Summary
X‑linked hypophosphatemia (XLH) is a phosphate wasting disorder. Typical serum constellations include low serum phosphate as well as high alkaline phosphatase (ALP) and fibroblast growth ...factor 23 (FGF-23 ) levels. Adult XLH patients usually suffer from (pseudo)fractures, enthesopathies, impaired mobility, and osteoarthritis. We report the case of a middle-aged woman with clinically mild disease, relatively balanced laboratory values, but bone non-healing of the femur post-surgery. Transiliac bone biopsy revealed pronounced osteomalacia and severe deterioration of bone microstructure. Due to the lack of XLH-typical symptoms, the patient was not substituted with calcitriol and phosphate in adulthood. Thus, laboratory findings and radiological examinations do not necessarily reflect bone metabolism in XLH. Bone biopsies should be considered in unclear cases or prior to surgery in adults with XLH.
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•Orphan drug approval strategies require specific ways to generate clinical evidence.•Real-world data today may well support regulatory submissions of novel cancer drugs.•Learn how ...individual patient data was used for hematological cancer drug approvals.•Consider carefully the multiple methodological concerns and pitfalls when using RWD.
Tafasitamab (TAF) plus lenalidomide (LEN) is a novel treatment option for patients with relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) who are not eligible for autologous stem cell transplantation. The initial US/EU approvals for TAF represent precedents because this is the first time that approval of a novel combination therapy was granted based on a pivotal single-arm trial (SAT). Matching real-world data (RWD) helped to disentangle the contribution of individual agents. In this review, we present the TAF development strategy, the prospective incorporation of RWD within the clinical development plan, the corresponding regulatory hurdles of this strategy, and the prior regulatory actions for other cancer drugs that previously incorporated RWD and propensity score matching in EU and US regulatory submissions. We also outline how RWD could further advance and impact orphan drug development.
Ice-nucleating particles (INPs) can initiate ice formation in clouds at temperatures above −38 ∘C through heterogeneous ice nucleation. As a result, INPs affect cloud microphysical and radiative ...properties, cloud lifetime, and precipitation behavior and thereby ultimately the Earth's climate. Yet, little is known regarding the sources, abundance and properties of INPs, especially in remote regions such as the Arctic. In this study, 2-year-long INP measurements (from July 2018 to September 2020) at Villum Research Station in northern Greenland are presented. A low-volume filter sampler was deployed to collect filter samples for offline INP analysis. An annual cycle of INP concentration (NINP) was observed, and the fraction of heat-labile INPs was found to be higher in months with low to no snow cover and lower in months when the surface was well covered in snow (> 0.8 m). Samples were categorized into three different types based only on the slope of their INP spectra, namely into summer, winter and mix type. For each of the types a temperature-dependent INP parameterization was derived, clearly different depending on the time of the year. Winter and summer types occurred only during their respective seasons and were seen 60 % of the time. The mixed type occurred in the remaining 40 % of the time throughout the year. April, May and November were found to be transition months. A case study comparing April 2019 and April 2020 was performed. The month of April was selected because a significant difference in NINP was observed during these two periods, with clearly higher NINP in April 2020. In parallel to the observed differences in NINP, also a higher cloud-ice fraction was observed in satellite data for April 2020, compared to April 2019. NINP in the case study period revealed no clear dependency on either meteorological parameters or different surface types which were passed by the collected air masses. Overall, the results suggest that the coastal regions of Greenland were the main sources of INPs in April 2019 and 2020, most likely including both local terrestrial and marine sources.
Immune checkpoint inhibitors (ICI) have demonstrated meaningful patterns of clinical efficacy across various cancers. During their development, novel regulatory strategies and clinical design ...approaches were explored. This metrics‐based narrative review examines submission strategies and clinical evidence expectations of the US, European, and Japanese drug agencies, as well as their impact on approval and overall development times. Also discussed is the role of emerging clinical science and biomarker evaluation to get the first six ICI initially approved.
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as ...therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.
In a warming Arctic the increased occurrence of new
particle formation (NPF) is believed to originate from the declining ice
coverage during summertime. Understanding the physico-chemical properties ...of
newly formed particles, as well as mechanisms that control both particle
formation and growth in this pristine environment, is important for
interpreting aerosol–cloud interactions, to which the Arctic climate can be
highly sensitive. In this investigation, we present the analysis of NPF and
growth in the high summer Arctic. The measurements were made on-board
research vessel Polarstern during the PS106 Arctic expedition. Four
distinctive NPF and subsequent particle growth events were observed, during
which particle (diameter in a range 10–50 nm) number concentrations
increased from background values of approx. 40 up to 4000 cm−3. Based
on particle formation and growth rates, as well as hygroscopicity of
nucleation and the Aitken mode particles, we distinguished two different
types of NPF events. First, some NPF events were favored by negative ions,
resulting in more-hygroscopic nucleation mode particles and suggesting
sulfuric acid as a precursor gas. Second, other NPF events resulted in
less-hygroscopic particles, indicating the influence of organic vapors on
particle formation and growth. To test the climatic relevance of NPF and its
influence on the cloud condensation nuclei (CCN) budget in the Arctic, we
applied a zero-dimensional, adiabatic cloud parcel model. At an updraft
velocity of 0.1 m s−1, the particle number size distribution (PNSD)
generated during nucleation processes resulted in an increase in the CCN
number concentration by a factor of 2 to 5 compared to the background CCN
concentrations. This result was confirmed by the directly measured CCN
number concentrations. Although particles did not grow beyond 50 nm in
diameter and the activated fraction of 15–50 nm particles was on average
below 10 %, it could be shown that the sheer number of particles produced
by the nucleation process is enough to significantly influence the
background CCN number concentration. This implies that NPF can be an important
source of CCN in the Arctic. However, more studies should be conducted in
the future to understand mechanisms of NPF, sources of precursor gases and
condensable vapors, as well as the role of the aged nucleation mode
particles in Arctic cloud formation.
