Nitrotyrosination of p4Y in H-2D^b/NY-gp33 directly affects recognition by H-2D^b/gp33-specific TCR.

<p>Nitrotyrosination of the main TCR-interacting peptide residue p4Y will affect the structural conformation of both TCR interacting residues on H-2D^b and of the TCR P14. The peptide binding cleft of H-2D^b and the TCR, both colored in white, are annotated. Hydrogen bond interactions appear as dotted lines. <b>A.</b> In H-2D^b/gp33, the side chain of p4Y protrudes out of the H-2D^bpeptide-binding cleft, positioning itself perfectly in the hot spot of the p14 TCR composed of the CDR3 loops from both Vα and Vβ. It forms three hydrogen bonds, two of them directly with Y36(Vα) and G102(Vβ) on the TCR P14. The last hydrogen bond is formed with the side chain of the H-2D^b histidine residue H155, linking this domain of the heavy chain to the TCR. <b>B.</b> The side chain of the nitrotyrosinated p4-NY can not be accommodated within the hot-spot of P14, resulting in sterical clashes with the side chain of the TCR residue Y36(Vα). Furthermore, the negatively charged side chain of the H-2D^b residue E163, important for TCR recognition, would also be repelled by the introduced negatively charged nitrotyrosination. <b>C.</b> Similarly, the other rotamer of the nitrotyrosinated p4-NY would result in sterical clashes with both G102(Vβ)the side chain of H155, abolishing all formed hydrogen bond interactions.</p

Protrusion of p1K in H-2K^b/gp33 does not affect the overall conformation of the N-terminal part of the peptide binding cleft and conserves the conformation of the epitopes.

<p><b>A.</b> Superimposed side views of the peptides gp33 (KAVYNFATM) and gp34 (AVYNFATM) depicting how residue p1K in gp33 protrudes out of the peptide binding cleft of H-2K^b. The remaining residues of gp33 take a similar conformation to all the side chains of gp34. The peptides gp33 and gp34, annotated in black and cyan, respectively, are depicted with their N termini to the left and their C termini to the right. The carbon atoms of the peptides gp33 and gp34 are colored in white and cyan, respectively. Carbon, nitrogen and oxygen atoms are in cyan, blue and red, respectively. The peptide-binding cleft of H-2K^b is colored white. <b>B.</b> Conformation of side chain residues interacting with the N-termini of peptides in the crystal structures of H-2K^b/gp33 (in white) and H-2K^b/gp34 (both MHC complexes from the asymmetric unit are displayed in cyan and light green, respectively), following superposition of the α₁α₂ domains. Note that the p2A residue in gp33 occupies the position corresponding to the p1A in gp34. The side chain of p1K in gp33 is not displayed. The orientation of the peptides is depicted by a black arrow (from the N terminus toward the C terminus). The α1 and α2 helices are indicated.</p

Nitrotyrosination of peptide residue p3Y results in a conformational change of the side-chain of the H-2K^b residue E152 only, altering TCR recognition.

<p><b>A.</b> Superposition of the peptide-binding clefts of H-2K^b/gp34 and H-2K^b/NY-gp34 demonstrate a subtle shift of the side chain of p3NY when compared to p3Y, resulting in a significant conformational change of the TCR-interacting H-2K^b heavy chain residue E152 (underlined). Both side chains of residues p3Y and p3NY protrude in the D-pocket of H-2K^b consisting of residues W147, E152, R155, L156 and Y159. The gp34 and NY-gp34 peptides are colored cyan and light green, respectively. <b>B.</b> Side view of the peptide gp34 when bound to H-2K^b. Three hydrogen bond interactions are formed between p3Y and the H-2K^b residues E152 and R155. No interactions are observed with the H-2K^b residues Q114 and Y116. <b>C.</b> A novel hydrogen bond and a long ionic range interaction are formed between p3NY and the H-2K^b residues Q114 and Y116, respectively. While two hydrogen bond interactions are maintained between p3NY and R155, all interactions are lost with E152.</p

