Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer

In vitro studies have suggested proteasome inhibitors could be effective in triple-negative breast cancer (TNBC). We found that bortezomib and carfilzomib induce proteotoxic stress and apoptosis via the unfolded protein response (UPR) in TNBC cell lines, with sensitivity correlated with expression of immuno-(PSMB8/9/10) but not constitutive-(PSMB5/6/7) proteasome subunits. Equally, the transcriptomes of i-proteasome-high human TNBCs are enriched with UPR gene sets, and the genomic copy number landscape reflects positive selection pressure favoring i-proteasome activity, but in the setting of adjuvant treatment, this is actually associated with favorable prognosis. Tumor expression of PSMB8 protein (β5i) is associated with levels of MHC-I, interferon-γ-inducible proteasome activator PA28β, and the densities of stromal antigen-presenting cells and lymphocytes (TILs). Crucially, TILs were protective among TNBCs that maintain high β5i but did not stratify survival amongst β5i-low TNBCs. Moreover, β5i expression was lower in brain metastases than in patient-matched primary breast tumors (n = 34; P = 0.007), suggesting that suppression contributes to immune evasion and metastatic progression. Hence, inhibiting proteasome activity could be counterproductive in the adjuvant treatment setting because it potentiates anti-TNBC immunity.Alaknanda Adwal, Priyakshi Kalita-de Croft, Reshma Shakya, Malcolm Lim, Emarene Kalaw, Lucinda D Taege, Amy E McCart Reed, Sunil R Lakhani, David F Callen, Jodi M Saunu

Quantum radiation pressure on a moving mirror at finite temperature

We compute the radiation pressure force on a moving mirror, in the nonrelativistic approximation, assuming the field to be at temperature $T.$ At high temperature, the force has a dissipative component proportional to the mirror velocity, which results from Doppler shift of the reflected thermal photons. In the case of a scalar field, the force has also a dispersive component associated to a mass correction. In the electromagnetic case, the separate contributions to the mass correction from the two polarizations cancel. We also derive explicit results in the low temperature regime, and present numerical results for the general case. As an application, we compute the dissipation and decoherence rates for a mirror in a harmonic potential well.Comment: Figure 3 replaced, changes mainly in Sections IV and V, new appendix introduced. To appear in Physical Review

Fluctuations, dissipation and the dynamical Casimir effect

Vacuum fluctuations provide a fundamental source of dissipation for systems coupled to quantum fields by radiation pressure. In the dynamical Casimir effect, accelerating neutral bodies in free space give rise to the emission of real photons while experiencing a damping force which plays the role of a radiation reaction force. Analog models where non-stationary conditions for the electromagnetic field simulate the presence of moving plates are currently under experimental investigation. A dissipative force might also appear in the case of uniform relative motion between two bodies, thus leading to a new kind of friction mechanism without mechanical contact. In this paper, we review recent advances on the dynamical Casimir and non-contact friction effects, highlighting their common physical origin.Comment: 39 pages, 4 figures. Review paper to appear in Lecture Notes in Physics, Volume on Casimir Physics, edited by Diego Dalvit, Peter Milonni, David Roberts, and Felipe da Rosa. Minor changes, a reference adde

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Characterization of constitutive marker chromosomes in humans

A marker chromosome is one that is morphologically different from any normal chromosome with its origin not being readily discernible by classical cytogenetic techniques. Marker chromosomes in neoplasia often represent the products of complex rearrangements and will not be discussed in this chapter. From a large series of 377,357 karyotyped amniocentesis specimens in a multicenter survey, an unbiased estimate of the frequency of de novo constitutional marker chromosomes was 1 in 2500 (1). The overall population frequency will be higher than this since markers identified as i(18p) or i(12p), and markers that were familial, were excluded. Since the proportion of familial markers is in the vicinity of 40% (2), the actual population frequency of marker chromosomes is about 1 in 1200.David F. Calle