[Study protocol of the monocentric prospective randomized placebo-controlled double-blind phase II study to explore the protective effects of the ginkgo biloba extract EGb 761® from temporary noise-induced hearing loss]. / Prüfplan für die monozentrische prospektive randomisierte placebokontrollierte doppelblinde Phase-II-Studie zur Exploration protektiver Effekte des Ginkgo-biloba-Spezialextrakts EGb 761® vor einer vorübergehenden Hörschädigung durch Lärm.

BACKGROUND: Hearing loss is frequently induced by occupational noise exposure and leads to rising hearing thresholds as well as reduced otoacoustic emissions (OAE), mostly caused by metabolic hair cell decompensation. OBJECTIVE: Primary endpoint is the increase in average pure tone thresholds after noise exposure, secondary endpoints are loss of distortion product and click-evoked OAE as well as reduction of their contralateral suppression. PARTICIPANTS AND METHODS: The present study design describes the verification of the anti-oxidant and neuroprotective properties of EGb 761® by evaluation of cochlear protection from noise impact as well as its safety and tolerance in 202 healthy male participants distributed equally to verum and placebo groups in a double-blind manner. Participants were assessed, medicated, exposed to noise, and then examined at timepoints up to 10 min and 4 weeks thereafter. CONCLUSION: This summary of the verification study protocol highlights the complexity of diligent and precise planning according to the European Medicines Agency criteria for controlled trials (EudraCT). Key points are the intervention rationale, definitions of in- and exclusion criteria, estimation of subject numbers, and examination method setting in terms of optimum endpoint description.

Lung organoids and other preclinical models of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease affecting over 100 000 people in Europe with an increasing incidence. Available treatments offer only slowing of disease progression and are poorly tolerated by patients leading to cessation of therapy. Lung transplant remains the only cure. Therefore, alternative treatments are urgently required. The pathology of IPF is complex and poorly understood and thus creates a major obstacle to the discovery of novel treatments. Additionally, preclinical assessment of new treatments currently relies upon animal models where disparities with human lung biology often hamper drug development. At a cellular level, IPF is characterized by persistent and abnormal deposition of extracellular matrix by fibroblasts and alveolar epithelial cell injury which is seen as a key event in initiation of disease progression. In-depth investigation of the role of alveolar epithelial cells in health and disease has been impeded due to difficulties in primary cell isolation and culture ex vivo. Novel strategies employing patient-derived induced pluripotent stem cells engineered to produce type 2 alveolar epithelial cells (iAEC2) cultured as three-dimensional organoids have the potential to overcome these hurdles and inform new effective precision treatments for IPF leading to improved survival and quality of life for patients worldwide.

Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson's disease.

Human retinal pigment epithelial (hRPE) cells are dopaminergic support cells in the neural retina. Stereotaxic intrastriatal implantation of hRPE cells attached to gelatin microcarriers (Spheramine) in rodent and non-human primate models of Parkinson's disease (PD) produces long term amelioration of motor and behavioral deficits, with histological and PET evidence of cell survival without immunosuppression. Long-term safety in cynomologous monkeys has also been demonstrated. Six H&Y stage III/IV PD patients were enrolled in a one-year, open-label, single center study to evaluate the safety and efficacy of Spheramine (approximately 325,000 cells) implanted in the most affected post-commissural putamen. All patients tolerated the implantation of Spheramine well and demonstrated improvement. At 6, 9, and 12 months post-operatively, the mean UPDRS-Motor score "off", the primary outcome measure, improved 33%, (n = 6), 42% (n = 6), and 48% (n = 3), respectively. No "off-state" dyskinesias have been observed. Based on these preliminary results, Spheramine appears to show promise in treating late stage PD patients.

PET imaging of implanted human retinal pigment epithelial cells in the MPTP-induced primate model of Parkinson's disease.

Human retinal pigment epithelial (hRPE) cells produce L-dopa, are easily harvested and expanded in culture, and, attached to microcarriers, can survive in the brain without immunosuppression. Studies in rats, primates, and parkinsonian patients have demonstrated that striatally implanted hRPE cells attached to gelatin microcarriers (RPE-GM) are able to improve parkinsonian symptoms and are well tolerated for extended periods. In moderately to severely impaired monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced parkinsonism receiving a unilateral RPE-GM implant in the putamen, there was a 39% improvement in clinical scores over the first 2 months post-implant. Positron emission tomography (PET) with [18F]fluoro-L-dopa (FDOPA) showed increased accumulation in the implanted putamen and a concomitant decrease in [11C]raclopride binding in the same area, suggesting increased dopamine release compared to the contralateral putamen. We report the first in vivo visualization of hRPE cells and their effects, implicating a dopaminergic mechanism of action.

Evaluation of the B-protein assay in cancer management.

Previous data have suggested that the B-protein assay might prove to be useful in the assessment of patients with cancer after various therapeutic modalities. The assay's effectiveness was evaluated by prospective study of 133 patients with cervical, uterine, or ovarian cancer. After therapy, B-protein levels remained elevated in 17 nonresponding patients who eventually died of the disease. In contrast, 88 patients experienced a significant reduction in B-protein levels measured 90 days after treatment. Among this group, 25 patients demonstrated elevated B-protein levels during the 2-year follow-up period and all were confirmed to have persistent or recurrent disease. These data indicate that monitoring serum B-protein levels can be beneficial in the posttherapeutic management of gynecologic malignancies.