Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722.

PURPOSE: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs). METHODS: Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR). RESULTS: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively. CONCLUSION: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR-mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.

Relationship between Dry Eye Disease and Dyslipidemia: A Systematic Review.

BACKGROUND: Dyslipidemia has been suggested to be associated with the occurrence of dry eye disease (DED). However, whether dyslipidemia is responsible for the development of DED remains unclear. In this systematic review, we explored the relationship between DED and dyslipidemia by using quantitative data. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a comprehensive literature search in several databases, including PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar, and obtained six relevant studies. RESULTS: Our findings indicated that the majority of the selected studies reported a statistically significant association between dyslipidemia and DED, particularly in women. However, our quantitative analysis revealed that only two studies reported statistically significant differences in total cholesterol and high-density lipoprotein cholesterol values. CONCLUSION: No statistically significant differences exist in the majority of lipid profile parameters between individuals with and without DED, but there is a statistically significant association between dyslipidemia and DED.

Optimal Timing of Targeted Temperature Management for Post-Cardiac Arrest Syndrome: Is Sooner Better?

Targeted temperature management (TTM) is often considered to improve post-cardiac arrest patients' outcomes. However, the optimal timing to initiate cooling remained uncertain. This retrospective analysis enrolled all non-traumatic post-cardiac arrest adult patients with either out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA) who received TTM from July 2015 to July 2021 at our hospital. The values of time delay before TTM and time to target temperature were divided into three periods according to optimal cut-off values identified using receiver operating characteristic curve analysis. A total of 177 patients were enrolled. A shorter time delay before TTM (pre-induction time) was associated with a lower survival chance at 28 days (32.00% vs. 54.00%, p = 0.0279). Patients with a longer cooling induction time (>440 minis) had better neurological outcomes (1.58% vs. 1.05%; p = 0.001) and survival at 28 days (58.06% vs. 29.25%; p = 0.006). After COX regression analysis, the influence of pre-induction time on survival became insignificant, but patients who cooled slowest still had a better chance of survival at 28 days. In conclusion, a shorter delay before TTM was not associated with better clinical outcomes. However, patients who took longer to reach the target temperature had better hospital survival and neurological outcomes than those who were cooled more rapidly. A further prospective study was warranted to evaluate the appropriate time window of TTM.

Predicting the successful application of high-flow nasal oxygen cannula in patients with COVID-19 respiratory failure: a retrospective analysis.

BACKGROUND: The right time of high-flow nasal cannulas (HFNCs) application in COVID-19 patients with acute respiratory failure remains uncertain. RESEARCH DESIGN AND METHODS: In this retrospective study, COVID-19-infected adult patients with hypoxemic respiratory failure were enrolled. Their baseline epidemiological data and respiratory failure related parameters, including the Ventilation in COVID-19 Estimation (VICE), and the ratio of oxygen saturation (ROX index), were recorded. The primary outcome measured was the 28-day mortality. RESULTS: A total of 69 patients were enrolled. Fifty-four (78%) patients who intubated and received invasive mechanical ventilatory (MV) support on day 1 were enrolled in the MV group. The remaining fifteen (22%) patients received HFNC initially (HFNC group), in which, ten (66%) patients were not intubated during hospitalization were belong to HFNC-success group and five (33%) of these patients were intubated later due to disease progression were attributed to HFNC-failure group. Compared with those in the MV group, those in the HFNC group had a lower mortality rate (6.7% vs. 40.7%, p = 0.0138). There were no differences in baseline characteristics among the two groups; however, the HFNC group had a lower VICE score (0.105 [0.049-0.269] vs. 0.260 [0.126-0.693], p = 0.0092) and higher ROX index (5.3 [5.1-10.7] vs. 4.3 [3.9-4.9], p = 0.0007) than the MV group. The ROX index was higher in the HFNC success group immediately before (p = 0.0136) and up to 12 hours of HFNC therapy than in the HFNC failure group. CONCLUSIONS: Early intubation may be considered in patients with a higher VICE score or a lower ROX index. The ROX score during HFNCs use can provide an early warning sign of treatment failure. Further investigations are warranted to confirm these results.

