Long-term outcomes of a randomized, open-label, phase II study comparing cabazitaxel versus paclitaxel as neoadjuvant treatment in patients with triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE).

BACKGROUND: The GENEVIEVE study, comparing neoadjuvant cabazitaxel versus paclitaxel in triple-negative breast cancer (TNBC) and luminal B/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC), previously reported significant differences in pathological complete response (pCR) rates. Effects on long-term outcome are unknown. PATIENTS AND METHODS: GENEVIEVE randomized patients with cT2-3, any cN or cT1, cN+/pNSLN+, centrally confirmed TNBC or luminal B/HER2-negative BC (latter defined as estrogen/progesterone receptor-positive and >14% Ki-67-stained cells) to receive either cabazitaxel 25 mg/m2 q3w for four cycles or paclitaxel 80 mg/m2 weekly for 12 weeks. Anthracycline-containing chemotherapy was allowed in case of histologically proven invasive residuals as neoadjuvant treatment or after surgery as adjuvant treatment. Here we report the secondary endpoints invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: Of the 333 patients randomized, 74.7% and 83.2% completed treatment in the cabazitaxel and paclitaxel arms, respectively. After a median follow-up of 89.3 months (interquartile range 68.8-97.3 months), 80 iDFS events (43 after cabazitaxel and 37 after paclitaxel) and 47 deaths (23 after cabazitaxel and 24 after paclitaxel) were reported. IDFS rates were not significantly different between the cabazitaxel and paclitaxel arms after a 3-year (83.6% versus 85.0%) and 5-year follow-up (76.2% versus 78.3%) [hazard ratio (HR) = 1.27, 95% confidence interval 0.82-1.96, P = 0.294], respectively. DDFS rates at 3 years (88.6% versus 87.8%) and 5 years (82.1% versus 82.8%) for cabazitaxel and paclitaxel were comparable (HR = 1.15, P = 0.573). Similarly, OS rates at 3 years (91.6% versus 91.8%) and 5 years (89.2% versus 86.8%) showed no significant differences (HR = 1.05, P = 0.872). Subgroup analysis for TNBC and luminal B/HER2-negative BCs indicated no significant variations in 3- or 5-year iDFS, DDFS, or OS. CONCLUSIONS: The significant differences in pCR rates observed in both treatment arms did not significantly impact long-term outcomes for patients treated with cabazitaxel versus paclitaxel in the GENEVIEVE trial.

Rapid reaction optimization by robust and economical quantitative benchtop 19F NMR spectroscopy.

The instrumental analysis of reaction mixtures is usually the rate-determining step in the optimization of chemical processes. Traditionally, reactions are analyzed by gas chromatography, HPLC or quantitative NMR spectroscopy on high-field spectrometers. However, chromatographic methods require elaborate work-up and calibration protocols, and high-field NMR spectrometers are expensive to purchase and operate. This protocol describes an inexpensive and highly effective analysis method based on low-field benchtop NMR spectroscopy. Its key feature is the use of fluorine-labeled model substrates that, because of the wide chemical shift range and high sensitivity of 19F, enable separate, quantitative detection of product and by-product signals even on low-field, permanent magnet spectrometers. An external lock/shim device obviates the need for deuterated solvents, permitting the direct, noninvasive measurement of crude reaction mixtures with minimal workup. The low field-strength facilitates a homogeneous excitation over a wide chemical shift range, minimizing systematic integration errors. The addition of the optimal amount of the nonshifting relaxation agent tris(acetylacetonato) iron(III) minimizes relaxation delays at full resolution, reducing the analysis time to 32 s per sample. The correct choice of processing parameters is also crucial. A step-by-step guideline is provided, the influence of all parameters, including adjustments needed when using high-field spectrometers, is discussed and potential pitfalls are highlighted. The wide applicability of the analytical protocol for reaction optimization is illustrated by three examples: a Buchwald-Hartwig amination, a Suzuki coupling and a C-H arylation reaction.

Photosynthetic quantum efficiency in south-eastern Amazonian trees may be already affected by climate change.

