Polyimide Films Based on ß-Cyclodextrin Polyrotaxane with Low Dielectric and Excellent Comprehensive Performance.

In order to prepare polyimide (PI) films with a low dielectric constant and excellent comprehensive performance, a two-step method was employed in this study to integrate ß-cyclodextrin into a semi-aromatic fluorine-containing polyimide ternary system. By introducing trifluoromethyl groups to reduce the dielectric constant, the dielectric constant was further reduced to 2.55 at 10 MHz. Simultaneously, the film exhibited noteworthy thermal stability (a glass transition temperature exceeding 300 °C) and a high coefficient of thermal expansion. The material also demonstrated outstanding mechanical properties, boasting a strength of 122 MPa and a modulus of 2.2 GPa, along with high optical transparency (transmittance reaching up to 89% at 450 nm). Moreover, the inherent high transparency of colorless polyimide (CPI) combined with good stretchability contributed to the attainment of a low dielectric constant. This strategic approach not only opens up new opportunities for novel electroactive polymers but also holds potential applications in flexible displays, circuit printing, and chip packaging.

Alkaline earth modified activated carbon supported Cu catalysts with enhanced selectivity in the hydrogenation of dimethyl oxalate to methyl glycolate.

In this work, the effect of alkaline earth metal modification on the catalytic performance of activated carbon supported Cu was investigated. The experimental results showed that the introduction of Ca and Sr improved the selectivity of methyl glycolate (MG) during hydrogenation of dimethyl oxalate (DMO) in gas phase. The optimal loading amount of Ca was 0.1 wt%, and under the optimal conditions (temperature 240 °C, pressure 2 MPa, hydrogen-ester ratio of 80, feedstock 15% DMO methanol solution, and WLHSVDMO = 0.9 h-1) the selectivity of MG was as high as 94%, and the conversion of DMO was 97%. The optimal loading of Sr was 0.2 wt% with MG selectivity up to 89% and DMO conversion of 98%. The results of catalyst characterization showed that both Ca and Sr modifications were beneficial to further reduce the particle size of Cu, improve the dispersion of Cu, increase the basicity of the catalyst, and improve the stable presence of Cu+ during the reaction process. Cu+ was beneficial to the stabilization of the MG species, in which Cu+ accounted for more in the Ca-modified catalysts Cu+/(Cu+ + Cu0) = 0.65, and in the Sr-modified ones Cu+/(Cu+ + Cu0) = 0.51. Therefore, both Ca and Sr modified catalysts showed improvement in the selectivity of MG.

Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma.

PURPOSE: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. EXPERIMENTAL DESIGN: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. RESULTS: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. CONCLUSIONS: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.

Doxofylline Protects Gram-Negative Pathogens against Antibiotic-Mediated Killing.

Given the growing rate of Gram-negative bacterial infections, antibiotics are now frequently prescribed for various respiratory diseases. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities, but its influence on antibiotics remains poorly understood. Here, we first report the discovery of doxofylline-induced high minimum inhibitory concentrations of antibiotics. We also showed that doxofylline blocked antimicrobial-mediated killing for Gram-negative pathogens in vitro and in murine lung infection models in vivo. By combining efflux pump inhibition tests, gene expression analyses, and using the gene tolC knockout strain, we found that doxofylline positively regulated gene expression of the AcrAB-TolC efflux pump and attenuated the effect of doxofylline on antibacterial activities in ΔtolC mutants. Notably, doxofylline-mediated protection correlated with decreased reactive oxygen species (ROS) production. Collectively, our study indicates that doxofylline protects Gram-negative bacteria from antimicrobial lethality by regulating the AcrAB-TolC efflux pump in a TolC-dependent manner and suppressing antibiotic-induced ROS accumulation. These results suggest caution when using antibiotics alongside doxofylline in clinical treatment.

Gut Microbiota Contributes to Host Defense Against Klebsiella pneumoniae-Induced Liver Abscess.

