Summary Introduction Bisphosphonates (BPs) have transformed our ability to treat certain malignancies, osteoporosis and hypercalcaemia. This class of drug is assumed to be well tolerated by most. ...There are some important caveats to this assumption, however, one of the significances being the risk of osteonecrosis of the jaw (ONJ). Material and methods This multi-centre retrospective study examined the role of different BPs on the development of ONJ, its clinical presentation and the efficacy of various treatment modalities, comparing these findings with the available literature. Results A total of 78 patients from 17 centres were identified with ONJ. A majority of patients identified with ONJ had used Pamidronate or Zoledronate (93.6%) intravenously. 94.9% of patients had received BP in the course of treatment for malignancies and a majority had also received prior chemotherapy or exogenous steroids. 82.1% of patients had received BP for more than 1 year. The mean time from the introduction of BP to the development of ONJ in 24 patients from our department was 31.8 months. Conclusions The most common intraoral manifestation was exposed necrotic jawbone. Tooth extractions and oral surgical intervention appear to place patients on BP therapy at risk of ONJ, especially after intravenous BP treatments. ONJ proved in this study to be remarkably refractory to treatment, with radical resection being the only curative approach. We recommend that all patients receive necessary dental treatment prior to commencing BP therapy.
Pseudouridine (Ψ) synthases catalyze the formation of one or more specific Ψs in structured RNAs. Five families of Ψ synthases have been characterized based on sequence homology. Pus10 has no ...significant sequence homology to these defined families and therefore represents a new family of Ψ synthases. Initial characterization studies show that an archael Pus10 catalyzes the universally conserved Ψ55 in tRNA. We present here the crystal structure of human Pus10 at 2.0 Å resolution, which is the first structural description from this novel Ψ synthase family. Pus10 is a crescent-shaped molecule with two domains, the universally conserved Ψ synthase catalytic domain and a THUMP-containing domain, which is unique to the Pus10 family. Superposition of the catalytic domains of Pus10 and other Ψ synthases identifies the full set of conserved Ψ synthase active site residues indicating that Pus10 likely employs a similar catalytic mechanism to other Ψ synthases. The Pus10 active site is located in a deep pocket of a basic cleft adjacent to flexible thumb and forefinger loops, which could provide further stabilization for binding the RNA substrate. Modeling studies demonstrate that the cleft between the catalytic and accessory domain is large enough and electrostatically compatible to accommodate an RNA stem and support the role of the N-terminal domain as an accessory RNA-binding domain.
Background
The detection of cutaneous metastases (CMs) from various primary tumours represents a diagnostic challenge.
Objectives
Our aim was to evaluate the general characteristics and dermatoscopic ...features of CMs from different primary tumours.
Methods
Retrospective, multicentre, descriptive, cross‐sectional study of biopsy‐proven CMs.
Results
We included 583 patients (247 females, median age: 64 years, 25%–75% percentiles: 54–74 years) with 632 CMs, of which 52.2% (n = 330) were local, and 26.7% (n = 169) were distant. The most common primary tumours were melanomas (n = 474) and breast cancer (n = 59). Most non‐melanoma CMs were non‐pigmented (n = 151, 95.6%). Of 169 distant metastases, 54 (32.0%) appeared on the head and neck region. On dermatoscopy, pigmented melanoma metastases were frequently structureless blue (63.6%, n = 201), while amelanotic metastases were typified by linear serpentine vessels and a white structureless pattern. No significant difference was found between amelanotic melanoma metastases and CMs of other primary tumours.
Conclusions
The head and neck area is a common site for distant CMs. Our study confirms that most pigmented melanoma metastasis are structureless blue on dermatoscopy and may mimic blue nevi. Amelanotic metastases are typified by linear serpentine vessels and a white structureless pattern, regardless of the primary tumour.
TRPV channels are important polymodal integrators of noxious stimuli mediating thermosensation and nociception. An ankyrin repeat domain (ARD), which is a common protein–protein recognition domain, ...is conserved in the N‐terminal intracellular domain of all TRPV channels and predicted to contain three to four ankyrin repeats. Here we report the first structure from the TRPV channel subfamily, a 1.7 Å resolution crystal structure of the human TRPV2 ARD. Our crystal structure reveals a six ankyrin repeat stack with multiple insertions in each repeat generating several unique features compared with a canonical ARD. The surface typically used for ligand recognition, the ankyrin groove, contains extended loops with an exposed hydrophobic patch and a prominent kink resulting from a large rotational shift of the last two repeats. The TRPV2 ARD provides the first structural insight into a domain that coordinates nociceptive sensory transduction and is likely to be a prototype for other TRPV channel ARDs.
