the micropapillary pattern in invasive mucinous adenocarcinoma and mixed mucinous adenocarcinoma may differ.

Molecular characterization of ferroptosis in soft tissue sarcoma constructs a prognostic and immunotherapeutic signature through experimental and bioinformatics analyses.

Ferroptosis regulators have been found to affect tumor progression. However, studies focusing on ferroptosis and soft tissue sarcoma (STS) are rare. Somatic mutation, copy number variation, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, consensus clustering, differentially expressed genes analysis (DEGs), principal component analysis (PCA) and gene set enrichment analysis (GSEA) were used to identify and explore different ferroptosis modifications in STS. A nomogram was constructed to predict the prognosis of STS. Moreover, three immunotherapy datasets were used to assess the Fescore. Western blotting, siRNA transfection, EdU assay and reactive oxygen species (ROS) measurement were performed. 16 prognostic ferroptosis regulators were screened and significant differences were observed in somatic mutation, copy number variation (CNV) and RT-qPCR among these ferroptosis regulators. 2 different ferroptosis modification patterns were found (Fe cluster A and B). Fe cluster A with higher Fescore was correlated with p53 pathway and had better prognosis of STS (p = 0.002) while Fe cluster B with lower Fescore was correlated with angiogenesis and MYC pathway and showed a poorer outcome. Besides, the nomogram effectively predicted the outcome of STS and the Fescore could also well predict the prognosis of other 16 tumors and immunotherapy response. Downregulation of LOX also inhibited growth and increased ROS production in sarcoma cells. The molecular characterization of ferroptosis regulators in STS was explored and an Fescore was constructed. The Fescore quantified ferroptosis modification in STS patients and effectively predicted the prognosis of a variety of tumors, providing novel insights for precision medicine.

Mortality of Escalation and Modulation Antithrombotic Therapy in Coronary Artery Disease Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The net clinical benefit of antithrombotic therapy (ATT) reflects the concomitant effects of bleeding and ischemic events. OBJECTIVES: We sought to assess the overall effect of the modulation or escalation of ATT on all-cause mortality as well as ischemic and bleeding events. METHODS: We performed a meta-analysis of randomized controlled trials comparing escalation or modulation of ATT versus standard ATT in patients with coronary artery disease. A total of 32 studies with 160,659 subjects were enrolled in this analysis. RESULTS: Neither escalation nor modulation of ATT has significant effect on all-cause mortality (escalation: relative risk [RR]: 0.94, 95% confidence interval [CI]: 0.85-1.04; modulation: RR: 0.90; 95% CI: 0.81-1.01). Compared with standard ATT therapy, escalation of ATT was associated with lower risk of myocardial infarction (MI; RR: 0.84, 95% CI: 0.76-0.94), but had a higher risk of major or minor bleeding (RR: 1.38, 95% CI: 1.15-1.66). Modulation of ATT was associated with a similar risk of MI (RR: 1.07, 95% CI: 0.96-1.19), but a reduced risk for major or minor bleeding (RR: 0.58, 95% CI: 0.51-0.66). Meta-regression combining both escalation and modulation studies found that the heterogeneity of all-cause mortality was mainly attributed to the heterogeneity of major or minor bleeding (adjusted R-squared = 100.00%, p = 0.004), but not to MI. CONCLUSION: Either escalation or modulation of ATT has little benefit in all-cause mortality. The variability of the treatment effects on all-cause mortality was mainly attributed to the variability of major or minor bleeding, but not to MI.

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.