The Use of Novel Drugs Can Effectively Improve Response, Delay Relapse and Enhance Overall Survival in Multiple Myeloma Patients with Renal Impairment

<div><p>Background</p><p>Renal impairment is a common feature in multiple myeloma and is considered a poor prognostic factor.</p><p>Aim</p><p>To determine the impact of novel drugs (i.e. bortezomib, lenalidomide and thalidomide) in the treatment of myeloma patients with renal impairment. The primary endpoint was overall survival and secondary endpoints were time to next treatment and response.</p><p>Methods</p><p>The study population included all patients diagnosed with treatment-demanding multiple myeloma January 2000 to June 2011 at 15 Swedish hospitals. Renal impairment was defined as an estimated glomerular filtration rate under 60 mL/min/1.73 m².</p><p>Result</p><p>The study population consisted of 1538 patients, of which 680 had renal impairment at diagnosis. The median overall survival in patients with renal impairment was 33 months, which was significantly shorter than 52 months in patients with normal renal function (<i>P</i><0.001). Novel agents in first line improved overall survival (median 60 months) in non-high-dose treated patients with renal impairment (n = 143) as compared to those treated with conventional cytotoxic drugs (n = 411) (median 27 months) (<i>P</i><0.001). In the multivariate analysis up front treatment with bortezomib was an independent factor for better overall survival in non-high-dose treated renally impaired patients. High-dose treated renally impaired patients had significantly better median overall survival than non-high-dose ones (74 versus 26 months) and novel drugs did not significantly improve survival further in these patients. Patients with renal impairment had both a shorter median time to next treatment and a lower response rate than those with normal renal function. However, novel drugs and high dose treatment lead to a significantly longer time to next treatment and the use of novel agents significantly improved the response rate of these patients.</p><p>Conclusion</p><p>High dose treatment and novel drugs, especially bortezomib, can effectively overcome the negative impact of renal impairment in patients with multiple myeloma.</p></div

Time to next treatment in patients with and without renal impairment at diagnosis.

<p>(A) In high-dose treated (HDT) patients with and without renal impairment after 2^nd line of therapy. (B) In non-HDT patients with and without renal impairment after 2^nd line of therapy. (C) Non-HDT patients with renal impairment treated with novel agents (bortezomib, lenalidomide or thalidomide) in the 1^st line compared to those treated with conventional agents (Conv.). (D) Non-HDT-patients with renal impairment treated with bortezomib (Bz) in the 1^st line compared to those treated with conventional agents. (E) HDT-patients with renal impairment treated with novel agents (bortezomib, lenalidomide or thalidomide) in the 1^st line compared to to those treated with conventional agents.</p

Overall survival for non-high-dose treated (non-HDT) patients with renal impairment.

<p>(A) Patients treated with novel agents (bortezomib, thalidomide or lenalidomide) compared to conventional agents in the 1^st treatment line. (B) Patients treated with bortezomib compared to conventional agents in the 1^st treatment line.</p

Overall survival in non-high-dose treated (non-HDT) patients with and without renal impairmet treated with novel agents.

<p>(A) Patients with renal impairment compared to those without renal impairment after the use of novel agents (bortezomib, lenalidomide or thalidomide) in the 1^st treatment line. (B) Patients with renal impairment compared to those without renal impairment after the use of bortezomib in the 1^st treatment line.</p

Population characteristics for all patients comparing those with and without renal impairment.

<p>The HDT patients are those that at some point have received high-dose treatment, irrespective of treatment line and the non-HDT those that have not. Patients classified has having received novel drugs implies that they have received this treatment in one or more treatment lines.</p><p>HDT, high-dose treated; non-HDT, non-high-dose treated; MM, multiple myeloma; novel drugs, bortezomib, lenalidomide or thalidomide; IgG, immunoglobulin G; IgA, immunoglobulin A; BJ, Bence Jones; Hb, hemoglobin; Ca, calcium; β2μ, beta-2-mikroglobulin.</p