PURPOSE: Klebsiella pneumoniae-induced liver abscess (KLA) is a type of pyogenic liver abscess (PLA), which is a distinct invasive syndrome that has been increasingly reported worldwide over the past two decades. The intestinal microbiota is increasingly recognized as an important modulator that can promote and maintain host immune homeostasis. However, its precise role in liver abscess is unknown. We aimed to investigate the function of the gut microbiota in the host defense against K. pneumoniae infection. METHODS: We constructed C57BL/6J mice with KLA and analyzed the diversity and richness of the intestinal microflora by 16S rRNA sequencing. Next, to create a microbiota-depleted (MD) mouse model, we administered multiple broad-spectrum antibiotics and validated the model using 16S rRNA sequencing. At 48 h after K. pneumoniae infection, we assessed the general health condition, liver injury, bacterial loads, and inflammatory factor levels in MD+KLA mice. Additionally, fecal microbiota transplantation (FMT) was conducted in another group of MD+KLA mice prior to K. pneumoniae infection, and we assessed whether the transplantation changed the outcomes. RESULTS: The diversity of the intestinal flora was significantly changed in KLA mice compared to control mice, with a decrease in beneficial bacteria and an increase in harmful bacteria. The MD+KLA mice exhibited impaired antimicrobial capacity, reduced survival, increased inflammation and liver damage at 48 h after K. pneumoniae infection compared to the KLA mice. However, FMT normalized the inflammatory cytokine levels, reduced liver damage, and increased survival. CONCLUSION: This study identified the gut microbiota as a protective factor against K. pneumoniae infection. The role of FMT in KLA should be investigated in future clinical studies.

Effects of Tigecycline Combined with Azithromycin Against Biofilms of Multidrug-Resistant Stenotrophomonas maltophilia Isolates from a Patient in China.

PURPOSE: Our aim was to investigate in vitro biofilm formation by S. maltophilia and the effects of antibacterial agents used to prevent biofilm formation. METHODS: Two trimethoprim/sulfamethoxazole-resistant S. maltophilia strains were isolated from the pleural effusion of a patient with cancer. The minimum inhibitory concentrations (MICs) of amikacin, azithromycin, cefoperazone/sulbactam, and tigecycline were determined. The checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs). A crystal violet biofilm assay and confocal laser scanning microscopy (CLSM) were used to observe biofilm formation. In vitro effects of azithromycin combined with tigecycline on biofilms of S. maltophilia strains were tested. RESULTS: The two S. maltophilia isolates were confirmed to produce strong biofilms. Crystal violet biofilm assay and CLSM analysis of S. maltophilia biofilm were in the initial adhesive stage after 2 h incubation. Biofilm was in the exponential phase of growth at 12 h and reached maximal growth at 36-48 h. Compared with tigecycline or azithromycin alone, the combination of tigecycline and azithromycin increased the inhibiting effect S. maltophilia biofilm biomass after incubation for 12 h. Compared with the control group, in almost all strains treated with tigecycline and azithromycin, the biofilm was significantly suppressed significance (P<0.001). We found that 2x MIC azithromycin combined with 1x MIC tigecycline had the best inhibiting effect against the biofilm, the biofilm inhibition rates of three strains were all over 60%, the biofilm thickness was inhibited from 36.00 ± 4.00 µm to 8.00 µm, from 40.00 µm to 6.67± 2.31 µm, and from 32.00 µm to 13.33 ± 2.31 µm in SMA1, SMA2 and ATCC17666, respectively. CONCLUSION: Azithromycin combined with tigecycline inhibited biofilm formation by S. maltophilia. Our study provides an experimental basis for a possible optimal treatment strategy for S. maltophilia biofilm-related infections.

Virulence-Related Gene Distribution Among Shigella Isolates in Anhui, China: The Association with Antimicrobial Resistance.