High flow nasal cannulas (HFNCs) were widely used in patients with COVID-19 infection related hypoxemic respiratory failure. However, there were concerns about its failure and related delayed intubation may be associated with a higher mortality rate. This retrospective study revealed patients with higher baseline disease severity and higher VICE scores may be treated with primary invasive mechanical ventilation. On the contrary, if their baseline VICE score is low and ROX index is high, HFNCs treatment might be safely applied initially. The trends of serial ROX index values during HFNC use could be a reliable periscope to predict the HFNC therapy outcome, therefore avoided delayed intubation.

Baseline characteristics and treatment response predictive of nAMD outcomes with ranibizumab therapy in treatment-naive patients: the RACER subgroup analysis.

BACKGROUND: The Ranibizumab AMD Clinical Efficacy Study (RACER) conducted in treatment-naive adult Taiwanese patients with neovascular age-related macular degeneration (nAMD) suggested the importance of early and intensive dosing of ranibizumab for optimal treatment outcomes. This subgroup analysis aims to provide clinical information on treatment response that can potentially guide on maintaining the treatment or switching anti-VEGF agents in the real-world setting. METHODS: Visual acuity (VA) and central retinal thickness (CRT) were assessed in the RACER subgroup population. Subgroup analysis sets were categorised based on: (1) baseline best-corrected VA (BCVA; ≤ 48 and > 48 letters); (2) baseline CRT (≤ 325 or > 325 µm); and (3) treatment response after three monthly initial injections: < or ≥ 5-letter gain in BCVA and reduction of < or ≥ 50 µm in CRT. RESULTS: Patient age, sex, nAMD duration and number of ranibizumab injections did not differ significantly between the treatment subgroups. Poor baseline BCVA (≤ 48 letters) and baseline CRT severity (> 325 µm) were predictors of maximum BCVA gains (9.6 ± 12.9 letters [95%CI: 6.3 to 12.9] and 5.1 ± 18.3 letters [95%CI: - 0.5 to 10.8] at Months 3 and 12, respectively) and better CRT reductions (- 127.6 ± 104.2 µm and - 104.2 ± 107.4 µm at Months 3 and 12, respectively; both P < 0.001). For the subgroup showing favourable treatment improvement with BCVA gains ≥ 5 letters after three monthly initial injections, 75.6% of patients maintained follow-up at Month 12 with a mean of 6.5 ± 14.3 letter gains (95% CI: 1.2 to 11.7). The BCVA gains < 5-letter subgroup nevertheless had stable BCVA (0.4 ± 12.1 letter gains) and CRT (- 41.9 ± 61.2 µm) at Month 12, respectively. In the subgroup with ≥ 50 µm CRT reduction after three monthly initial injections, there are significantly higher BCVA improvements vs. the < 50 µm CRT reduction subgroup at Month 3 (5.0 ± 8.6 letter gains vs. 1.5 ± 11.6 letter gains, respectively; intergroup P = 0.005). CONCLUSION: Lower baseline BCVA and higher baseline CRT were associated with BCVA gains and CRT reductions throughout the 12-month study period. Early CRT improvements after three monthly initial injections were associated with BCVA gains as early as Month 3.

Clinical benefits of inhaled ciclesonide for hospitalized patients with COVID-19 infection: a retrospective study.

BACKGROUND: The successful management of patients infected with coronavirus disease 2019 (COVID-19) with inhaled ciclesonide has been reported, however few studies have investigated its application among hospitalized patients. METHODS: This retrospective cohort study enrolled all adult patients admitted to our hospital with confirmed COVID-19 infection from May to June 2021. Critical patients who received mechanical ventilation within 24 h after admission and those who started ciclesonide more than 14 days after symptom onset were excluded. The in-hospital mortality rate was compared between those who did and did not receive inhaled ciclesonide. RESULTS: A total of 269 patients were enrolled, of whom 184 received inhaled ciclesonide and 85 did not. The use of ciclesonide was associated with lower in-hospital mortality (7.6% vs. 23.5%, p = 0.0003) and a trend of shorter hospital stay (12.0 (10.0-18.0) days vs. 13.0 (10.0-25.3) days, p = 0.0577). In subgroup analysis, the use of inhaled ciclesonide significantly reduced mortality in the patients with severe COVID-19 infection (6.8% vs. 50.0%, p < 0.0001) and in those with a high risk of mortality (16.4% vs. 43.2%, p = 0.0037). The use of inhaled ciclesonide also reduced the likelihood of receiving mechanical ventilation in the patients with severe COVID-19 infection. After multivariate analysis, inhaled ciclesonide remained positively correlated with a lower risk of in-hospital mortality (odds ratio: 0.2724, 95% confidence interval: 0.087-0.8763, p = 0.0291). CONCLUSIONS: The use of inhaled ciclesonide in hospitalized patients with COVID-19 infection can reduce in-hospital mortality. Further randomized studies in patients with moderate to severe COVID-19 infection are urgently needed.

