Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS).

BACKGROUND: Guselkumab, a fully human interleukin-23 antibody, is approved for systemic treatment of patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To compare the efficacy and safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment. METHODS: Eligible patients were randomized to this multicentre, randomized, open-label, assessor-blinded, active-comparator-controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines. RESULTS: Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with ≥ 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0·001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0·001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0·001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0·001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab. CONCLUSIONS: Guselkumab demonstrated superiority over FAE in systemic-treatment-naive patients with moderate-to-severe plaque psoriasis through 24 weeks.

Feedback regulation of glucose transporter gene transcription in Kluyveromyces lactis by glucose uptake.

In the respirofermentative yeast Kluyveromyces lactis, only a single genetic locus encodes glucose transporters that can support fermentative growth. This locus is polymorphic in wild-type isolates carrying either KHT1 and KHT2, two tandemly arranged HXT-like genes, or RAG1, a low-affinity transporter gene that arose by recombination between KHT1 and KHT2. Here we show that KHT1 is a glucose-induced gene encoding a low-affinity transporter very similar to Rag1p. Kht2p has a lower K(m) (3.7 mM) and a more complex regulation. Transcription is high in the absence of glucose, further induced by low glucose concentrations, and repressed at higher glucose concentrations. The response of KHT1 and KHT2 gene regulation to high but not to low concentrations of glucose depends on glucose transport. The function of either Kht1p or Kht2p is sufficient to mediate the characteristic response to high glucose, which is impaired in a kht1 kht2 deletion mutant. Thus, the KHT genes are subject to mutual feedback regulation. Moreover, glucose repression of the endogenous beta-galactosidase (LAC4) promoter and glucose induction of pyruvate decarboxylase were abolished in the kht1 kht2 mutant. These phenotypes could be partially restored by HXT gene family members from Saccharomyces cerevisiae. The results indicate that the specific responses to high but not to low glucose concentrations require a high rate of glucose uptake.

Concurrent knock-out of at least 20 transporter genes is required to block uptake of hexoses in Saccharomyces cerevisiae.

The hexose transporter family of Saccharomyces cerevisiae comprises 18 proteins (Hxt1-17, Gal2). Here, we demonstrate that all these proteins, except Hxt12, and additionally three members of the maltose transporter family (Agt1, Ydl247, Yjr160) are able to transport hexoses. In a yeast strain deleted for HXT1-17, GAL2, AGT1, YDL247w and YJR160c, glucose consumption and transport activity were completely abolished. However, as additional deletion of the glucose sensor gene SNF3 partially restored growth on hexoses, our data indicate the existence of even more proteins able to transport hexoses in yeast.

[Automated quantitative image cytometry of bronchial washings in suspected lung cancer: comparison with cytology, histology and clinical diagnosis]. / Automatisierte quantitative Image-Zytometrie bronchialer Spülflüssigkeiten bei Verdacht auf broncho-pulmonale Tumoren: Vergleich mit Zytologie, Histologie und Klinischer Diagnose.

INTRODUCTION: Automated image cytometry represents a new method for the quantitative analysis of nuclear structure and DNA-content of exfoliative airway epithelial cells. In the present investigation, we examined the correlation between automated cytometry, conventional cytology and histopathology with the final diagnosis as the "gold standard". METHODS: In 142 patients (100 males and 42 females) with suspected lung cancer and 50 controls (COPD, asthma), bronchial washings (5-10 ml) were obtained during bronchoscopy before taking biopsies for cytological and/or histological examinations. The washings were collected in 20 ml Saccomanno's fixative and centrifuged (500 g, 15 min). The cell pellet was resuspended in Saccomanno's solution. Two specimens were stained according to Papanicolaou and another two using the Feulgen reaction with thionine. Image cytometry was performed by means of a special, trainable classifier for exfoliative cells of the respiratory tract, using the Cyto-Sacant (Oncometrics, Vancouver). RESULTS: In the patients with suspected lung cancer we found numerous abnormal nuclei in 97 samples, 36 samples contained normal cells only, and 9 samples were insufficient. In our control group there was no sample with abnormal nuclei, and all washings were evaluable. Compared to the final diagnosis of lung cancer, we found a sensitivity of 90% (92/102) and a specificity of 84% (26/31). For histology sensitivity was 91% (73/80) and specificity 100%, while we found a sensitivity of 92% (92/100) and specificity of 100% for cytology. For automated cytometry the positive predicted value was 95%, the negative predicted value 71%. CONCLUSIONS: In the investigation of patients with suspected lung cancer, automated image cytometry of bronchial washings is a sensitive and reliable method for the detection of malignant changes in the tracheobronchial mucosa. The automated procedure seems well suited not only for analysing bronchial washings, but also for a screening procedure.