Tropical forests are experiencing unprecedented high-temperature conditions due to climate change that could limit their photosynthetic functions. We studied the high-temperature sensitivity of photosynthesis in a rainforest site in southern Amazonia, where some of the highest temperatures and most rapid warming in the Tropics have been recorded. The quantum yield (Fv /Fm ) of photosystem II was measured in seven dominant tree species using leaf discs exposed to varying levels of heat stress. T50 was calculated as the temperature at which Fv /Fm was half the maximum value. T5 is defined as the breakpoint temperature, at which Fv /Fm decline was initiated. Leaf thermotolerance in the rapidly warming southern Amazonia was the highest recorded for forest tree species globally. T50 and T5 varied between species, with one mid-storey species, Amaioua guianensis, exhibiting particularly high T50 and T5 values. While the T50 values of the species sampled were several degrees above the maximum air temperatures experienced in southern Amazonia, the T5 values of several species are now exceeded under present-day maximum air temperatures.

Ventricular Rupture due to Myocardial Infarction without Obstructive Coronary Artery Disease.

An 87-year-old woman presenting with myocardial infarction and ST-segment elevation in the electrocardiogram suffered from pericardial effusion due to left ventricular rupture. After ruling out obstructive coronary artery disease and aortic dissection, she underwent cardiac surgery showing typical infarct-macerated myocardial tissue in situ. This case shows that even etiologically unclear and small-sized myocardial infarctions can cause life-threatening mechanical complications.

Analytic Form of the Full Two-Loop Five-Gluon All-Plus Helicity Amplitude.

We compute the full-color two-loop five-gluon amplitude for the all-plus helicity configuration. In order to achieve this, we calculate the required master integrals for all permutations of the external legs, in the physical scattering region. We verify the expected divergence structure of the amplitude and extract the finite hard function. We further validate our result by checking the factorization properties in the collinear limit. Our result is fully analytic and valid in the physical scattering region. We express it in a compact form containing logarithms, dilogarithms, and rational functions.

Rubber contact mechanics: adhesion, friction and leakage of seals.

We study the adhesion, friction and leak rate of seals for four different elastomers: Acrylonitrile Butadiene Rubber (NBR), Ethylene Propylene Diene (EPDM), Polyepichlorohydrin (GECO) and Polydimethylsiloxane (PDMS). Adhesion between smooth clean glass balls and all the elastomers is studied both in the dry state and in water. In water, adhesion is observed for the NBR and PDMS elastomers, but not for the EPDM and GECO elastomers, which we attribute to the differences in surface energy and dewetting. The leakage of water is studied with rubber square-ring seals squeezed against sandblasted glass surfaces. Here we observe a strongly non-linear dependence of the leak rate on the water pressure ΔP for the elastomers exhibiting adhesion in water, while the leak rate depends nearly linearly on ΔP for the other elastomers. We attribute the non-linearity to some adhesion-related phenomena, such as dewetting or the (time-dependent) formation of gas bubbles, which blocks fluid flow channels. Finally, rubber friction is studied at low sliding speeds using smooth glass and sandblasted glass as substrates, both in the dry state and in water. The measured friction coefficients are compared to theory, and the origin of the frictional shear stress acting in the area of real contact is discussed. The NBR rubber, which exhibits the strongest adhesion both in the dry state and in water, also shows the highest friction both in the dry state and in water.

Genetic Breast Cancer Susceptibility Variants and Prognosis in the Prospectively Randomized SUCCESS A Study.