OBJECTIVE: The aim of this study was to investigate the antimicrobial resistance profiles and distribution of virulence-related genes (VRGs) among Shigella isolates in Anhui, China, and to identify the correlation between the VRGs and antimicrobial resistance. MATERIALS AND METHODS: A total of 525 non-duplicate Shigella isolates (449 S. flexneri, 68 S. sonnei, 3 S. boydii, and 5 S. dysenteriae) were collected in Anhui Province, China between September 2011 and September 2015. The antimicrobial resistance of the strains was determined by the agar dilution method according to CLSI guidelines. The presence of 16 VRGs, including ipaH, ipaA-D, ial, virB, virF, set, sen, icsA, icsB, sigA, sat, pic, and sepA, was evaluated using PCR amplification and sequencing. RESULTS: Shigella flexneri was the most abundant (85.5%), followed by S. sonnei (13.0%). The proportion of males with S. flexneri was higher than that of females (57% vs 43%; P<0.0001). The most common resistance pattern was the combination of ampicillin, nalidixic acid, and tetracycline for S. flexneri (90.2%) and S. sonnei (94.1%). Resistance to ciprofloxacin and levofloxacin was more common among S. flexneri than among S. sonnei (49.7% vs.19.1%, P<0.0001; 30.5% vs 10.3%, P=0.001, respectively). All the isolates were positive for the ipaH gene, while the set, sat, pic, and sepA genes were not detected among the S. sonnei isolates. Except for sigA and sen, resistance to chloramphenicol and ciprofloxacin was more common among VRG-positive S. flexneri than among VRG-negative S. flexneri (P<0.05). Furthermore, resistance to ceftriaxone and ceftazidime was more frequently detected among sat- and set-positive S. flexneri than among sat- and set-negative S. flexneri (P<0.05). However, gentamicin resistance was more prevalent among VRG-negative (ial, virF, set, sat, pic, and sepA) S. flexneri than among VRG-positive S. flexneri (P<0.05). CONCLUSION: Shigella flexneri remains the predominant species in Anhui, China, and the resistance to fluoroquinolones was more widespread among S. flexneri than among S. sonnei. Shigella flexneri strains harboring specific VRGs were associated with antimicrobial resistance. To the best of our knowledge, this is the first report of the correlation between the VRGs and antimicrobial resistance in Anhui, China.

Retrospective analysis of risk factors of postoperative nausea and vomiting in patients undergoing ambulatory strabismus surgery via general anaesthesia.

BACKGROUND AND AIMS: Postoperative nausea and vomiting (PONV), one of the common complications following strabismus surgery, would delay the ambulatory discharge time. The aim of this retrospective study was to determine the risk factors of PONV in patients undergoing ambulatory strabismus surgery under general anaesthesia, with the treatments of dexamethasone and 5-HT3 antagonist combination. METHODS: We reviewed 721 consecutive patients (12-60 years old) undergoing ambulatory strabismus surgery under general anaesthesia at an academic eye centre between December 2016 and January 2019. Patients received prophylactic treatment of dexamethasone and 5-HT3 antagonist combination during anaesthesia induction, and PONV was evaluated during the early recovery period before discharge. RESULTS: The dexamethasone and 5-HT3 antagonist combination effectively reduced the incidence of PONV (3.05%, 22/721), and the patients who experienced PONV had statistically prolonged phase II recovery time as compared those who did not (P = 0.006). The sum of the extraocular muscles manipulated and the use of nalbuphine (vs flurbiprofen axetil) were the independent risk factors for PONV (P < 0.05). CONCLUSION: The sum of the extraocular muscles manipulated and the use of nalbuphine are potentially modifiable risk factors for PONV after strabismus surgery with the treatments of dexamethasone and 5-HT3 antagonist combination.

Desflurane anesthesia compared with total intravenous anesthesia on anesthesia-controlled operating room time in ambulatory surgery following strabotomy: a randomized controlled study.

