ROS Function in Redox Signaling and Oxidative Stress

Purpose
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients and Methods
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).

Results
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.

Conclusion
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the first of a 2-part review focused on phenotypic heterogeneity of blood vessel endothelium. This review provides an historical perspective of our understanding of endothelial heterogeneity, discusses the scope of phenotypic diversity across the vascular tree, and addresses proximate and evolutionary mechanisms of endothelial cell heterogeneity. The overall goal is to underscore the importance of phenotypic heterogeneity as a core property of the endothelium.

Phenotypic Heterogeneity of the Endothelium: I. Structure, Function, and Mechanisms

Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the second of a 2-part review on the phenotypic heterogeneity of blood vessel endothelial cells. The first part discusses the scope, the underlying mechanisms, and the diagnostic and therapeutic implications of phenotypic heterogeneity. Here, these principles are applied to an understanding of organ-specific phenotypes in representative vascular beds including arteries and veins, heart, lung, liver, and kidney. The goal is to underscore the importance of site-specific properties of the endothelium in mediating homeostasis and focal vascular pathology, while at the same time emphasizing the value of approaching the endothelium as an integrated system.

/pdf/phenotypic-heterogeneity-of-the-endothelium-ii-4bmhmf3l34.pdf

Phenotypic Heterogeneity of the Endothelium II. Representative Vascular Beds

Neutrophils: molecules, functions and pathophysiological aspects.

L'invention concerne un appareil de sechage par atomisation Elle se rapporte a un appareil qui comprend une chambre principale (3) de sechage, un collecteur a cyclone (4), des condenseurs (5, 6), un ventilateur (7) et un organe de chauffage (8) Un echantillon dissous transmis par une pompe (P1 ) est introduit par une buse de pulverisation (10) dont la presence ou l'absence est detectee par un capteur qui permet la commande d'une soupape de reglage (S1 ) Lorsque la buse est absente, la soupape de reglage est ouverte afin que la chambre (3) soit en surpression et empeche l'entree d'oxygene de l'air Application aux appareils de sechage par atomisation destines a des laboratoires

Appareil de sechage pour atomisation d'un echantillon dissous dans un solvant organique.

We investigated the effects of various doses (0.2 to 2000 micrograms/kg) of endotoxin on physiological and hematological parameters in our guinea pig model. Bronchoalveolar lavage (BAL) and lung tissue sampling were performed 6 hours after endotoxin injection. Lung damage was assessed by measuring wet to dry lung weight ratio (W/D), lung tissue to plasma accumulation of 125I-albumin (AL: albumin leakage) and BAL fluid to plasma accumulation of 125I-albumin (BALL: bronchoalveolar lavage leakage). Changes in peripheral cell counts were estimated at times 0, 1, 2, 4 and 6 hours after endotoxin injection. Pulmonary cell accumulation was determined by counting the number of cells in BAL fluid and tissue samples fixed for light microscopic examination. Increased W/D and AL were observed only in the high dose endotoxin treatment groups (200 and 2000 micrograms/kg), while BALL increased even in the low dose endotoxin treatment groups (2 micrograms/kg). Decreases in peripheral neutrophil counts at one hour were observed in all endotoxin treated groups. Increase in BAL fluid neutrophils was seen in the 20, 200, and 2000 micrograms/kg groups, while neutrophil accumulation assessed by light microscope was observed in all endotoxin treated groups. We conclude that different amounts of endotoxin are required to affect different parameters of lung injury.

Effects of various doses of endotoxin on physiological and hematological parameters in conscious guinea pigs

A 48-year-old woman was admitted because of increased bloody sputum. Since she had had a history of repeated thrombotic episodes including venous thrombosis in the lower limbs (21 year old) and pulmonary emboli developing into pulmonary infarction (41 years old), the patient was treated with anti-coagulant therapy using Warfarin for 7 years. Warfarin was discontinued after admission and heparin was administered instead at a relatively low dose of 5,000 units daily, resulting in a considerable diminution of hemoptysis. Unfortunately however, it caused a relapse of active thrombosis associated not only with a significant increase of the product of fibrinolysis (FDP), LDH and GOT but with a concomitant decrease of the platelet count. Hematological examinations concerning coagulation and fibrinolysis remained within a normal range except for the serum concentration of antithrombin III (AT III) and its functional property with regard to the heparin cofactor, which were 8.8 mg/dl and 48%, respectively. Since the findings were consistent with congenital deficiency of AT III, some members of her family were also examined. The concentration of AT III and its activity in the patient's son and her daughter deteriorated in a similar manner, indicating that this was a definite case of congenital deficiency of AT III. The clinical manifestations of 87 cases with congenital AT III deficiency, belonging to 24 families reported in Japan were reviewed.