Catabolite inactivation of the high-affinity hexose transporters Hxt6 and Hxt7 of Saccharomyces cerevisiae occurs in the vacuole after internalization by endocytosis.

After addition of high concentrations of glucose, rates of high-affinity glucose uptake in Saccharomyces cerevisiae decrease rapidly. We found that the high-affinity hexose transporters Hxt6 and Hxt7 are subject to glucose-induced proteolytic degradation (catabolite inactivation). Degradation occurs in the vacuole, as Hxt6/7 were stabilized in proteinase A-deficient mutant cells. Degradation was independent of the proteasome. The half-life of Hxt6 and Hxt7 strongly increased in end4, ren1 and act1 mutant strains, indicating that the proteins are delivered to the vacuole by endocytosis. Moreover, both proteins were also stabilized in mutants defective in ubiquitination. However, the initial signal that triggers catabolite inactivation is not relayed via the glucose sensors Snf3 and Rgt2.

[Respiratory and cardiovascular effects of acetylcholine provocation after inhalation exposure to various occupational pollutants--studies in the rabbit]. / Respiratorische und kardiovaskuläre Auswirkungen der Azetylcholinprovokation nach inhalativer Belastung mit verschiedenen Arbeitsstoffen--Untersuchungen am Kaninchen.

Airway hyperresponsiveness, manifested by increased flow resistance and resulting drop in oxygen partial pressure when conducting provocation tests, is considered an early sign of a developing obstructive airway disease, an example of which is a professionally conditioned asthma. We conducted a detailed study exploring the interrelation between the respiratory mechanical parameters and the partial pressures of oxygen and carbon dioxide (PaO2, PaCO2). Reproducibility tests for the studied cardiovascular, ventilatory and respiratory mechanical parameters at rest and under various conditions of stress (external stenoses, inhalation of hypercapnic and hypoxic gas mixtures, infusion of an acetylcholine solution) showed good reproducibility of the measured data with variation coefficients < 10%. In blood gas analyses we also found comparable variation coefficients. Four groups of experimental animals were exposed for different periods of time to various working place substances (coolants, ammonium peroxodisulfate, hair bleaches [blondizing agents], isocyanates). After the exposure we checked on the bronchial sensitivity to aerosols of 0.2% and 2% acetylcholine solutions. Concomitant with an increased response of dynamic elastance, we found an increased drop in oxygen partial pressure and an almost constant carbon dioxide partial pressure, dependent on the working place substance used and on its concentration. In untreated controls the inhalation of acetylcholine resulted in bronchoconstriction and drop in oxygen partial pressure only on provocation with 2% acetylcholine. However, in the groups exposed to coolants and ammonium peroxodisulfate there was a significant drop in oxygen partial pressure already on provocation with 0.2% acetylcholine, as well as a noticeable bronchial respiratory response. The drop in oxygen partial pressure increases further after provocation with 2% acetylcholine, whereas the oxygen partial pressure dropped to a maximum of one-third of its original level by more than 10%. Placing the drop in oxygen partial pressure provoked by acetylcholine in relation to the increase in dynamic elastance, this can be well expressed by a logarithmic formula (y = -6.2. In (x) + 0.72, r = 0.96) that does not change significantly after exposure to working place substances (y = -7.0. In (x) + 3.33, r = 0.93). The close correlation of both parameters suggests that study of the oxygen partial pressures to determine the airway hyperresponsiveness should be considered important, since a marked drop in oxygen partial pressure is seen even if obstructive respiratory response is only slightly increased (slight increase in dynamic elastance). The reason for the behaviour of the blood gases is probably an increased ventilation-perfusion imbalance due to inhomogenous peripheral bronchial reactions. In the hyperresponsive animals the reactions were merely enhanced without demonstrating any differences.