Risk of intraoperative floppy iris syndrome among selective alpha-1 blockers-A consistency model of 6,488 cases.

Selective α1-blockers are commonly administered to patients with lower urinary tract syndrome and benign prostatic hyperplasia, but may increase the risk of intraoperative floppy iris syndrome (IFIS). The purpose of this study aimed to clarify the risk of IFIS among various selective α1-blockers. Four databases were searched for prospective studies comparing alpha-1-antagonists. Data were pooled using the consistency model, and used risk ratio (RR) and mean difference (MD) for IFIS and pupil diameter, respectively. This study finally included 25 prospective comparative studies. Based on 51 direct comparisons with 6488 cases, risks of IFIS in patients who received tamsulosin [RR, 13.85; 95% confidence interval (CI): 7.34 to 26.11], terazosin (RR, 8.94; 95% CI 2.88 to 27.74), alfuzosin (RR, 7.73; 95% CI: 3.05 to 19.62), and doxazosin (RR, 3.88; 95% CI: 1.13 to 13.28) were significantly higher than those did not receive α1-antagonists. Based on 11 direct comparisons with 564 cases, as compared to no α1-antagonists, patients who received tamsulosin (MD, -0.36; 95% CI: -0.71 to -0.01) and alfuzosin (MD, -0.34; 95% CI: -0.62 to -0.07) showed smaller pupil diameter under mesopic light levels, while those received silodosin did not show significantly smaller mesopic pupil diameter than people without α1-antagonists. IFIS seems to be inevitable with the usage of α1-antagonists, and tamsulosin needs to be cautious due to the significantly higher risk of severe IFIS. With regard to silodosin, there is no strong evidence to support the uses of italthough it does not significantly decrease mesopic pupil diameter.

Association between Ocular Parameters and Intraocular Pressure Elevation during Femtosecond Laser-Assisted Cataract Surgery in Open-Angle Glaucoma and Nonglaucoma Individuals.

In this study, we evaluate the association between biometrics and intraocular pressure (IOP) during femtosecond laser-assisted cataract surgery (FLACS) in normal patients and those with open-angle glaucoma (OAG). A retrospective cross-sectional study was conducted. A total of 103 patients who had received elective FLACS were enrolled, and those with OAG who received FLACS were further divided into a subgroup. The perioperative IOP of FLACS was measured before, during, and after the suction procedure. Demographic data and preoperative biometrics were collected from the medical records. The generalized linear model was applied to yield the adjusted odds ratio (aOR) and corresponding 95% confidence interval (CI) of each biometric for the IOP elevation in the whole group and the OAG subgroup. The mean preoperative IOP was 20.96 ± 4.79 mmHg, which rose to 55.37 ± 11.58 mmHg during suction, and decreased to 23.75 ± 6.42 mmHg after suction; the IOP both during and after suction was significantly higher than the presuction IOP (both p < 0.001). The mean IOP elevation was 34.41 ± 9.70 mmHg in the whole study population, and the difference in IOP elevation between OAG and nonglaucoma subgroups was not significant (p = 0.159). In the whole group, the presuction IOP, postdilated pupil size (PPS), and central corneal thickness (CCT) were positively corrected to higher IOP elevation (all p < 0.05), while axial length (AL) was negatively related to IOP elevation (aOR: 0.020, 95% CI: 0.008-0.699, p = 0.042). For the OAG subgroup, the longer AL was more significantly correlated to lower IOP elevation compared to those without glaucoma (aOR: 0.231, 95% CI: 0.106-0.502, p = 0.006). In conclusion, presuction IOP, PPS, and CCT are related to higher IOP during FLAC, while the AL is negatively correlated to the IOP elevation in FLACS, especially for patients with OAG. Reviewing these parameters before FLACS may enable physicians to find patients who are at risk of IOP elevation.

Association of interleukin-6 gene polymorphisms and glaucoma: Systematic review and meta-analysis.

