Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications

Triple-negative breast cancer (TNBC) accounts for ~15\u201320% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness

Long-Term Implications of Atrial Fibrillation in Patients With Degenerative Mitral Regurgitation

Background: Scientific guidelines consider atrial fibrillation (AF) complicating degenerative mitral regurgitation (DMR) a debated indication for surgery. Objectives: This study analyzed the prognostic/therapeutic implications of AF at DMR diagnosis and long-term. Methods: Patients were enrolled in the MIDA (Mitral Regurgitation International Database) registry, which reported the consecutive, multicenter, international experience with DMR due to flail leaflets echocardiographically diagnosed. Results: Among 2,425 patients (age 67 \ub1 13 years; 71% male, 67% asymptomatic, ejection fraction 64 \ub1 10%), 1,646 presented at diagnosis with sinus rhythm (SR), 317 with paroxysmal AD, and 462 with persistent AF. Underlying clinical/instrumental characteristics progressively worsened from SR to paroxysmal to persistent AF. During follow-up, paroxysmal and persistent AF were associated with excess mortality (10-year survival in SR and in paroxysmal and persistent AF was 74 \ub1 1%, 59 \ub1 3%, and 46 \ub1 2%, respectively; p < 0.0001), that persisted 20 years post-diagnosis and independently of all baseline characteristics (p values <0.0001). Surgery (n = 1,889, repair 88%) was associated with better survival versus medical management, regardless of all baseline characteristics and rhythm (adjusted hazard ratio: 0.26; 95% confidence interval: 0.23 to 0.30; p < 0.0001) but post-surgical outcome remained affected by AF (10-year post-surgical survival in SR and in paroxysmal and persistent AF was 82 \ub1 1%, 70 \ub1 4%, and 57 \ub1 3%, respectively; p < 0.0001). Conclusions: AF is a frequent occurrence at DMR diagnosis. Although AF is associated with older age and more severe presentation of DMR, it is independently associated with excess mortality long-term after diagnosis. Surgery is followed by improved survival in each cardiac rhythm subset, but persistence of excess risk is observed for each type of AF. Our study indicates that detection of AF, even paroxysmal, should trigger prompt consideration for surgery

Sub-threshold states in 19Ne relevant to 18F(p, alpha) 15O

International audienceClassical novae result from thermonuclear explosions producing several $\gamma$-ray emitters which are prime targets for satellites observing in the MeV range. The early 511 keV gamma-ray emission depends critically on the $^{18}$F(p,$\alpha$)$^{15}$O reaction rate which, despite many experimental and theoretical efforts, still remains uncertain. One of the main uncertainties in the $^{18}$F(p,$\alpha$)$^{15}$O reaction rate is the contribution in the Gamow window of interference between sub-threshold $^{19}$Ne states and known broad states at higher energies. Therefore the goal of this work is to clarify the existence and the nature of these sub-threshold states. States in the $^{19}$Ne compound nucleus were studied at the Tandem-ALTO facility using the $^{19}$F($^3$He,t)$^{19}$Ne charge exchange reaction. Tritons were detected with an Enge Split-pole spectrometer while decaying protons or $\alpha$-particles from unbound $^{19}$Ne states were collected, in coincidence, with a double-sided silicon strip detector array. Angular correlations were extracted and constraints on the spin and parity of decaying states established. The coincidence yield at $E_x$ = 6.29 MeV was observed to be high spin, supporting the conclusion that it is indeed a doublet consisting of high spin and low spin components. Evidence for a broad, low spin state was observed around 6 MeV. Branching ratios were extracted for several states above the proton threshold and were found to be consistent with the literature. R-matrix calculations show the relative contribution of sub-threshold states to the astrophysically important energy region above the proton threshold. The levels schemes of $^{19}$Ne and $^{19}$F are still not sufficiently well known and further studies of the analogue assignments are needed. The tentative broad state at 6 MeV may only play a role if the reduced proton width is large

Detection of p53 in Hodgkin's disease using the monoclonal antibody PAb248.

The recent demonstration that the murine anti-p53 monoclonal antibody PAb248 can identify human p53 in a variety of normal tissues proves that immunohistochemical detection does not necessarily indicate the presence of mutations. PAb248 can detect p53 protein in a cytoplasmic-perinuclear localization, not previously described. The present study presents the expression of this antibody in a series of 34 cases of Hodgkin's disease, comparing it with the antibodies CM1, PAb1801, and PAb240. In all cases, PAb248 showed uniform cytoplasmic-perinuclear staining in small and medium-sized lymphocytes, while it was constantly negative in Hodgkin, Reed-Sternberg (R-S/H) cells, and variants. This pattern of staining was the opposite to that observed with the antibodies CM1, PAb1801, and PAb240, where the staining was nuclear and restricted to the R-S/H cells, with the small lymphocytes being negative. p53 can be found in different conformations and localizations, with the cytoplasmic-perinuclear localization mainly, although not exclusively, being found in normal and reactive tissues and the nuclear localization being mainly expressed by neoplastic cells. These results give further support to the theory that the R-S/H cells are the neoplastic population in Hodgkin's disease, while the surrounding lymphocytes are reactive

Detection of p53 in Hodgkin's disease using the monoclonal antibody PAb248.

The recent demonstration that the murine anti-p53 monoclonal antibody PAb248 can identify human p53 in a variety of normal tissues proves that immunohistochemical detection does not necessarily indicate the presence of mutations. PAb248 can detect p53 protein in a cytoplasmic-perinuclear localization, not previously described. The present study presents the expression of this antibody in a series of 34 cases of Hodgkin's disease, comparing it with the antibodies CM1, PAb1801, and PAb240. In all cases, PAb248 showed uniform cytoplasmic-perinuclear staining in small and medium-sized lymphocytes, while it was constantly negative in Hodgkin, Reed-Sternberg (R-S/H) cells, and variants. This pattern of staining was the opposite to that observed with the antibodies CM1, PAb1801, and PAb240, where the staining was nuclear and restricted to the R-S/H cells, with the small lymphocytes being negative. p53 can be found in different conformations and localizations, with the cytoplasmic-perinuclear localization mainly, although not exclusively, being found in normal and reactive tissues and the nuclear localization being mainly expressed by neoplastic cells. These results give further support to the theory that the R-S/H cells are the neoplastic population in Hodgkin's disease, while the surrounding lymphocytes are reactive