Bimekizumab for the treatment of moderate-to-severe plaque psoriasis: efficacy, safety, pharmacokinetics, pharmacodynamics and transcriptomics from a phase IIa, randomized, double-blind multicentre study.

BACKGROUND: Bimekizumab is a monoclonal antibody that selectively inhibits both interleukin (IL)-17A and IL-17F, which is currently under investigation for treatment of moderate-to-severe plaque psoriasis. Maintenance dosing every 4 weeks is well established with IL-17 inhibitors for psoriasis. OBJECTIVES: To investigate the possible dosing interval during bimekizumab maintenance therapy to maintain clear skin, to inform phase III studies. METHODS: Forty-nine patients with moderate-to-severe plaque psoriasis received bimekizumab 320 mg at weeks 0/4, followed at week 16 by bimekizumab 320 mg (n = 17) or placebo (n = 32). Efficacy, safety, pharmacokinetics, immunogenicity and biopsy transcriptomic analyses were assessed to week 28. RESULTS: At week 8, 47% of patients achieved a 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100), increasing to 57% at week 12 (8 weeks after the second dose) before decreasing. In those who received bimekizumab at week 16, PASI 100 rate increased to comparable peak levels at week 20, but reduced by week 28 to 41% (12 weeks after the third dose). The week 8 transcriptional signature observed in lesional psoriatic skin rapidly normalized to levels consistent with nonlesional skin, resulting in molecular remission. Keratinocyte-related gene products such as CXCL1 (C-X-C motif chemokine ligand 1), IL-8 (encoded by the CXCL8 gene), CCL20 (C-C motif chemokine 20), IL-36γ and IL-17C were profoundly normalized to levels associated with nonlesional skin. CONCLUSIONS: Here, inhibition of IL-17F in addition to IL-17A resulted in rapid, deep clinical responses. Additionally, profound normalization of keratinocyte biology and the psoriatic transcriptome was observed, including normalization of both IL17 and IL23 gene expression by week 8. These data provide evidence to support evaluation of bimekizumab maintenance dosing both every 8 and every 4 weeks in phase III clinical trials.

Personalized nuclear imaging protocol in cases with nodular goiter and parathyroid adenoma.

A 62 years old woman was diagnosed with multinodular toxic goiter and primary hyperparathyroidism/left parathyroid adenoma by hormonal assessment, ultrasound and nuclear thyroid/parathyroid scans. Cervical ultrasound illustrated a multinodular aspect of the thyroid with solid nodules and cystic-component nodules; the larger one represented a multinodular complex with necrosis areas in the left thyroid lobe, ACR TI-RADS score 4 (moderately suspicious). Functional nuclear imaging was performed for accurate differential diagnosis between thyroid vs. parathyroid localization, between cold vs. hot nodules, and eventually, for guiding the choice of a subsequent Fine-Needle Aspiration Biopsy (FNAB). Scans described an early intense 99mTc-sestaMIBI uptake with no 99mTc-pertechnetate uptake in the left thyroid lobe larger nodule. Due to the suspicion of malignancy for this nodule, we performed an additional scan (1 hour before the classical 2 hours parathyroid delayed scan). The intense uptake persists in both delayed scans suggesting no malignant phenotype and which was confirmed after surgery by benign histology. In conclusion, using a 99mTc-sestaMIBI personalized protocol, related to the radiotracer cellular uptake mechanisms: 1 hour scan (supplementary image, corresponding to the maximum uptake pattern of 99mTc-sestaMIBI for cancer cells) and 2 hours scan (for parathyroid washout evaluation) may avoid unnecessary extensive thyroid surgery.

VITAMIN D DEFICIENCY, A NONINVASIVE MARKER OF STEATOHEPATITIS IN PATIENTS WITH OBESITY AND BIOPSY PROVEN NONALCOHOLIC FATTY LIVER DISEASE.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) includes simple steatosis, steatohepatitis (NASH) which can evolve with progressive fibrosis, cirrhosis and hepatocellular carcinoma. As liver biopsy cannot be used as a screening method, noninvasive markers are needed. OBJECTIVE: The aim of this study was to test if there is a significant association between vitamin D deficit and the severity of NAFLD. DESIGN: The patients were divided into two groups (vitamin D insufficiency/deficiency) and statistical analyses were performed on the correlation of clinical and biochemical characteristics with histopathological hepatic changes. SUBJECTS AND METHODS: We prospectively studied 64 obese patients referred for bariatric surgery between 2014 and 2016 to our Surgical Unit. Anthropometric, clinical measurements, general and specific biological balance were noted. NAFLD diagnosis and activity score (NAS) were evaluated on liver biopsies. RESULTS: Increased serum fibrinogen was correlated with NASH (p=0.005) and higher NAS grade. T2DM was positively correlated with liver fibrosis (p=0.002). 84.37% of the patients had vitamin D deficit and 15.62% were vitamin D insufficient. Lobular inflammation correlated with vitamin D deficit (p=0.040). Fibrosis (p=0.050) and steatohepatitis (p=0.032) were independent predictors of low vitamin D concentration. CONCLUSIONS: Vitamin D status in conjunction with other parameters - such as T2DM - or serum biomarkers - namely fibrinogen level and PCR level - may point out the aggressive forms of NAFLD and the need for liver biopsy for appropriate management.

