A brief instrument to measure health-related quality-of-life in patients with bone metastasis: validation of the German version of Bone Metastases Quality-of-Life-10 (BOMET-QoL-10)

<p><b>Aims:</b> This prospective, epidemiologic study was designed to translate the original Spanish Bone Metastases Quality-of-Life-10 (BOMET-QoL-10) questionnaire and undertake a validation of the translated German version of BOMET-QoL-10 in Germany to assess health-related quality-of-life (HRQoL) in patients with bone metastases (BM).</p> <p><b>Methods:</b> The translation process included forward and backward translations, and a linguistic validation. Patients aged ≥18 years with histological confirmation of cancer, diagnosed with BM, life expectancy ≥6 months, and fluency in German were eligible for this study (enrolled consecutively in 33 outpatient centers in Germany). Patients were given the German version of BOMET-QoL-10, together with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 and EORTC QLQ-BM22 questionnaires at inclusion, 6 weeks, 3 months, and 6 months after inclusion. A debriefing questionnaire was administered at inclusion to determine patient acceptability and understanding.</p> <p><b>Results:</b> Data include 364 patients with BM (median age = 68 years; females = 71.7%). The BOMET-QoL-10 is brief and clear (median completion time = 5 minutes; >90% of patients completed the questionnaire without assistance). The BOMET-QoL-10 forms only one overall scale. All 10 items showed a substantial correlation with the first factor (factor loading, range = 0.58–0.86). BOMET-QoL-10 exhibits high internal consistency and reproducibility (Cronbach’s alpha = 0.91; intra-class correlation coefficient = 0.76). BOMET-QoL-10 showed significant correlations (range = 0.69–0.79) both with EORTC QLQ-C30 and EORTC QLQ-BM22 within the functioning (physical, social, interference) and symptom (fatigue, pain) scales, displayed significant sensitivity to change in EORTC QLQ-BM22 scores, and proved the potential ability to detect change in HRQoL in patients with different disease status.</p> <p><b>Limitations:</b> There was a high proportion of females in this study, which might represent a limitation.</p> <p><b>Conclusions:</b> The German version of BOMET-QoL-10 is a valid, reliable, brief, and clear instrument able to measure HRQoL in patients with BM.</p

Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases

<div><p>The origin of the machinery that realizes protein biosynthesis in all organisms is still unclear. One key component of this machinery are aminoacyl tRNA synthetases (aaRS), which ligate tRNAs to amino acids while consuming ATP. Sequence analyses revealed that these enzymes can be divided into two complementary classes. Both classes differ significantly on a sequence and structural level, feature different reaction mechanisms, and occur in diverse oligomerization states. The one unifying aspect of both classes is their function of binding ATP. We identified Backbone Brackets and Arginine Tweezers as most compact ATP binding motifs characteristic for each Class. Geometric analysis shows a structural rearrangement of the Backbone Brackets upon ATP binding, indicating a general mechanism of all Class I structures. Regarding the origin of aaRS, the Rodin-Ohno hypothesis states that the peculiar nature of the two aaRS classes is the result of their primordial forms, called Protozymes, being encoded on opposite strands of the same gene. Backbone Brackets and Arginine Tweezers were traced back to the proposed Protozymes and their more efficient successors, the Urzymes. Both structural motifs can be observed as pairs of residues in contemporary structures and it seems that the time of their addition, indicated by their placement in the ancient aaRS, coincides with the evolutionary trace of Proto- and Urzymes.</p></div

Integrative sequence view for aaRS Class I (A) and Class II (B).

<p>Boxes delineate sequence motifs previously described in literature [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref046" target="_blank">46</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref057" target="_blank">57</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref058" target="_blank">58</a>]. The trace depicts the sequence conservation score of each position in the MSA (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.s017" target="_blank">S5</a> and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.s018" target="_blank">S6</a> Files). These scores were computed with Jalview [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref040" target="_blank">40</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref087" target="_blank">87</a>], positions composed of sets of amino acids with similar characteristics result in high values. Furthermore, all positions relevant for ligand binding (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.g005" target="_blank">Fig 5</a>) are depicted. Backbone Brackets and Arginine Tweezers have been emphasized by their respective pictograms. Positions of low conservation or those not encompassed by sequence motifs were intangible to studies primarily based on sequence data. Especially backbone interactions might be conserved independently from sequence. (<b>C</b>) Sequence representation of the Rodin-Ohno hypothesis [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref008" target="_blank">8</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref009" target="_blank">9</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref011" target="_blank">11</a>] with equivalents of the Backbone Brackets or Arginine Tweezers residues shown as green dots. The N-terminal residue of each, the Backbone Brackets and the Arginine Tweezers motif, is present in the Protozyme region (shaded red). Additionally, the C-terminal Backbone Brackets residue is located in the Urzyme region.</p

Geometric analysis of the ligand recognition motifs responsible for the adenosine phosphate interaction for aaRS Class I and Class II representative and nonredundant structures.

