Search for dark matter at √s=13 TeV in final states containing an energetic photon and large missing transverse momentum with the ATLAS detector

Results of a search for physics beyond the Standard Model in events containing an energetic photon and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. As the number of events observed in data, corresponding to an integrated luminosity of 36.1 fb−1 of proton–proton collisions at a centre-of-mass energy of 13 TeV, is in agreement with the Standard Model expectations, model-independent limits are set on the fiducial cross section for the production of events in this final state. Exclusion limits are also placed in models where dark-matter candidates are pair-produced. For dark-matter production via an axial-vector or a vector mediator in the s-channel, this search excludes mediator masses below 750–1200 GeV for dark-matter candidate masses below 230–480 GeV at 95% confidence level, depending on the couplings. In an effective theory of dark-matter production, the limits restrict the value of the suppression scale M∗ to be above 790 GeV at 95% confidence level. A limit is also reported on the production of a high-mass scalar resonance by processes beyond the Standard Model, in which the resonance decays to Zγ and the Z boson subsequently decays into neutrinos

Transition to a 1‐year deferral for male blood donors who report sexual contact with men: staff perspectives at one blood collection organization

BACKGROUND:Front-line staff at blood collection organizations (BCOs) play important roles in keeping the blood supply safe, yet research on their professional practice and perspectives on training needs is sparse. This qualitative study explored these topics with regard to the then-impending change in donor eligibility for men reporting sex with another man (MSM). STUDY DESIGN AND METHODS:Semistructured, individual interviews with BCO staff (n = 13) in Northern California covered experiences of and opinions on indefinite deferral, the revised 1-year deferral, and anticipated potential challenges arising from the new policy. Transcripts were thematically coded, using deductive and inductive approaches. Analysis identified recurrent and divergent themes. RESULTS:Interviewees reported strong values of professionalism and respect for donors and supported the change to a 1-year deferral for MSM donors. Nonetheless, nearly all voiced the need for more in-depth training to maximize the likelihood of successful implementation. Specific recommendations included the use of role-play, provision of science-based talking points or FAQs, and empathy for donors and staff. CONCLUSION:More than the usual training may be required to help BCO staff feel prepared to educate the public about changes to MSM-related deferrals and communicate effectively with donors about potentially deferrable behavior. Overall, these findings suggest that before future policy changes, BCO staff's opinions about and role in implementing new donor eligibility screening procedures merit consideration

Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

<div><p>The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph⁺ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph⁺ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ∼30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph⁺ALL as compared to just 4.8% of Ph⁻ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM). Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph⁺ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients.</p></div

Downregulation of pro-survival signaling induced by canertinib.

<p>(A) Protein expression values from RPPA analyses of Z119 (white) and Z181 (black) cells were quantified, and expression relative to the mean graphed. Triangles indicate drug concentrations of 0–5 µM. *p<0.05 compared to untreated. (B) Z119 and Z181 cells were treated with canertinib for 18 hours and then lysed. Samples were subjected to SDS-PAGE followed by immunoblotting with the indicated antibodies.</p

ErbB2 activation, but not expression, varies between ALL cytogenetic categories.

<p>RPPA was performed using antibodies directed against ErbB2 (A) and ErbB2p (B) on 129 ALL patient samples and normalized to CD34+ normal cells on a log₂ scale. Zero indicates the median of CD34+ normal cells. Patient cytogenetics were retroactively analyzed to categorize expression values. Box represents 25–75% of the median population; whiskers represent the range of data. Misc: Miscellaneous, IM: insufficient metaphases, NAM: no analyzable metaphases.</p

Small molecule ErbB2 inhibitors increase sensitivity to BCR/ABL-directed TKI.

<p>Z119 cells were treated with indicated doses canertinib or lapatinib and (A) imatinib, (B) nilotinib or (C) dasatinib for 72 hours. Cells were stained with PI and the subdiploid population was measured by flow cytometry. Bars indicate the mean and SEM of at least three independent experiments.</p

Phosphorylated ErbB2 expression in ALL patient samples.

<p>Log₂ expression values were median centered (median of CD34+ = 0). All ALL: combined statistics with no subgroup analysis; T-ALL: T-cell ALL samples; B-ALL: B-cell ALL samples; Ph⁺ALL: all ALL samples expressing the Philadelphia chromosome; Ph⁻ALL: samples not containing the Philadelphia chromosome; SD: standard deviation; >norm (%): percentage above values within the 95% confidence interval based on the range of expression of the normal CD34+ cells; </p