99mTc MIBI THYMIC SCINTIGRAPHY IN DIAGNOSIS AND THERAPEUTIC DECISION MAKING: WHAT IS BEHIND THE IMAGE?

CONTEXT: Despite CT being generally used in thymic pathology, in the case of regions with the same tissue density, only functional radioisotopic imaging can hint towards malignity. OBJECTIVES: To assess the usefulness of 99mTc MIBI scintigraphy for diagnosis and treatment planning in thymoma, in relation with the radiotracer uptake mechanism. PATIENTS AND METHODS: 99mTc MIBI thymic scans for 19 patients diagnosed with thymic disorders were assessed using tumor uptake ratio (UR). Specimens of thymectomies were examined and cytological assessments were correlated with the UR. RESULTS: The UR of all surgical patients was higher than 1.2, with a 1.5 cutoff between lymphoid hyperplasia and thymoma. The UR values were correlated with the histopathologic diagnosis (Pearson correlation 0.91, significant at p<0.01). The highest UR was 3.24, found in the case of an AB thymoma where the rate lymphocytes/epithelial cells (L/E) was 1.6. In B1 thymoma UR was 1.14 and L/E was 2.46. CONCLUSION: Phenotype differences between thymoma types correlate with 99mTc MIBI cellular uptake: lower rate L/E corresponds to higher UR, higher malignity potential and invasiveness. A thymic 99mTc MIBI UR higher than 1.5, corresponding to a CT tumoral image, is suggestive for a thymoma, requiring surgical treatment first.

Functional inhibition of PAR2 alleviates allergen-induced airway hyperresponsiveness and inflammation.

BACKGROUND: Proteinase-activated receptor 2 (PAR2 ) is a G protein-coupled receptor activated by trypsin-like serine proteinases. PAR2 activation has been associated with inflammation including allergic airway inflammation. We have also shown that PAR2 activation in the airways leads to allergic sensitization. The exact contribution of PAR2 in the development of eosinophilic inflammation and airway hyperresponsiveness (AHR) in sensitized individuals is not clear. OBJECTIVE: To investigate whether functional inhibition of PAR2 during allergen challenge of allergic mice would inhibit allergen-induced AHR and inflammation in mouse models of asthma. METHODS: Mice were sensitized and challenged with ovalbumin (OVA) or cockroach extract (CE). To investigate the role of PAR2 in the development of AHR and airway inflammation, we administered blocking anti-PAR2 antibodies, or a cell permeable peptide inhibitor of PAR2 signalling, pepducin, i.n. before allergen challenges and then assessed AHR and airway inflammation. RESULTS: Administration of anti-PAR2 antibodies significantly inhibited OVA- and CE-induced AHR and airway inflammation. In particular, two anti-PAR2 antibodies, the monoclonal SAM-11 and polyclonal B5, inhibited AHR, airway eosinophilia, the increase of cytokines in the lung tissue and antigen-specific T cell proliferation, but had no effect on antigen-specific IgG and IgE levels. Pepducin was also effective in inhibiting AHR and airway inflammation in an OVA model of allergic airway inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: Functional blockade of PAR2 in the airways during allergen challenge improves allergen-induced AHR and inflammation in mice. Therefore, topical PAR2 blockade in the airways, through anti-PAR2 antibodies or molecules that interrupt PAR2 signalling, has the potential to be used as a therapeutic option in allergic asthma.

5 nm structures produced by direct laser writing.

Here we present a new approach to overcome the optical diffraction limit by using novel materials. In the paper, we report experimental results obtained by high-resolution transmission electron microscopy (HRTEM) and optical absorption spectroscopy, for a fluorescent photosensitive glass-ceramic containing rare-earth ions such as samarium (Sm). Using a home built dynamic tester, with a low power laser, we recorded nanostructures having 5 nm line widths. In the line structure, measurements reveal the presence of silver nanocrystals with few nanometre sizes. HRTEM shows that there is a random orientation of the nanocrystals. A writing mechanism with three steps is proposed.

Molecular analysis of the first avian influenza H5N1 isolates from fowl in Romania.

Since the events of avian influenza (AI) caused by H5N1 subtype from Hong Kong (1997), the people worldwide have been confronted with new waves of epizootic influenza. In 2005 in Romania an unprecedent H5N1 epizootic occurred in domestic and wild birds. Therefore an immediate investigation by molecular approach of this highly pathogenic H5N1 strain was necessary. The virus isolation and the RNA extraction were performed in the Institute of Diagnosis and Animal Health while PCR and sequencing were carried out in Cantacuzino Institute. Herein we report the first evidence of H5N1 presence in Romanian fowls. The phylogenetic analysis of haemagglutinin and neuraminidase gene indicated a close relationship of Romanian strains to those from Siberia and China. The virological and molecular analysis of the first strains of avian virus from Romania confirmed the presence of H5N1 subtype, belonging to the genetic line Z. These results indicate that the avian virus from this genetic line is directly derived from the highly pathogenic viruses isolated in China and Russia in 2005.

