We present an investigation of the optical spectra of 264 low-redshift (z < 0.2) Type Ia supernovae (SNe Ia) discovered by the Palomar Transient Factory, an untargeted transient survey. We focus on ...velocity and pseudo-equivalent width measurements of the Si ii 4130, 5972, and 6355 Å lines, as well those of the Ca ii near-infrared (NIR) triplet, up to +5 days relative to the SN B-band maximum light. We find that a high-velocity component of the Ca ii NIR triplet is needed to explain the spectrum in ∼95 per cent of SNe Ia observed before −5 days, decreasing to ∼80 per cent at maximum. The average velocity of the Ca ii high-velocity component is ∼8500 km s−1 higher than the photospheric component. We confirm previous results that SNe Ia around maximum light with a larger contribution from the high-velocity component relative to the photospheric component in their Ca ii NIR feature have, on average, broader light curves and lower Ca ii NIR photospheric velocities. We find that these relations are driven by both a stronger high-velocity component and a weaker contribution from the photospheric Ca ii NIR component in broader light curve SNe Ia. We identify the presence of C ii in very-early-time SN Ia spectra (before −10 days), finding that >40 per cent of SNe Ia observed at these phases show signs of unburnt material in their spectra, and that C ii features are more likely to be found in SNe Ia having narrower light curves.
Quantum circuits interact with the environment via several temperature-dependent degrees of freedom. Multiple experiments to-date have shown that most properties of superconducting devices appear to ...plateau out at T ≈ 50 mK - far above the refrigerator base temperature. This is for example reflected in the thermal state population of qubits, in excess numbers of quasiparticles, and polarisation of surface spins - factors contributing to reduced coherence. We demonstrate how to remove this thermal constraint by operating a circuit immersed in liquid
He. This allows to efficiently cool the decohering environment of a superconducting resonator, and we see a continuous change in measured physical quantities down to previously unexplored sub-mK temperatures. The
He acts as a heat sink which increases the energy relaxation rate of the quantum bath coupled to the circuit a thousand times, yet the suppressed bath does not introduce additional circuit losses or noise. Such quantum bath suppression can reduce decoherence in quantum circuits and opens a route for both thermal and coherence management in quantum processors.
Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib ...when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1
⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.
Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly ...in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2
mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer.
We present an analysis of 507 spectra of 173 stripped-envelope (SE) supernovae (SNe) discovered by the untargeted Palomar Transient Factory (PTF) and intermediate PTF (iPTF) surveys. Our sample ...contains 55 Type IIb SNe (SNe IIb), 45 Type Ib SNe (SNe Ib), 56 Type Ic SNe (SNe Ic), and 17 Type Ib/c SNe (SNe Ib/c). We have compared the SE SN subtypes via measurements of the pseudo-equivalent widths (pEWs) and velocities of the He I λλ5876, 7065 and O I λ7774 absorption lines. Consistent with previous work, we find that SNe Ic show higher pEWs and velocities in O I λ7774 compared to SNe IIb and Ib. The pEWs of the He I λλ5876, 7065 lines are similar in SNe Ib and IIb after maximum light. The He I λλ5876, 7065 velocities at maximum light are higher in SNe Ib compared to SNe IIb. We identify an anticorrelation between the He I λ7065 pEW and O I λ7774 velocity among SNe IIb and Ib. This can be interpreted as a continuum in the amount of He present at the time of explosion. It has been suggested that SNe Ib and Ic have similar amounts of He, and that lower mixing could be responsible for hiding He in SNe Ic. However, our data contradict this mixing hypothesis. The observed difference in the expansion rate of the ejecta around maximum light of SNe Ic (Vm = √2Ek/Mej ≈ 15 000 km s−1Vm=2Ek/Mej≈15 000 km s−1${V_{\rm{m}}} = \sqrt {2{E_{\rm{k}}}/{M_{{\rm{ej}}} \approx 1{\rm{5 \, 000 \, km }} \, {{\rm{s}}^{ - 1}}$) and SNe Ib (Vm ≈ 9000 km s−1) would imply an average He mass difference of ∼1.4 M⊙, if the other explosion parameters are assumed to be unchanged between the SE SN subtypes. We conclude that SNe Ic do not hide He but lose He due to envelope stripping.
In chronic myeloid leukemia (CML) cell lines, brief exposure to pharmacologically relevant dasatinib concentrations results in apoptosis. In this study, we assess the impact of intensity and duration ...of Bcr-Abl kinase inhibition on primary CD34(+) progenitors of chronic phase CML patients. As CML cells exposed to dasatinib in vivo are in a cytokine-rich environment, we also assessed the effect of cytokines (six growth factors cocktail or granulocyte-macrophage colony-stimulating factor (CSF) or granulocyte-CSF) in combination with dasatinib. In the presence of cytokines, short-term intense Bcr-Abl kinase inhibition (>or=90% p-Crkl inhibition) with 100 nM dasatinib did not reduce CD34(+) colony-forming cells (CFCs). In contrast, without cytokines, short-term exposure to dasatinib reduced CML-CD34(+) CFCs by 70-80%. When cytokines were added immediately after short-term exposure to dasatinib, CML-CD34(+) cells remained viable, suggesting that oncogene dependence of these cells can be overcome by concomitant or subsequent exposure to cytokines. Additional inhibition of Janus tyrosine kinase (Jak) activity re-established the sensitivity of CML progenitors to intense Bcr-Abl kinase inhibition despite the presence of cytokines. These findings support the contention that therapeutic strategies combining intense Bcr-Abl kinase inhibition and blockade of cytokine signaling pathways can be effective for eradication of CML progenitors.
Active influx of imatinib in chronic myeloid leukemia (CML) cells is mediated by the organic cation transporter 1 (OCT-1). Functional activity of OCT-1 (OCT-1 Activity) in mononuclear cells is an ...excellent predictor of molecular response over the first 24 months of imatinib therapy for chronic phase patients. CML progenitor cells are less sensitive to imatinib-induced apoptosis and are likely contributors to disease persistence. We investigated whether alterations in the expression and function of OCT-1 have a role in imatinib resistance in progenitors. We found the intracellular uptake and retention (IUR) of imatinib, OCT-1 Activity and OCT-1 mRNA expression are all significantly lower in CML CD34+ cells compared with mature CD34- cells (P<0.001). However, no differences in IUR or OCT-1 Activity were observed between these subsets in healthy donors. In contrast to OCT-1, ABCB1 and ABCG2 seemed to have no functional role in the transport of imatinib in CML CD34+ cells. Consistent with the observation that nilotinib uptake is not OCT-1 dependent, the IUR of nilotinib did not differ between CML CD34+ and CD34- cells. These results indicate that low imatinib accumulation in primitive CML cells, mediated through reduced OCT-1 Activity may be a critical determinant of long-term disease persistence.
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