AIM: To conduct a systematic review and meta-analysis to explore the association between IL-6 gene polymorphisms (rs1800795 and rs1524107) and glaucoma. METHODS: A comprehensive search was performed to select eligible studies regarding IL-6 polymorphisms and glaucoma. The effect sizes in the fixed-effects model were calculated using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Four eligible studies comprising 762 cases and 799 controls were selected for meta-analysis. Regarding the association between the IL-6 rs1800795 polymorphism and glaucoma, those who carried the G/G+G/C genotypes had a non-significant higher risk of glaucoma (OR = 1.29, 95% CI = 0.76-2.19) in the dominant model. However, no obvious association (OR = 0.97, 95% CI = 0.68-1.37) was found for the recessive model (G/G vs G/C+C/C). In the subgroup analysis stratified by ethnicity, no significant associations were observed in populations of Asian or European heritage. Significantly higher glaucoma risks of 15.9 and 99.0 were observed for the dominant (C/C+C/T vs T/T) and recessive (C/C vs C/T+T/T) models, respectively. CONCLUSION: No statistically significant glaucoma risks were observed for the rs1800795 except rs1524107 polymorphism of IL-6. Further studies with a larger sample size are required to validate the effects of IL-6 polymorphisms on glaucoma risk.

A 12-month, prospective, observational study of ranibizumab in treatment-naïve Taiwanese patients with neovascular age-related macular degeneration: the RACER study.

BACKGROUND: The current National Health Insurance scheme in Taiwan reimburses 3 initial plus 4 additional injections of ranibizumab 0.5 mg for eligible patients with neovascular age-related macular degeneration (nAMD). The Ranibizumab AMD Clinical Efficacy in Real-world practice (RACER) study aimed to observe the effectiveness of ranibizumab injections under this reimbursement system. METHODS: RACER was a 12-month, prospective, observational study conducted in treatment-naïve, adult Taiwanese patients with nAMD. Patients received intravitreal ranibizumab 0.5 mg injections in adherence with local prescribing information. RESULTS: Of 161 patients enrolled, 114 (70.8%) completed the 12-month study. Overall, patients received a mean (standard deviation [SD]) of 4.3 (1.7) ranibizumab injections. The mean (SD, [95% confidence interval], P value) gain in best-corrected visual acuity (BCVA) from baseline at Month 3 was 5.2 (12.2, [3.1, 7.3] letters, P < 0.0001) and at Month 12 was 3.4 (15.4, [0.2-6.6] letters, P = 0.0352). Mean central retinal thickness also decreased from baseline at Months 3 and 12 (both P < 0.001). In subgroup analyses, better treatment outcomes at Months 3 and 12 were observed among patients who received a loading dose and those who had a shorter duration of nAMD at baseline. Adverse events were reported in 58.4% of patients; most (94.4%) were mild-to-moderate in severity and 98.8% were deemed unrelated to study treatment. CONCLUSIONS: Treatment with ranibizumab 0.5 mg resulted in significant improvements in visual outcomes among treatment-naïve Taiwanese patients with nAMD. Early treatment and frequent dosing in the real-world setting may be the key to achieving better outcomes.

Chitosan-cartilage extracellular matrix hybrid scaffold induces chondrogenic differentiation to adipose-derived stem cells.

INTRODUCTION: Adipose-derived stem cells (ASCs) are potential cell sources for cartilage tissue engineering. Chitosan has been shown to enhance the stemness and differentiation capability of ASCs, and the native extracellular matrix (ECM) derived from articular cartilage has been also reported to induce chondrogenic differentiation of ASCs. Here we tested the hypothesis that a porous three-dimensional (3D) hybrid scaffold composed of chitosan and cartilage ECM can provide a better environment to induce ASC chondrogenesis. METHODS: Mixed solution composed of chitosan and cartilage ECM was frozen and lyophilized to form a composite construct. The porous 3D scaffolds were further crosslinked by genipin and used for ASC culture. RESULTS: Cultivation of ASCs in the chitosan/cartilage ECM composite 3D scaffolds induced the formation of cell spheroids with profound glycosaminoglycan production after 14 and 28 days culture. Chondrogenesis of ASCs seeded in the 3D scaffolds was also evident by mRNA expressions of cartilage-specific gene COL2A1 and ACAN on day 14. Histology and immunohistochemistry on day 28 also showed abundant cartilage-specific macromolecules, namely collagen type II and proteoglycan, deposited in a surface layer of the composite scaffold with tangential layer, transitional layer, and lacunae-like structures. Otherwise, hypertrophic markers collagen type I and X were concentrated in the area beneath the surface. CONCLUSION: Our findings demonstrated spatial chondrogenic differentiation of ASCs in the chitosan-cartilage ECM composite scaffolds. This 3D hybrid scaffold exhibits great potentials for ASC-based cartilage tissue engineering.

