Ein neutraler Rezeptor, der auch in wässrigen Lösungen Anionen über Wasserstoffbrücken bindet, ist das hier vorgestellte Cyclopeptid. Dies ist auf die besondere Komplexstruktur zurückzuführen, bei ...der die Anionen effektiv vom umgebenden Lösungsmittel abgeschirmt werden, wie an der gezeigten Struktur des Iodidkomplexes zu erkennen ist.
Osteosarcoma may arise as a secondary cancer following leukemias or lymphomas. We intended to increase the knowledge about such rare events.
We searched the Cooperative Osteosarcoma Study Group's ...database for individuals who developed their osteosarcoma following a previous hematological malignancy. The presentation and treatment of both malignancies was investigated, and additional neoplasms were noted. Outcomes after osteosarcoma were analyzed and potential prognostic factors were searched for.
A total of 33 eligible patients were identified (male: 23, female: 10; median age: 12.9 years at diagnosis of hematological cancer; 20 lymphomas, 13 leukemias). A cancer predisposition syndrome was evident in one patient only. The hematological cancers had been treated by radiotherapy in 28 (1 unknown) and chemotherapy in 26 cases, including bone-marrow transplantation in 9. The secondary bone sarcomas (high-grade central 27, periosteal 2, extra-osseous 2, undifferentiated pleomorphic sarcoma of bone 2) arose after a median lag-time of 9.4 years, when patients were a median of 19.1 years old. Tumors were considered radiation-related in 26 cases (1 unknown). Osteosarcoma-sites were in the extremities (19), trunk (12), or head and neck (2). Metastases at diagnosis affected eight patients. Information on osteosarcoma therapy was available for 31 cases. All of these received chemotherapy. Local therapy involved surgery in 27 patients, with a good response reported for 9/18 eligible patients. Local radiotherapy was given to three patients. The median follow-up was 3.9 (0.3-12.0) years after bone tumor diagnosis. During this period, 21 patients had developed events as defined, and 15 had died, resulting in 5-year event-free and overall survival rates of 40% (standard error: 9%) and 56% (10%), respectively. There were multiple instances of additional neoplasms. Several factors were found to be of prognostic value (
< 0.05) for event-free (osteosarcoma site in the extremities) or overall (achievement of a surgical osteosarcoma-remission, receiving chemotherapy for the hematologic malignancy) survival.
We were able to prove radiation therapy for hematological malignancies to be the predominant risk factor for later osteosarcomas. A resulting overrepresentation of axial and a tendency towards additional neoplasms affects prognosis. Still, selected patients may become long-term survivors with appropriate therapies, which is an argument against therapeutic negligence.
The pharmacology and regulation of Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel activity is intricate due to the physiological function as an integrator of multiple chemical, ...mechanical, and temperature stimuli as well as differences in species pharmacology. In this study, we describe and compare the current inhibition efficacy of human TRPA1 on three different TRPA1 antagonists. We used a homology model of TRPA1 based on Kv1.2 to select pore vestibule residues available for interaction with ligands entering the vestibule. Site-directed mutation constructs were expressed in Xenopus oocytes and their functionality and pharmacology assessed to support and improve our homology model. Based on the functional pharmacology results we propose an antagonist-binding site in the vestibule of the TRPA1 ion channel. We use the results to describe the proposed intravestibular ligand-binding site in TRPA1 in detail. Based on the single site substitutions, we designed a human TRPA1 receptor by substituting several residues in the vestibule and adjacent regions from the rat receptor to address and explain observed species pharmacology differences. In parallel, the lack of effect on HC-030031 inhibition by the vestibule substitutions suggests that this molecule interacts with TRPA1 via a binding site not situated in the vestibule.
Many publications address the epidemiology of secondary osteosarcomas following retinoblastoma. Treatment- and outcome-related information is, however, scarce. We used a large cooperative group’s ...database to study this issue.
The database Cooperative Osteosarcoma Study Group COSS was searched for patients with osteosarcoma following a previous retinoblastoma. Patients were then analyzed for demographic factors, local/systemic treatments received, and outcomes.
28 eligible patients were identified. Median age at retinoblastoma was .5 years, 89% occurred bilaterally. Retinoblastoma-therapy was by surgery in 26/27, radiotherapy in 26/27, chemotherapy in 10/26 (rest unknown). Osteosarcoma was diagnosed after 13.7 (3.1 – 36.1) years, extremities and head/neck affected in 14/28, each. Four/28 patients had primary metastases. Osteosarcoma treatment included chemotherapy in all cases, local therapy surgery in 27/28. Histological response was good in 9/16 evaluable cases. Surgery of all sites was macroscopically complete in 23/27 operated tumors and microscopically complete in 17/26 (1 unknown). Radiotherapy was administered to 3 craniofacial tumors. Median follow-up was 3.5 (.4 – 30.1) years from osteosarcoma diagnosis, 8/28 patients remaining event-free. Altogether, five patients suffered further secondary malignancies. Actuarial overall and event-free survival at 2 and 5 years from osteosarcoma were 73% (standard error: 8%) / 50% (10%) and 47% (10%) / 22% (9%), respectively.
