Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis

Public Health Rep

13004220PMCnul

Distribution of trace gases with adverse effects on fuel cells

The introduction of fuel cell technology into the field of motor vehicle propulsionenables both a reduction in primary energy consumption and a reduction independence on the primary energy source mineral oil. A major advantage of thispropulsion technology is reduction of greenhouse gas emissions when renewableenergy is used for fuels as hydrogen [Robinius, 2019]. Moreover, fluctuations inelectricity energy supply from renewable sources can be dampened when electricityis efficiently converted and stored as hydrogen.For the competitive application of this technology of fuel cell technology in the field ofvehicle propulsion, however, considerable research is still required in some areas. Inaddition to the necessary cost and weight reduction, this also applies to the long-termstability and robustness of fuel cell stack itself.It is known that fuel cell stacks react to the admixture of harmful gases into the intakecathode air with performance losses, which primarily result from the poisoning of thecatalysts. The effect does not only depend on the total burden of pollutants but on theirpeak concentrations. With this regard there is a need for research into both the effectsof pollutants on fuel stacks and their distribution in the atmosphere.The work presented here was funded by BMWi in the period from December 2014 toNovember 2017 and describes the results of the subproject 03ET6036D, which wascarried out by Forschungszentrum Jülic

Crizotinib Efficacy in ALK-Positive Advanced Stage Non-Small Cell Lung Cancer Patients: A Real-World Experience from Turkey

WOS: 000454014501235

NIVOLUMAB FOR RELAPSED OR REFRACTORY HODGKIN LYMPHOMA: EXPERIENCE IN TURKEY

22nd Congress of the European-Hematology-Association -- JUN 22-25, 2017 -- Madrid, SPAINWOS: 000404127001176…European Hematol Asso

Brentuximab vedotin for relapsed or refractory Hodgkin lymphoma: experience in Turkey

PubMedID: 25231929Current treatment modalities can cure up to 70–80 % of patients with classical Hodgkin lymphoma. Approximately, 20–30 % of patients require further treatment options. Brentuximab vedotin has been approved for the treatment of relapsed and refractory Hodgkin lymphoma. In the present study, we report the experience with brentuximab vedotin as single agent in 58 patients with relapsed or refractory Hodgkin lymphoma. The objective response rate was 63.5 % with 13 complete responders (26.5 %) among 49 patients evaluated at the early phase of treatment (2–5 cycles). Upon treatment prolongation (?6 cycles), 37 patients achieved a final objective response rate of 32.4 % with 21.6 % of complete and 10.8 % of partial response. Overall survival at 12 months was 70.6 %, and progression-free survival at 12 months was 32.8 %. Median overall survival could not be reached and median progression-free survival was 7 months. While the median duration of response was 9 months in the whole cohort, it was 11.5 months in the complete responders. Complete response rates in patients treated with >3 chemotherapy regimens before brentuximab vedotin were significantly lower (p = 0.016). Fourteen patients were subsequently transplanted. In conclusion, brentuximab vedotin provided a bridge to transplantation in approximately one quarter of the patients. The declining response rates during the course of treatment suggest that transplantation should be implemented early during brentuximab vedotin treatment. © 2014, The Author(s)