Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer.

Skeletal metastasis occurs in around 75% of advanced breast cancers, with the disease incurable once cancer cells disseminate to bone, but there remains an unmet need for biomarkers to identify patients at high risk of bone recurrence. This study aimed to identify such a biomarker and to assess its utility in predicting response to adjuvant zoledronic acid. We used quantitative proteomics (SILAC-MS), to compare protein expression in a bone-homed variant (BM1) of the human breast cancer cell line MDA-MB-231 with parental non-bone-homing cells to identify novel biomarkers for risk of subsequent bone metastasis in early breast cancer. SILAC-MS showed that Dedicator of cytokinesis protein 4 (DOCK4) was upregulated in bone-homing BM1 cells, confirmed by Western blotting. BM1 cells also had enhanced invasive ability compared with parental cells which could be reduced by DOCK4-shRNA. In a training Tissue Microarray (TMA) comprising 345 patients with early breast cancer, immunohistochemistry followed by Cox regression revealed that high DOCK4 expression correlated with histological grade (p=0.004) but not oestrogen receptor status (p=0.19) or lymph node involvement (p=0.15). A clinical validation TMA used tissue samples and the clinical database from the large AZURE adjuvant study (n=689). Adjusted Cox regression analyses showed that high DOCK4 expression in the control arm (no zoledronic acid) was significantly prognostic for first recurrence in bone (HR 2.13, 95%CI 1.06-4.30, p=0.034). No corresponding association was found in patients who received zoledronic acid (HR 0.812, 95%CI 0.176-3.76, p=0.790), suggesting that treatment with zoledronic acid may counteract the higher risk for bone relapse from high DOCK4-expressing tumours. High DOCK4 expression was not associated with metastasis to non-skeletal sites when these were assessed collectively. In conclusion, high DOCK4 in early breast cancer is significantly associated with aggressive disease and with future bone metastasis and is a potentially useful biomarker for subsequent bone metastasis risk

Accessing the strong interaction between Λ baryons and charged kaons with the femtoscopy technique at the LHC

The interaction between Λ baryons and kaons/antikaons is a crucial ingredient for the strangeness S=0 and S=-2 sector of the meson–baryon interaction at low energies. In particular, the Lambda-Kbar might help in understanding the origin of states such as the Csi(1620), whose nature and properties are still under debate. Experimental data on Lambda-K and Lambda-Kbar systems are scarce, leading to large uncertainties and tension between the available theoretical predictions constrained by such data. In this Letter we present the measurements of Λ–KK− and Λ–KK+ correlations obtained in the high-multiplicity triggered data sample in pp collisions at sqrt(s) = 13 TeV recorded by ALICE at the LHC. The correlation function for both pairs is modeled using the Lednický–Lyuboshits analytical formula and the corresponding scattering parameters are extracted. The Λ–KK+ correlations show the presence of several structures at relative momenta k* above 200 MeV/c, compatible with the Ω baryon, the , and resonances decaying into Λ–K− pairs. The low k* region in the Λ–KK+ also exhibits the presence of the state, expected to strongly couple to the measured pair. The presented data allow to access the ΛK+ and ΛK− strong interaction with an unprecedented precision and deliver the first experimental observation of the decaying into ΛK−

Fusion of mature HIV-1 particles leads to complete release of a gag-GFP-based content marker and raises the intraviral pH

By imaging the release of a GFP-based viral content marker produced upon virus maturation, we have previously found that HIV-1 fuses with endosomes. In contrast, fusion at the cell surface did not progress beyond a lipid mixing stage (hemifusion). However, recent evidence suggesting that free GFP can be trapped within the mature HIV-1 capsid raises concerns that this content marker may not be released immediately after the formation of a fusion pore. To determine whether a significant portion of GFP is trapped in the mature capsid, we first permeabilized the viral membrane with saponin. The overwhelming majority of pseudoviruses fully released GFP while the remaining particles exhibited partial loss or no loss of content. The extent of GFP release correlated with HIV-1 maturation, implying that incomplete Gag processing, but not GFP entrapment by mature capsids, causes partial content release. Next, we designed a complementary assay for visualizing pore formation by monitoring the intraviral pH with an additional pH-sensitive fluorescent marker. The loss of GFP through saponin-mediated pores was associated with a concomitant increase in the intraviral pH due to equilibration with the pH of an external buffer. We next imaged single HIV-cell fusion and found that these events were manifested in a highly correlated loss of content and increase in the intraviral pH, as it equilibrated with the cytosolic pH. Fused or saponin-permeabilized pseudoviruses that partially lost GFP did not release the remaining content marker under conditions expected to promote the capsid dissociation. We were thus unable to detect significant entrapment of GFP by the mature HIV-1 capsid. Together, our results validate the use of the GFP-based content marker for imaging single virus fusion and inferring the sites of HIV-1 entry

Effect of ceramic material on heat dissipation from multi-stage depressed collector used in high efficiency traveling-wave tubes

657-660To increase reliability, the thermal and structural integrity of a multi-stage depressed collector (MDC) used in traveling wave tubes (TWTs) has been improved. Highly reliable TWTs can be achieved by careful consideration of design requirements and constraints, material selection, weight reduction and cost effectiveness. In a TWT, maximum heat generated in MDC is due to maximum power dissipation and, hence, needs for proper thermal management. In the present paper, the thermal characteristics of MDC for different ceramic insulator materials have been studied

Effect of neoadjuvant chemotherapy on breast cancer phenotype, ER/PR and HER2 expression - Implications for the practising oncologist

Purpose To assess the effect of neoadjuvant chemotherapy (NACT) on breast cancer characteristics, hormone receptors and human epidermal growth factor receptor 2 (HER2) expression and whether testing should be repeated on residual tumours. Material and methods Patients with primary operable breast cancer who received NACT at a single United Kingdom tertiary referral centre were included. Tumour type, grade (including details of mitotic grade, tubule formation and pleomorphism), oestrogen receptor (ER), progesterone receptor (PR) and HER2 status were compared between pre-treatment and post-treatment residual samples using tissue microarrays. A control group of paired core and excision tumours from patients who did not receive NACT was also assessed. Results Two hundred forty-six cases and 113 controls were included. Pathological complete response (path CR) was achieved in 21.5% of patients. In those patients failing to achieve a path CR, a change in the histological type was noted in 29 out of 178 cases (16.3%, p < 0.001) with increase in the lobular and metaplastic types. Downgrading occurred in 28.8%, due to significant reduction in mitotic rate and prominent tubule formation. A change in ER/PR/HER2 status occurred in 12%, 14.5% and 7.1% of cases, respectively, predominantly as a switch from negative to positive status for ER and from positive to negative status for HER2. Further alterations in expression levels were also noted. Minimal changes in the low ER/PR expressors and the HER2 2+ tumours were found in the control group. Conclusion Significant changes in tumour morphology, grade, hormone receptors and HER2 status occur following NACT. We recommend testing on residual invasive carcinoma. A switch from negative to positive status warrants offering endocrine/trastuzumab-based therapy to this group of patients