This comparatively large cohort of osteosarcomas after retinoblastoma proves that the latter may be treated curatively. While their prognosis is far worse than that of primary osteosarcomas, partly due to a predilection for craniofacial involvement, selected patients may still become long-term survivors with appropriate therapies.
•28 patients, generally pediatric, developed osteosarcoma after retinoblastoma.•Half had extremity and half head & neck tumors, often in irradiated sites.•Despite pretreatments, standard osteosarcoma therapy seemed feasible.•Surgery was quite successful in extremity sites but challenging craniofacially.•A small select subgroup managed to become long-term osteosarcoma survivors.
The year 2020 saw the emergence of a worldwide pandemic caused by the novel coronavirus COVID-19. Measures against further spread of the virus were taken nearly everywhere in the world. Many ...countries also imposed social distancing rules and lockdowns on their population. This situation has caused a lot of fear and insecurity, along with reactance and even unrest in some countries. In this study, we measured the psychological concepts of resilience, reactance, positive schemas, social solidarity, and anxiety among psychiatric patients and in how far these factors influence their psychopathological anxiety during the pandemic. The aim was to better understand in what ways these factors influence pandemic anxiety to be able to reduce its negative psychological effects. Findings show a significant effect of positive schemas and social solidarity on the level of pandemic anxiety in a sample of psychiatric patients, but no correlation between resilience or reactance and pandemic anxiety. Based on these insights, the inclusion of positive schemas and social solidarity for therapy should be considered. Looking deeper into the relation between positive schemas and pandemic anxiety could provide insight into the different ways that schemas influence people’s anxiety and determine whether some of them are particularly important.
We examined whether the N-terminus of Kv4.2 A-type channels (4.2NT) possesses an autoinhibitory N-terminal peptide domain, which, similar to the one of
Shaker, mediates inactivation of the open ...state. We found that chimeric Kv2.1(4.2NT) channels, where the cytoplasmic Kv2.1 N-terminus had been replaced by corresponding Kv4.2 domains, inactivated relatively fast, with a mean time constant of 120
ms as compared to 3.4
s in Kv2.1 wild-type. Notably, Kv2.1(4.2NT) showed features typically observed for
Shaker N-type inactivation: fast inactivation of Kv2.1(4.2NT) channels was slowed by intracellular tetraethylammonium and removed by N-terminal truncation (Δ40). Kv2.1(4.2NT) channels reopened during recovery from inactivation, and recovery was accelerated in high external K
+. Moreover, the application of synthetic N-terminal Kv4.2 and
ShB peptides to inside-out patches containing slowly inactivating Kv2.1 channels mimicked N-type inactivation. Kv4.2 channels, after fractional inactivation, mediated tail currents with biphasic decay, indicative of passage through the open state during recovery from inactivation. Biphasic tail current kinetics were less prominent in Kv4.2/KChIP2.1 channel complexes and virtually absent in Kv4.2Δ40 channels. N-type inactivation features of Kv4.2 open-state inactivation, which may be suppressed by KChIP association, were also revealed by the finding that application of Kv4.2 N-terminal peptide accelerated the decay kinetics of both Kv4.2Δ40 and Kv4.2/KChIP2.1 patch currents. However, double mutant cycle analysis of N-terminal inactivating and pore domains indicated differences in the energetics and structural determinants between Kv4.2 and
Shaker N-type inactivation.
AZ465 is a novel selective transient receptor potential cation channel, member A1 (TRPA1) antagonist identified during a focused drug discovery effort. In vitro, AZ465 fully inhibits activation by ...zinc, O-chlorobenzylidene malononitrile (CS), or cinnamaldehyde of the human TRPA1 channel heterologously expressed in human embryonic kidney cells. Our data using patch-clamp recordings and mouse/human TRPA1 chimeras suggest that AZ465 binds reversibly in the pore region of the human TRPA1 channel. Finally, in an ex vivo model measuring TRPA1 agonist-stimulated release of neuropeptides from human dental pulp biopsies, AZD465 was able to block 50%-60% of CS-induced calcitonin gene-related peptide release, confirming that AZ465 inhibits the native human TRPA1 channel in neuronal tissue.
PDF