No relationship between insulin antibodies and transient remission in type 1 diabetic patients.

It has been speculated that the insulin antibodies may contribute to the prevention of the onset of the transient remission in insulin-treated diabetic patients. To address this hypothesis, we analysed the titre of insulin antibodies (determined by RIA method, using polyethylenglycol separation technique and expressed as percentage of binding of insulin) in two groups of patients: group A: 46 type 1 diabetics, 25 males and 21 females aged 24 +/- 11.2 years, mean +/- SD, who did not manifest during the first period of the disease any clinical sign of remission; group B: 21 type I diabetics, 13 males and 8 females, aged 25.3 +/- 8.0 years, who manifested in the first year either a partial (18 cases) or a total (3 cases) transient remission. Thirty-eight of cases with disease onset before 1984 were treated with conventional insulins (27 of 46 cases in A group and 11 of 21 cases in B group); the remaining cases were treated with monocomponent (MC) insulins. The binding of the insulin was significantly higher in the patients treated with conventional insulins vs those treated with MC insulins, i.e., 18 +/- 7.1% vs 10.2 +/- 5.2% (p < 0.001). However, no difference was found in the binding of insulin in A group (14.5 +/- 1.3%) compared with B group (13.7 +/- 11.1%). Moreover, in 3 cases from B group the onset of the remission was coincident with the increase of insulin antibodies.

Insulin resistance: the link between impaired glucose tolerance, body mass index and plasma lipids.

Body mass index defined as weight (Kg)/height (cm2) and plasma lipids (total lipids-TL, triglycerides-TG and cholesterol-CH) were determined in 131 patients (61 males and 70 females aged between 21 and 63 years) with impaired glucose tolerance (IGT) defined according to WHO criteria. Blood glucose (BG) values and plasma insulin (PI) levels (radioimmunological assay) were determined during 2 hours OGTT with samples obtained before and after 1 h and 2 h after the intake of 75 g glucose. The sum of blood glucose and plasma insulin levels (0 + 1h + 2h) were compared in each of the following 5 groups of subjects: A--25 cases with IGT but without obesity (BMI: 23.2 +/- 2.6) and hyperlipidaemia (PL: 627 +/- 112; TG: 102 +/- 109 and CH: 208 +/- 35 mg/dl); B--35 cases with IGT and obesity (BMI: 31.2 +/- 2.6) but without hyperlipidaemia (PL: 807 +/- 109; TG: 136 +/- 31 and CH: 254 +/- 41 mg/dl); C--23 cases with IGT and hyperlipidaemia (PL: 1013 +/- 217; TG: 214 +/- 85 and CH: 311 +/- 52 mg/dl) but without obesity (BMI: 25.4 +/- 1.9); D--48 cases with IGT and both obesity (BMI: 30.9 +/- 2.8) and hyperlipidaemia (PL: 1457 +/- 155; TG: 597 +/- 188 and CH: 483 +/- 184 mg/dl); a control group of 49 cases without IGT, obesity (BMI: 26.2 +/- 1.9) or hyperlipidaemia (PL: 726 +/- 99 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Type I and type IV collagen promote adherence and spreading of human type II pneumocytes in vitro.

Human lung tissue was enzymatically digested with dispase and type II pneumocytes were subsequently separated on a discontinuous metrizamide gradient. In primary adherence assays with freshly isolated cells, mean adherence values of 21.7, 19.6, 13.4, 6.8 and 7.0% were obtained after 48 hours on type I collagen (CI), type IV collagen (CIV), fibronectin (FN), laminin (LM) and tissue culture plastic, respectively. Secondly, readherence and spreading assays were performed with type II pneumocytes, previously cultured on CI, FN, matrix of murine EHS cells, and culture plastic. After a culture period of 48 to 72 hours, the cells were replated and tested on CI, CIV, FN, LM, CI + FN, CI + LM, CIV + FN and CIV + LM substrata in order to find out whether preculture substrata can modulate the adherence response of these cells. Readherence values, 1 hour after replating, were 3.3- to 8.6-fold higher than primary adherence values after 48 hours. The highest readherence values were always obtained on collagen-containing substrata after preculture on fibronectin. Spreading values after replating ranged between 35.4 and 6.6% on collagen-containing substrata, the highest values were again obtained after preculture on FN. Less than 6.9% and 0.5% of the cells spread on pure FN and pure LM, respectively. The data of the present investigation indicate that human type II pneumocytes adhere and spread preferentially on collagenous substrata rather than on other components of the extracellular matrix. This might be important in helping us to understand the functional in vivo activity of these cells, especially as regards re-epithelialization of the injured pulmonary alveolus.