•The association between polysubstance use and inhibition is as-yet-unknown.•This association was tested with a mega-analysis using individual participant data.•Only lifetime cannabis use was ...associated with suboptimal inhibition (stop-task).•Lifetime cannabis use moderated tobacco’s effect on response inhibition.•In cannabis non-users only, tobacco use was associated with suboptimal inhibition.
Many studies have reported that heavy substance use is associated with impaired response inhibition. Studies typically focused on associations with a single substance, while polysubstance use is common. Further, most studies compared heavy users with light/non-users, though substance use occurs along a continuum. The current mega-analysis accounted for these issues by aggregating individual data from 43 studies (3610 adult participants) that used the Go/No-Go (GNG) or Stop-signal task (SST) to assess inhibition among mostly “recreational” substance users (i.e., the rate of substance use disorders was low). Main and interaction effects of substance use, demographics, and task-characteristics were entered in a linear mixed model. Contrary to many studies and reviews in the field, we found that only lifetime cannabis use was associated with impaired response inhibition in the SST. An interaction effect was also observed: the relationship between tobacco use and response inhibition (in the SST) differed between cannabis users and non-users, with a negative association between tobacco use and inhibition in the cannabis non-users. In addition, participants’ age, education level, and some task characteristics influenced inhibition outcomes. Overall, we found limited support for impaired inhibition among substance users when controlling for demographics and task-characteristics.
Voltage-dependent, ion-selective channels such as Na+, Ca
2+ and K+ channel proteins function as tetrameric assemblies
of identical or similar subunits. The clustering of
four subunits is thought to ...create an aqueous pore,
centred at the four-fold symmetry axis. The highly conserved, amino-terminal
cytoplasmic domain (∼130 amino acids) immediately preceding the first
putative transmembrane helix S1 is designated T1. It is known to confer specificity
for tetramer formation,, so the heteromeric
assembly of K+-channel subunits is an important mechanism for
the observed channel diversity. We have determined
the crystal structure of the T1 domain of a Shaker potassium channel
at 1.55 Å resolution. The structure reveals that four identical subunits
are arranged in a four-fold symmetry surrounding a centrally located pore
about 20 Å in length. Subfamily-specific assembly is provided primarily
by polar interactions encoded in a conserved set of amino acids at its tetramerization
interface. Most highly conserved amino acids in the T1 domain of all known
potassium channels are found in the core of the protein, indicating a common
structural framework for the tetramer assembly.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and ...resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.
Abstract Introduction Bisphosphonates (BPs) are powerful drugs that inhibit bone metabolism. Adverse side effects are rare but potentially severe such as bisphosphonate-related osteonecrosis of the ...jaw (BRONJ). To date, research has primarily focused on the development and progression of BRONJ in cancer patients with bone metastasis, who have received high dosages of BPs intravenously. However, a potential dilemma may arise from a far larger cohort, namely the millions of osteoporosis patients on long-term oral BP therapy. Patients and methods This current study assessed 470 cases of BRONJ diagnosed between 2004 and 2008 at eleven different European clinical centres and has resulted in the identification of a considerable cohort of osteoporosis patients suffering from BRONJ. Each patient was clinically examined and a detailed medical history was raised. Results In total, 37/470 cases (7.8%) were associated with oral BP therapy due to osteoporosis. The majority (57%) of affected individuals did not have any risk factors for BRONJ as defined by the American Association of Oral and Maxillofacial Surgery. The average duration of BP intake of patients without risk factors was longer and the respective patients were older compared to patients with risk factors, but no statistical significant difference was found. In 78% of patients the duration of oral BP therapy exceeded 3 years prior to BRONJ diagnosis. Discussion The results from this study suggest that the relative frequency of osteoporosis patients on oral BPs suffering from BRONJ is higher than previously reported. There is an urgent need to substantiate epidemiological characteristics of BRONJ in large cohorts of individuals.
Structural genomics is emerging as a principal approach to define protein structure-function relationships. To apply this approach on a genomic scale, novel methods and technologies must be developed ...to determine large numbers of structures. We describe the design and implementation of a high-throughput structural genomics pipeline and its application to the proteome of the thermophilic bacterium Thermotoga maritima. By using this pipeline, we successfully cloned and attempted expression of 1,376 of the predicted 1,877 genes (73%) and have identified crystallization conditions for 432 proteins, comprising 23% of the T. maritima proteome. Representative structures from TM0423 glycerol dehydrogenase and TM0449 thymidylate synthase-complementing protein are presented as examples of final outputs from the pipeline.
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