Design and Study of a Portable High-frequency Ventilator for Clinical Applications.

Treatment costs for ventilator-dependent patients are a substantial burden not only for their family but also for medical systems in general. Recently, using high-frequency ventilators have been shown to reduce the risk of lung injury through low-volume airflow. However, the machines used today remain bulky, costly, and only for use in hospital settings. To provide intermediate therapy for patients between hospitalization and complete discharge, a portable, light-weight high-frequency ventilator is an urgent need. This work presents the design of a portable high-frequency ventilator and a study of its practicality for further clinical medical applications. Through the integration of advanced electronics and mechanical instruments, we develop a portable high-frequency ventilator with reconfigurable oxygen flow rate, applied pressure, and air volume for the needs of individual patients. A miniaturized portable high-frequency ventilator with digital controller and feedback system for stabilization and precision control is implemented. The efficiency of CO2 washout using the proposed ventilator has been demonstrated in animal trials.

Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation.

INTRODUCTION: Anti-EGFR agents are standard treatments for patients with EGFR-mutant advanced NSCLC. The feasibility of combining erlotinib or gefitinib with the anti-programmed death 1 immunotherapy pembrolizumab was evaluated in the phase 1/2 KEYNOTE-021 study (NCT02039674). METHODS: Adults with previously untreated stage IIIB/IV EGFR-mutant NSCLC were treated with pembrolizumab 2 mg/kg intravenously every 3 weeks plus oral erlotinib 150 mg daily in cohort E or oral gefitinib 250 mg daily in cohort F, using a 3 + 3 design with cohort expansion. rTumor response was evaluated per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review. The primary objective was determination of a recommended phase 2 dose. RESULTS: Twelve patients enrolled to receive pembrolizumab plus erlotinib and seven to receive pembrolizumab plus gefitinib. No dose-limiting toxicities or grade 5 events occurred. Pembrolizumab plus erlotinib was feasible, with adverse events similar to those expected for monotherapy. However, pembrolizumab plus gefitinib was not feasible due to grade 3/4 liver toxicity in five of seven patients (71.4%), leading to permanent treatment discontinuation in four patients. The most frequently occurring treatment-related adverse events with pembrolizumab plus erlotinib were rash (50.0%), dermatitis acneiform, diarrhea, hypothyroidism, and pruritus (33.3% each). The objective response rate was 41.7%, including response in all four patients with programmed death ligand 1 expression 50% or greater. CONCLUSIONS: Although pembrolizumab plus gefitinib was not feasible, the toxicity profile observed with pembrolizumab plus erlotinib suggests combining immunotherapy with anti-EGFR therapy is feasible. Pembrolizumab plus erlotinib did not improve objective response rate compared with previous monotherapy studies; further evaluation would be necessary to evaluate potential effects on other efficacy outcomes.

Comparative efficacy and tolerability of beclomethasone/formoterol and fluticasone/salmeterol fixed combination in Taiwanese asthmatic patients.

BACKGROUND: The study was designed to compare the efficacy and tolerability of a fixed combination of extra-fine beclomethasone and formoterol, with the fixed combination fluticasone and salmeterol in Taiwanese asthmatic patients. METHODS: This was a phase III, multicentre, randomized, two-arm parallel groups, controlled study. Patients with moderate to severe asthma were randomized to a 12-week treatment with either beclomethasone 100 mcg plus formoterol 6 mcg (BDP/F) or fluticasone 125 mcg plus salmeterol 25 mcg (FP/S), both delivered 2 inhalations twice daily. The efficacy and tolerability of these two combinations were compared. RESULTS: Among the 253 randomized subjects, 244 patients were evaluable (119 in the BDP/F group and 125 in the FP/S group). A significant improvement from baseline to the end of treatment period was observed in both BDP/F and FP/S groups in forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), morning and evening peak expiratory flow (PEF), Asthma Control Test (ACT) score and the use of rescue medication. FVC increase from pre-dose was significant after 5 min post inhalation in the BDP/F group only, while statistically significant within group improvement was not achieved until 30 min post inhalation in the FP/S group. CONCLUSION: The BDP/F combination is comparable in efficacy and tolerability to FP/S combination in Taiwanese asthmatic patients, with the advantage of rapid onset of improvement of FVC, consistent with the faster improvement of pulmonary hyperinflation with BDP/F.