Mechanisms behind the phenomenon of Arctic amplification are widely discussed. To contribute to this debate, the (AC)(3) project was established in 2016 (www.ac3-tr.de/). It comprises modeling and ...data analysis efforts as well as observational elements. The project has assembled a wealth of ground-based, airborne, shipborne, and satellite data of physical, chemical, and meteorological properties of the Arctic atmosphere, cryosphere, and upper ocean that are available for the Arctic climate research community. Short-term changes and indications of long-term trends in Arctic climate parameters have been detected using existing and new data. For example, a distinct atmospheric moistening, an increase of regional storm activities, an amplified winter warming in the Svalbard and North Pole regions, and a decrease of sea ice thickness in the Fram Strait and of snow depth on sea ice have been identified. A positive trend of tropospheric bromine monoxide (BrO) column densities during polar spring was verified. Local marine/biogenic sources for cloud condensation nuclei and ice nucleating particles were found. Atmospheric-ocean and radiative transfer models were advanced by applying new parameterizations of surface albedo, cloud droplet activation, convective plumes and related processes over leads, and turbulent transfer coefficients for stable surface layers. Four modes of the surface radiative energy budget were explored and reproduced by simulations. To advance the future synthesis of the results, cross-cutting activities are being developed aiming to answer key questions in four focus areas: lapse rate feedback, surface processes, Arctic mixed-phase clouds, and airmass transport and transformation.
Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps ...of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure–activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).
Autophagy is a highly conserved cellular process that allows degradation of large macromolecules. p62/SQSTM1 is a key adaptor protein that interacts both with material to be degraded and with LC3 at ...the autophagosome, enabling degradation of cargos such as protein aggregates, lipid droplets and damaged organelles by selective autophagy. Dysregulation of autophagy contributes to the pathogenesis of many diseases. In this study, we investigated if the interaction of p62/SQSTM1 with LC3B could be regulated. We purified full‐length p62/SQSTM1 and established an in vitro assay that measures the interaction with LC3B. We used the assay to determine the role of the different domains of p62/SQSTM1 in the interaction with LC3B. We identified a mechanism of regulation of p62/SQSTM1 where the ZZ and the PB1 domains regulate the exposure of the LIR‐sequence to enable or inhibit the interaction with LC3B. A mutation to mimic the phosphorylation of a site on the ZZ domain leads to increased interaction with LC3B. Also, a small compound that binds to the ZZ domain enhances interaction with LC3B. Dysregulation of these mechanisms in p62/SQSTM1 could have implications for diseases where autophagy is affected. In conclusion, our study highlights the regulated nature of p62/SQSTM1 and its ability to modulate the interaction with LC3B through a LIR‐sequence Accessibility Mechanism (LAM). Furthermore, our findings suggest the potential for pharmacological modulation of the exposure of LIR, paving the way for future therapeutic strategies.
During the PAMARCMiP 2018 campaign (March and April 2018) a proton-transfer-reaction mass spectrometer (PTR-MS) was deployed onboard the POLAR 5 research aircraft and sampled the high Arctic ...atmosphere under Arctic haze conditions. More than 100 compounds exhibited levels above 1 pmol/mol in at least 25% of the measurements. We used acetone mixing ratios, ozone concentrations, and back trajectories to identify periods with and without long-range transport from continental sources. During two flights, surface ozone depletion events (ODE) were observed that coincided with enhanced levels of acetone, and methylethylketone, and ice nucleating particles (INP).
Air masses with continental influence contained elevated levels of compounds associated with aged biogenic emissions and anthropogenic pollution (e.g., methanol, peroxyacetylnitrate (PAN), acetone, acetic acid, methylethylketone (MEK), proprionic acid, and pentanone). Almost half of all positively detected compounds (>100) in the high Arctic atmosphere can be associated with terpene oxidation products, likely produced from monoterpenes and sesquiterpenes emitted from boreal forests. We speculate that the transport of biogenic terpene emissions may constitute an important control of the High Arctic aerosol burden. The sum concentration of the detected aerosol forming vapours is ∼12 pmol/mol, which is of the same order than measured dimethylsulfide (DMS) mixing ratios and their mass density corresponds to approximately one fifth of the measured non-black-carbon particles.
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•A PTR-MS instrument onboard the POLAR 5 aircraft detected more than 100 compounds above 1 pmol/mol in at least 25% of the measurements.•During ozone depletion events enhanced levels of acetone, and methylethylketone, and ice nucleating particles (INP) were observed.•Acetone and ozone mixing ratios were used as metric for continental influence.•Continentally influenced air exhibited enhanced signals of biogenic and anthropogenic emissions.•∼50% of all positively detected compounds (>100) can be associated with terpene oxidation products.
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