A case of congenital antithrombin II deficiency with pulmonary infarction

The 99mTc-DTPA aerosol inhalation method permits detection of pulmonary epithelial damage. We investigated one of several problems, airway deposition of inhaled aerosol, on the assessment of pulmonary epithelial permeability in healthy nonsmokers and patients with interstitial lung diseases. We used the rate constant of pulmonary 99mTc-DTPA clearance curve, k, as a parameter of the epithelial permeability. The alveolar-peripheral airway deposition of aerosol was estimated by the duplicated inhalation method, which we newly developed. The mean k in patients with interstitial lung diseases (2.52 +/- 0.72%/min, n = 8; p less than 0.01) was significantly greater than that in healthy nonsmokers (0.92 +/- 0.20%/min, n = 4). The alveolar-peripheral airway deposition was similar in both healthy nonsmokers and interstitial lung diseases (73.5 +/- 7.8% and 75.5 +/- 9.2%, respectively). The mean k corrected for alveolar-peripheral airway deposition (corrected k; kc) was higher in patients with interstitial lung diseases (4.08 +/- 1.63%/min; p less than 0.01) as compared with healthy nonsmokers (1.36 +/- 0.47%/min). The mean k was significantly greater than the mean kc in both groups (p less than 0.01, p less than 0.01). However, there was a significant correlation between the k and kc obtained among the subjects (r = 0.951; p less than 0.01). We, therefore, conclude that correction for alveolar-peripheral airway deposition was not necessary to distinguish the patients with interstitial lung diseases from the healthy nonsmokers using 99mTc-DTPA aerosol inhalation method although the correction was significant in the individual subjects.

[The effect of airway deposition on the assessment of lung injury by 99mTc-DTPA clearance--lung injury in interstitial lung diseases assessed by using the duplicated 99mTc-DTPA aerosol inhalation method].

Objective:At Kitasato Institute Hospital,Kitasato University(henceforth,the hospital),the first edition of an antimicrobial use guidebook(henceforth, the guidebook)was produced in 2000. This time,the Pharmaceutical Department’s members on the hospital’s Infection Control Committee(ICC)took the lead and revised the guidebook so that it better conforms to clinical conditions and assessed the guidebook they created. Methods:A Working Group (WG)consisting of two ICC Pharmaceutical Department members and two members of the Medical Products Information Office staff examined the items to be listed in the guidebook. These items were approved by the ICC and then assigned to physicians and pharmacists to be written up. A questionnaire survey was conducted on the physicians and pharmacists in the hospital as to their assessment of the content and the conditions of use of the guidebook created. Results:In the revised edition,“Antimicrobials PK/PD,”“TDM,”“Empiric Therapy for Infections in Each Department,”etc.have been added, the physicians wrote“Empiric Therapy for Infections in Each Department”and everything else was written by the WG. The return rate of the questionnaire was65.7%(N=99),and the guidebook utilization rate was75.4%. Frequently viewed items were“List of Antimicrobials Used In-Hospital,”“How to Administer Medication during Decreased Renal Function,”“Empiric Therapy for Infections in Each Department,”etc. by the internal medicine physicians,“List of Antimicrobials Used In-Hospital”and“How to Administer Medication during Decreased Renal Function,”etc.by the surgeons,and “Classification of Antimicrobials,”“List of Antimicrobials Used In-Hospital,”“When Renal Function is Decreased,”“TDM,”and“Empiric Therapy for Infections in Each Department,”etc.by the residents. Furthermore,there were no items deemed“not necessary for inclusion”for a clear reason. As to be expected in this guidebook,72.3%of all respondents mentioned it was“a source of information on basic antimicrobial use”and next,“a source of information for treating infections outside one’s area of specialty.” Conclusion:The items listed in the guidebook are thought to be appropriate, and its usage conditions are also good. As they are specialists on antimicrobials,the pharmacists playing a central role while cooperating with the physicians on the ICC led to the creation of a highly useful guidebook.

http://www.jstage.jst.go.jp/article/jjdi/13/1/13_1_2/_pdf

Yukio Suzuki

Papers

Appareil de sechage pour atomisation d'un echantillon dissous dans un solvant organique.

Effects of various doses of endotoxin on physiological and hematological parameters in conscious guinea pigs

A case of congenital antithrombin II deficiency with pulmonary infarction

[The effect of airway deposition on the assessment of lung injury by 99mTc-DTPA clearance--lung injury in interstitial lung diseases assessed by using the duplicated 99mTc-DTPA aerosol inhalation method].

Creation of a Guidebook for the Use of Antimicrobials In-Hospital and Its Assessment