BACKGROUND: Ophthalmic ambulatory surgery is preferred to be performed under general anesthesia either by total intravenous anesthesia (TIVA) or by inhalational anesthesia to increase the patient comfort. However, anesthesia-controlled time (ACT) can cause increased non-operative operating room (OR) time which may adversely affect the ORs efficiency. This study was aimed to compare the ACT of desflurane with that of propofol-remifentanil in strabismus ambulatory surgery. METHODS: From November 2016 to December 2017, a total of 200 strabismus patients (aged 18-60 years old, and scheduled for elective ambulatory surgery at Zhongshan Ophthalmic Center) were randomly assigned to receive either propofol-based TIVA (group TIVA) or desflurane anesthesia (group DES) for maintenance of anesthesia. The primary outcome was the extubation time. Secondary outcomes included surgical time, anesthetic time, OR exit time, and Phase I and II recovery time. The intraoperative incidences of hypotension, bradycardia and oculocardiac reflex (OCR), and the incidences of any post-operative complications were recorded. Mann-Whitney U test and Chi-square or Fisher exact tests were used to compare the two groups. RESULTS: We found that the extubation time (5.5 [3.9-7.0] vs. 9.7 [8.5-11.4] min, P < 0.001) and the incidence of prolonged time to extubation (0 vs. 6%, P = 0.029) in the DES group were significantly decreased compared with those in the TIVA group. The patients in the DES group displayed shorter OR exit time as compared with that in the TIVA group (7.3 [5.5-8.7] vs. 10.8 [9.3-12.3] min, P < 0.001). The patients using desflurane exhibited more stable hemodynamics during surgery than the patients using propofol-based TIVA, as demonstrated by lower incidences of hypotension (1% vs. 22%, P < 0.001), bradycardia (2% vs. 13%, P = 0.002), and OCR (17% vs. 44%, P < 0.001). CONCLUSION: DES enhanced the ophthalmic OR efficiency by reducing the extubation time and OR exit time, and provided more stable hemodynamics intra-operatively than TIVA in patients undergoing strabismus ambulatory surgery. TRIAL REGISTRATION: ClinicalTrials.gov, No. NCT02922660; https://clinicaltrials.gov/ct2/show/NCT02922660?id=NCT02922660&draw=2&rank=1.

Dexmedetomidine versus other sedatives for non-painful pediatric examinations: A systematic review and meta-analysis of randomized controlled trials.

STUDY OBJECTIVE: Procedural sedation for non-painful pediatric examinations outside the operating room remains a challenge, this study was designed to compare the safety and effectiveness of sedation provided by dexmedetomidine versus other sedatives including chloral hydrate, midazolam, and pentobarbital for pediatric patients to complete diagnostic examinations. DESIGN: Systematic review and meta-analysis of RCTs. SETTING: Pediatric procedural sedation. INTERVENTIONS: Comparison of sedation by dexmedetomidine and chloral hydrate, or pentobarbital, or midazolam for pediatric non-painful sedation. PATIENTS: The PubMed, Embase, and Cochrane Library databases and the Cochrane Controlled Trials Register for randomized clinical trials were searched and limited the studies to those published in English through July 30, 2018. MEASUREMENTS: Prospective randomized clinical trials (RCTs) comparing dexmedetomidine to chloral hydrate, pentobarbital, and midazolam for pediatric procedural examinations outside the operating room were included in the meta-analysis. Search terms included dexmedetomidine, precede, adrenergic alpha-2 receptor agonists, adrenergic alpha 2 agonists, adrenergic alpha-agonists, adrenergic alpha 2 receptor agonists, chloral hydrate, pentobarbital, midazolam, AND sedation. MAIN RESULTS: A total of 1486 studies were screened and nine RCTs were identified; 1076 patients were analyzed. Sedation with dexmedetomidine provided statistically higher incidences in completing examinations with fewer episodes of desaturation than the other sedatives did (OR 2.90, 95% CI: 1.39-6.07, P = 0.005, I2 = 77%; OR 0.29, 95% CI: 0.15-0.57, P = 0.0004, I2 = 0%, respectively). CONCLUSIONS: The meta-analysis shows that sedation by dexmedetomidine has lower incidence of respiratory depression and provides higher success rates in completing examinations than other traditional sedatives without compromising safety, indicating a prospective clinical use for procedural sedation.

ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

Cricoid-mental distance-based versus weight-based criteria for size selection of classic laryngeal mask airway in adults: a randomized controlled study.

The optimal size selection of laryngeal mask airway (LMA) based on body weight is not always applicable. This study was prospectively conducted to evaluate the efficacy of cricoid-mental distance-based method versus weight-based method in optimal size selection of LMA in adults. Seventy-four patients (aged from 18 to 65) undergoing ophthalmic surgery were randomly assigned into cricoid-mental (CM) distance-based group or weight-based group to select appropriate size of LMA. The primary outcome was oropharyngeal leak pressure (OLP). Secondary outcomes included overall insertion success rate, number of insertion attempts, time to successful insertion, ease of insertion, score of fiber-optic view, peak inspiratory pressure during mechanical ventilation and postoperative pharyngolaryngeal morbidity. The OLP was significantly higher in CM distance-based group than that in weight-based group (19.38 ± 3.52 vs. 17.50 ± 3.18, P = 0.022). The successful placement at the first attempt in CM distance-based group was dramatically increased as compared with weight-based group (89.2% vs. 62.2%, P = 0.005). The overall success rate of LMA insertion in CM distance-based group was slightly increased in comparison with the weight-based group (100% vs. 91.9%, P = 0.240). There were no significant differences in score of fiber-optic view and postoperative pharyngolaryngeal morbidity between both groups (all P > 0.05). CM distance-based criteria is an alternative choice for optimizing size selection of classic LMA in adults.

Comparison of sedation by intranasal dexmedetomidine and oral chloral hydrate for pediatric ophthalmic examination.

BACKGROUND AND AIM: Pediatric ophthalmic examinations can be conducted under sedation either by chloral hydrate or by dexmedetomidine. The objective was to compare the success rates and quality of ophthalmic examination of children sedated by intranasal dexmedetomidine vs oral chloral hydrate. METHODS: One hundred and forty-one children aged from 3 to 36 months (5-15 kg) scheduled to ophthalmic examinations were randomly sedated by either intranasal dexmedetomidine (2 µg·kg-1 , n = 71) or oral chloral hydrate (80 mg·kg-1 , n = 70). The primary endpoint was successful sedation to complete the examinations including slit-lamp photography, tonometry, anterior segment analysis, and refractive error inspection. The secondary endpoints included quality of eye position, intraocular pressure, onset time, duration of examination, recovery time, discharge time, any side effects during examination, and within 48 h after discharge. RESULTS: Sixty-one children were sedated by dexmedetomidine with a success rate of 85.9%, which is significantly higher than that by chloral hydrate (64.3%) [OR 3.39, 95% CI: 1.48-7.76, P = 0.003]. Furthermore, children in the dexmedetomidine group displayed better eye position in anterior segment analysis than in chloral hydrate group median difference. All children displayed stable hemodynamics and none suffered hypoxemia in both groups. Oral chloral hydrate induced higher percentages of vomiting and altered bowel habit after discharge than dexmedetomidine. CONCLUSIONS: Intranasal dexmedetomidine provides more successful sedation and better quality of ophthalmic examinations than oral chloral hydrate for small children.

Sedation effects of intranasal dexmedetomidine delivered as sprays versus drops on pediatric response to venous cannulation.