<p>The alpha carbon distance is plotted against the side chain angle <i>θ</i>. Binding modes refer to states containing an adenosine phosphate ligand (M1) or not (M2). Backbone Brackets in M1 allow for minor variance with respect to their alpha carbon distance, constrained by the position of the bound ligand. In contrast, Arginine Tweezers in M1 adapt an orthogonal orientation in order to fixate the ligand.</p

Comparison of Backbone Brackets and Arginine Tweezers.

<p>(<b>A</b>) Structural representation of the Backbone Brackets motif interacting with Tryptophanyl-5’AMP ligand in TrpRS (PDB:1r6u chain A). The ligand interaction is mediated by backbone hydrogen bonds (solid blue lines). Residue numbers are given in accordance to the structure of origin. (<b>B</b>) The geometry of the Backbone Brackets motif resembles brackets encircling the ligand. (<b>C</b>) WebLogo [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref075" target="_blank">75</a>] representation of the sequence of Backbone Brackets residues (274 and 1361) and three surrounding sequence positions. Residue numbers are given in accordance to the MSA. (<b>D</b>) Structural representation of the Arginine Tweezers motif in interaction with Lysyl-5’AMP ligand in LysRS (PDB:1e1t chain A). Salt bridges (yellow dashed lines) as well as <i>π</i>-cation interactions are established. Residue numbers are given in accordance to the structure of origin. (<b>E</b>) The Arginine Tweezers geometry mimics a pair of tweezers grasping the ligand. (<b>F</b>) Sequence of Arginine Tweezers residues (698 and 1786) and surrounding sequence positions. The Backbone Brackets show nearly no conservation on sequence level since backbone interactions can be established by all amino acids, while the Arginine Tweezers rely on salt bridge interactions, always mediated by two arginines. Residue numbers are given in accordance to the MSA.</p

The Rodin-Ohno hypothesis states that both aaRS classes descended from the opposite strands of a single gene.

<p>The signature motifs of each class were fully complementary on this gene. Both Protozymes originated from the complementary “HIGH-Motif 2” region (shaded in red). Contemporary aaRS feature insertion domains (ID) and Connecting Peptides (CP1) as well as the addition of the anticodon binding domain (ABD). Figure adapted from [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref009" target="_blank">9</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref067" target="_blank">67</a>].</p

Backbone Brackets and Arginine Tweezers.

<p>Based on the analysis of 972 protein 3D structures (448 protein chains for Class I and 524 chains for Class II), Backbone Brackets and Arginine Tweezers were identified as structural motifs distinctive for their respective aaRS Class.</p

“HIGH-Motif 2” codon assignment and base pairing.

<p>First and last row are consensus residues according to the structure-based MSA, “+” indicates gaps. Signature regions according to [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref008" target="_blank">8</a>] are emphasized. Sequence numbers are given according to the MSA. Middle rows indicate consensus codons; unassigned positions are indicated by dots, matches by vertical lines, and mismatches by “x”. Arginine Tweezers and Backbone Brackets residues are framed by boxes.</p

Protein-ligand contacts in representative adenosine phosphate-binding complexes for aaRS Class I and Class II.

<p>Residues are grouped according to the non-amino acid ligand fragment (phosphate, ribose, or adenine) that they are interacting with. Preferred interaction types for each aaRS Type and binding site residue are color-coded. Fields split into two triangles indicate two equally preferred interactions. The asterisk (*) indicates aaRS Types incorporating noncanonical amino acids. Automatically retrieved [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref077" target="_blank">77</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref078" target="_blank">78</a>] mutation effects [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref079" target="_blank">79</a>–<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref085" target="_blank">85</a>] are shown as centered shapes. In essence, Class I interactions are mainly hydrogen bonds, while Class II adenosine phosphate-binding is realized by an array of different interaction types. All sequence numbers are given according to the MSA.</p

The two aaRS classes and amino acids they ligate to the cognate tRNA.

<p>Based on the physicochemical properties of the amino acids (colored according to [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref040" target="_blank">40</a>]) no distinction can be made between the two classes. However, statistically significant differences based on amino acid side chain size [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref026" target="_blank">26</a>] and binding site size [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref041" target="_blank">41</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref042" target="_blank">42</a>] are evident. Lysine is mostly processed by Class II aaRS, but in all archaic organisms a Class I aaRS is responsible for lysine [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006101#pcbi.1006101.ref043" target="_blank">43</a>]. Prior to tRNA ligation, the amino acid ligand is converted to its activated form: aminoacyl adenylate.</p