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Background: Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods: A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results: The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions: This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting.
Vom Boulevard bis zur seriösen Wochenzeitung, vom Lokalsender bis zu den öffentlich-rechtlichen – Mitte Juni ging eine Wissenschaftsnachricht aus der Goethe-Universität »viral«, die ein ernüchterndes Bild vom Distanzlernen in Pandemiezeiten zeichnete. Ein systematisches Review, das die Ergebnisse einzelner anderer Studien auswertete, hat ergeben, dass Kinder und Jugendliche im ersten Lockdown 2020 im Durchschnitt nicht nur weniger gelernt haben als im Präsenzunterricht, sondern dass ihre Leistungen teilweise auch zurückgegangen sind – »wie nach den Sommerferien«, beschrieb es Studienleiter Prof. Dr. Andreas Frey. Ein Interview mit dem Pädagogischen Psychologen über seine Untersuchungsergebnisse – und die Reaktionen darauf.
CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
Background: Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer.
Methods: Study design: “RACE IT” (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb.
Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11–15.
Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15.
Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up).
Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy.
Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy.
Planned sample size: 33 patients, interim analysis after 11 patients.
Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions: From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
Thermally stable and highly conductive SAMs on Ag substrate — the impact of the anchoring group
(2021)
Self-assembled monolayers (SAMs) on metal substrates are an important part of modern interfacial chemistry and nanotechnology. The robustness of SAMs strongly depends on their thermal stability, which, together with electric conductivity, crucial for their applications in molecular/organic electronics. In this context, using a multidisciplinary approach, the structure, stability, and conductivity properties of conjugated aromatic SAMs featuring the naphthalene backbone and S, Se, or COO group, mediating bonding to the Ag substrate are addressed. Whereas thermal stability of these SAMs exhibits a strong dependence on anchoring group, their conductivity is similar, which is rationalized by tentative model considering redistribution of charge density along the molecular framework. The thermal stability of model naphthalenethiol SAM, emphasized by desorption energy of ≈1.69 eV, is better than that of typical N-heterocyclic carbene (NHC) monolayers considered currently as the most stable SAMs on metal substrates. However, in contrast to NHC SAMs, which are highly insulating, the naphtalene-based SAM, with S, Se or COO anchoring groups, are highly conductive, even in comparison with analogous oligophenyl SAMs (by a factor of 10). A unique combination of the ultimate thermal stability and superior conductivity for the naphthalenethiol SAM on Ag makes it highly attractive for applications.
Optogenetic manipulation of neuronal activity through excitatory and inhibitory opsins has become an indispensable experimental strategy in neuroscience research. For many applications bidirectional control of neuronal activity allowing both excitation and inhibition of the same neurons in a single experiment is desired. This requires low spectral overlap between the excitatory and inhibitory opsin, matched photocurrent amplitudes and a fixed expression ratio. Moreover, independent activation of two distinct neuronal populations with different optogenetic actuators is still challenging due to blue-light sensitivity of all opsins. Here we report BiPOLES, an optogenetic tool for potent neuronal excitation and inhibition with light of two different wavelengths. BiPOLES enables sensitive, reliable dual-color neuronal spiking and silencing with single- or two-photon excitation, optical tuning of the membrane voltage, and independent optogenetic control of two neuronal populations using a second, blue-light sensitive opsin. The utility of BiPOLES is demonstrated in worms, flies, mice and ferrets.