Potential effect of ezetimibe against Mycobacterium tuberculosis infection in type II diabetes.

BACKGROUND AND OBJECTIVE: Tuberculosis (TB) risk might be increased in patients with diabetes by factors other than hyperglycaemia, such as dyslipidaemia. Host lipids are essential energy sources used by mycobacteria to persist in a latent TB state. A potential therapy targeting cholesterol catabolism of mycobacteria has been proposed, but the potential of cholesterol-lowering drugs as anti-TB therapy is unclear. The purpose of this study was to determine the effects of ezetimibe, a 2-azetidinone cholesterol absorption inhibitor, on intracellular mycobacteria survival and dormancy. METHODS: Intracellular mycobacteria survival was determined by measurements of ATP activity and colony-formation units (CFUs). Gene expression profiles of hypoxia-induced dormant Mycobacterium tuberculosis (Mtb) were analysed by real-time PCR. Flow cytometry and microscopy analysis were used to measure the lipid loads of human macrophages with or without ezetimibe treatment. QuantiFERON-TB Gold In-Tube (QFT-G-IT) assays were performed to diagnose latent TB infection. The levels of intracellular cholesterol/ triglyceride were measured by an enzymatic fluorometric method. RESULTS: Ezetimibe was capable of effectively lowering intracellular growth of Mtb and hypoxia-induced dormant Mtb. There was a significant decrease in Mtb growth in leucocytes from ezetimibe-treated patients with diabetes in terms of ATP levels of intracellular mycobacteria and CFU formation. Also, patients receiving ezetimibe therapy had a lower prevalence of latent TB and had lower intracellular lipid contents. CONCLUSION: Ezetimibe, which is a currently marketed drug, could hold promise as an adjunctive, host-directed therapy for TB.

Alternative Roles of STAT3 and MAPK Signaling Pathways in the MMPs Activation and Progression of Lung Injury Induced by Cigarette Smoke Exposure in ACE2 Knockout Mice.

Inflammation-mediated abnormalities in the renin-angiotensin system (RAS) and expression of matrix metalloproteinases (MMPs) are implicated in the pathogenesis of lung injury. Angiotensin converting enzyme II (ACE2), an angiotensin converting enzyme (ACE) homologue that displays antagonist effects on ACE/angiotensin II (Ang II) axis, could also play a protective role against lung diseases. However, the relationship between ACE2 and MMPs activation in lung injury is still largely unclear. The purpose of this study is to investigate whether MMPs activity could be affected by ACE2 and which ACE2 derived signaling pathways could be also involved via using a mouse model with lung injury induced by cigarette smoke (CS) exposure for 1 to 3 weeks. Wild-type (WT; C57BL/6) and ACE2 KO mice (ACE2(-/-)) were utilized to study CS-induced lung injury. Increases in the resting respiratory rate (RRR), pulmonary immunokines, leukocyte infiltration and bronchial hyperplasia were observed in the CS-exposed mice. Compared to WT mice, more serious physiopathological changes were found in ACE2(-/-) mice in the first week of CS exposure. CS exposure increased pulmonary ACE and ACE2 activities in WT mice, and significantly increased ACE in ACE2(-/-) mice. Furthermore, the activity of pulmonary MMPs was decreased in CS-exposed WT mice, whereas this activity was increased in ACE2(-/-) mice. CS exposure increased the pulmonary p-p38, p-JNK and p-ERK1/2 level in all mice. In ACE2(-/-) mice, a significant increase p-STAT3 signaling was detected; however, no effect was observed on the p-STAT3 level in WT mice. Our results support the hypothesis that ACE2 deficiency influences MMPs activation and STAT3 phosphorylation signaling to promote more pulmonary inflammation in the development of lung injury.

Analysis of the immune response of human dendritic cells to Mycobacterium tuberculosis by quantitative proteomics.