OBJECTIVES: Mucosal atomization device (MAD) was designed to increase the bioavailability of intranasal medications by facilitating absorption, the present study aimed to evaluate and compare the sedation effects of intranasal dexmedetomidine delivered as drops versus sprays on pediatric responses to intravenous cannulation. METHODS: One hundred and six pediatric patients (aged from 2 to 5years) scheduled for elective ophthalmic surgery were intranasally received a dose of 2µg/kg in 20µl/kg of dexmedetomidine for sedation to reduce response to venous cannulation. The patients were randomized into syringe group and MAD group in which dexmedetomidine was delivered as drops or sprays via syringe or MAD respectively. The primary outcome was the response to peripheral vein cannulation assessed by the FLACC scores (faces, legs, activity, cry and consolability) 30min after intranasal administration of dexmedetomidine. The secondary outcomes included acceptance for intranasal medication, sedation onset time, and needle insertion times and any adverse event at the preoperative holding area. RESULTS: The FLACC scores in MAD group were significantly decreased than that treated by drops (P=0.021). The acceptance for intranasal administration between both groups was comparable (P>0.05), the onset time and the incidences in two and more times of needle insertion did not differ significantly between syringe and MAD groups (all P>0.05). None of patients were required to clinically intervene in heart rates reduction and none suffered respiratory depression after administrations of dexmedetomidine in either group. CONCLUSION: Intranasal dexmedetomidine by sprays offers better sedation effects to reduce responses to venous cannulation than drops.

Efficacy of premedication with intranasal dexmedetomidine on inhalational induction and postoperative emergence agitation in pediatric undergoing cataract surgery with sevoflurane.

STUDY OBJECTIVES: This study aimed to test the hypothesis that premedication with a single dose of intranasal dexmedetomidine (DEX) could not only reduce preoperative anxiety but also minimize the emergence agitation in children undergoing cataract surgery with sevoflurane anesthesia. DESIGN: Single-blinded, randomized, placebo-controlled clinical comparison study. SETTING: Academic medical center. PATIENTS: Ninety American Society of Anesthesiologists physical status 1 and 2 children scheduled for cataract surgery. INTERVENTIONS: Patients were randomized into 3 groups: group D1, group D2, and saline group (group C), in which the children received 1 or 2 µg/kg of intranasal DEX or saline, respectively, and each group comprises 30 patients. MEASUREMENTS: The mask induction score and the incidences of postoperative emergence agitation evaluated by the Pediatric Anesthesia Emergence Delirium scale were assessed. The emergence time, postanesthesia care unit (PACU) stay time, and any adverse events were recorded. MAIN RESULTS: The mask induction scores were significantly higher in the saline group than those in the D1 and D2 groups (P<.001). The incidences of emergence agitation in the D1 and D2 groups were significantly lower than that in the saline group (7/30 in group D1 and 3/30 in group D2 vs 24/30 in group C, P<.001). The emergence time and PACU stay time were comparable among the 3 groups (P>.05). The emergence time and PACU stay time did not differ significantly in DEX-treated groups as compared with the saline group; there were no differences between 1- and 2-µg/kg groups. None of the patients exhibited significant clinical complications. CONCLUSION: Intranasal DEX (1 or 2 µg/kg) dose independently improves the incidences of mask acceptance and prevents the incidences of postoperative emergency agitation mainly from sevoflurane without delaying the emergency time or inducing severe adverse events.

Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma.

Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g. T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, we observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.

A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes.

Protein tyrosine phosphatases (PTPs) constitute a large family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. A detailed understanding of PTP functions in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific, cell-permeable small-molecule agents. We present a stepwise focused library approach that transforms a weak and general non-hydrolyzable pTyr mimetic (F(2)Pmp, phosphonodifluoromethyl phenylalanine) into a highly potent and selective inhibitor of PTP-MEG2, an antagonist of hepatic insulin signaling. The crystal structures of the PTP-MEG2-inhibitor complexes provide direct evidence that potent and selective PTP inhibitors can be obtained by introducing molecular diversity into the F(2)Pmp scaffold to engage both the active site and unique nearby peripheral binding pockets. Importantly, the PTP-MEG2 inhibitor possesses highly efficacious cellular activity and is capable of augmenting insulin signaling and improving insulin sensitivity and glucose homeostasis in diet-induced obese mice. The results indicate that F(2)Pmp can be converted into highly potent and selective PTP inhibitory agents with excellent in vivo efficacy. Given the general nature of the approach, this strategy should be applicable to other members of the PTP superfamily.