BACKGROUND: The cellular immune response for Mycobacterium tuberculosis (M. tuberculosis) infection remained incompletely understood. To uncover membrane proteins involved in this infection mechanism, an integrated approach consisting of an organic solvent-assisted membrane protein digestion, stable-isotope dimethyl labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to comparatively profile the membrane protein expression of human dendritic cells upon heat-killed M. tuberculosis (HKTB) treatment. RESULTS: Organic solvent-assisted trypsin digestion coupled with stable-isotope labeling and LC-MS/MS analysis was applied to quantitatively analyze the membrane protein expression of THP-1 derived dendritic cells. We evaluated proteins that were upregulated in response to HKTB treatment, and applied STRING website database to analyze the correlations between these proteins. Of the investigated proteins, aminopeptidase N (CD13) was found to be largely expressed after HKTB treatment. By using confocal microscopy and flow cytometry, we found that membranous CD13 expression was upregulated and was capable of binding to live mycobacteria. Treatment dendritic cell with anti-CD13 antibody during M. tuberculosis infection enhanced the ability of T cell activation. CONCLUSIONS: Via proteomics data and STRING analysis, we demonstrated that the highly-expressed CD13 is also associated with proteins involved in the antigen presenting process, especially with CD1 proteins. Increasing expression of CD13 on dendritic cells while M. tuberculosis infection and enhancement of T cell activation after CD13 treated with anti-CD13 antibody indicates CD13 positively involved in the pathogenesis of M. tuberculosis.

Chemogenomic analysis of neuronal differentiation with pathway changes in PC12 cells.

The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database creates networks from interrelations between molecular biology and underlying chemical elements. This allows for analysis of biologic networks, genomic information, and higher-order functional information at a system level. Through high throughput experiments and system biology analysis, we investigated the genes and pathways associated with NGF induced neuronal differentiation. We performed microarray experiments and used the KEGG database, system biology analysis, and annotation of pathway functions to study NGF-induced differentiation in PC12 cells. We identified 2020 NGF-induced genes with altered expressions over time. Cross-matching with the KEGG database revealed 830 genes; among which, 395 altered genes were found to have a 2-fold increase in gene expression over a two-hour period. We then identified 191 associated biologic pathways in the KEGG database; the top 15 pathways showed correlation with neural differentiation. These included the neurotrophin pathways, mitogen-activated protein kinase (MAPK) pathways, genes associated with axonal guidance and the Wnt pathways. The activation of these pathways synchronized with nerve growth factor (NGF)-induced differentiation in PC12 cells. In summary, we have established a model system that allows one to systematically characterize the functional pathway changes in a group of neuronal population after an external stimulus.

A correlational study of suicidal ideation with psychological distress, depression, and demoralization in patients with cancer.

PURPOSE: This study aims to study the effects of depression and demoralization on suicidal ideation and to determine the feasibility of the Distress Thermometer as a screening tool for patients with cancer who experience depression and demoralization, and thus to establish a model screening process for suicide prevention. METHODS: Purposive sampling was used to invite inpatients and outpatients with lung cancer, leukemia, and lymphoma. Two hundred participants completed the questionnaire, which included the Distress Thermometer (DT), Patient Health Questionnaire-9 (PHQ-9), Demoralization Scale-Mandarin Version (DS-MV), and Beck Scale for Suicide Ideation. All data obtained were analyzed using SPSS 18.0 and SAS 9.3. RESULTS: Tobit regression analysis showed that demoralization influenced suicidal ideation more than depression did (t = 2.84, p < 0.01). When PHQ-9 ≥ 10 and DS-MV ≥42 were used as criteria for the DT, receiver operating characteristic analysis revealed that the AUC values were 0.77-0.79, with optimal cutoff points for both of DT ≥5; sensitivity 76.9 and 80.6 %, respectively; and specificity of 73.9 and 72.2 %, respectively. CONCLUSIONS: Demoralization had more influence on suicidal ideation than depression did. Therefore, attention should be paid to highly demoralized patients with cancer or high demoralization comorbid with depression for the purposes of suicide evaluation and prevention. The DT scale (with a cutoff of ≥5 points) has discriminative ability as a screening tool for demoralization or depression and can also be used in clinical settings for the preliminary screening of patients with cancer and high suicide risk.