Large-scale genotyping studies have identified over 70 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. However, knowledge regarding genetic risk factors associated with the prognosis is limited. The aim of this study was therefore to investigate the prognostic effect of nine known breast cancer risk SNPs. BC patients (n = 1687) randomly sampled in an adjuvant, randomized phase III trial (SUCCESS A study) were genotyped for nine BC risk SNPs: rs17468277 (CASP8) , rs2981582 (FGFR2) , rs13281615(8q24), rs3817198 (LSP1) , rs889312 (MAP3K1) , rs3803662 (TOX3) , rs13387042(2q35), rs4973768 (SLC4A7) , rs6504950 (COX11) . Cox proportional hazards models were used to test the SNPs' association with overall survival (OS) and progression-free survival (PFS). Additional analyses were carried out for molecular subgroups. rs3817198 in LSP1 (lymphocyte-specific protein 1) was the only SNP that significantly influenced OS (p = 0.01) and PFS (p < 0.01) in the likelihood ratio test comparing the genetic survival model with the clinical survival model. In the molecular subgroups, triple-negative patients with two minor alleles in rs3817198 had a much better prognosis relative to OS (adjusted HR 0.03; 95% CI 0.002 - 0.279) and PFS (HR 0.09; 95% CI 0.02 - 0.36) than patients with the common alleles. The same effect on PFS was shown for patients with luminal A tumors (HR 0.19; 95% CI 0.05 - 0.84), whereas patients with luminal B tumors had a poorer PFS with two minor alleles (HR 2.13; 95% CI 1.02 - 4.40). The variant in rs3817198 has a prognostic effect particularly in the subgroup of patients with triple-negative BC, suggesting a possible link with immunomodulation and BC.

The HER2 phenotype of circulating tumor cells in HER2-positive early breast cancer: A translational research project of a prospective randomized phase III trial.

BACKGROUND: HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy. METHODS: The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining. RESULTS: 258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC. CONCLUSION: This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance.

Filler flocculation in polymers - a simplified model derived from thermodynamics and game theory.

The performance of elastomeric materials, i.e. in car tires, is substantially determined by the used reinforcing filler system. In particular, the flocculation tendency of filler particles to form clusters and even network-like structures significantly determines the mechanical properties of these elastomer materials and enhances especially their energy dissipation under periodic mechanical deformations. In a simplified thermodynamic model, inspired by a segregation model from game theory, we describe fundamental mechanisms of filler structure formation. As the final goal of this paper we want to demonstrate how similar structures in society, nature or materials like rubbers emerge when supposing obvious cardinal mechanisms of structure formation in complex systems.

Chronic total coronary occlusion recanalization: Current techniques and new devices.

Percutaneous coronary intervention (PCI) of total chronic coronary occlusion (CTO) still remains a major challenge. The prevalence of a CTO has been reported to be up to 30% among patients with a clinical indication for coronary angiography. Progress has been made with further advanced interventional techniques and continuously sophisticated interventional tools. Nevertheless the number of interventions carried out to recanalize a CTO is less than 10% of all procedures. Benefits of a successful CTO recanalization include relief of angina pectoris and ischemia-related dyspnea, substantial improvement in left ventricular function and, avoidance of surgery treatment. A vast variety of new CTO PCI techniques and materials has been introduced into clinical practise and pushed success rates of reopening a CTO up to around 90% in experienced hands. Particulary the introduction of the retrograde technique was a milestone. New developed microcatheters and special polymer coated wires allow to recanalize via small collaterals and vessels. Other tools such as intravascular ultrasound (IVUS) and multislice computertomography (MSCT) help to identify the anatomy and the characteristic of the lesions. Any invasive cardiac center should adopt CTO PCI procedures as standard therapy. OBJECTIVE: This review wants to assess and describe the latest development in CTO recanalization strategies.

The effect of surface roughness and viscoelasticity on rubber adhesion.

Adhesion between silica glass or acrylic balls and silicone elastomers and various industrial rubbers is investigated. The work of adhesion during pull-off is found to strongly vary depending on the system, which we attribute to the two opposite effects: (1) viscoelastic energy dissipation close to an opening crack tip and (2) surface roughness. Introducing surface roughness on the glass ball is found to increase the work of adhesion for soft elastomers, while for the stiffer elastomers it results in a strong reduction in the work of adhesion. For the soft silicone elastomers a strong increase in the work of adhesion with increasing pull-off velocity is observed, which may result from the non-adiabatic processes associated with molecular chain pull-out. In general, the work of adhesion is decreased after repeated contacts due to the transfer of molecules from the elastomers to the glass ball. Thus, extracting the free chains (oligomers) from the silicone elastomers is shown to make the work of adhesion independent of the number of contacts. The viscoelastic properties (linear and nonlinear) of all of the rubber compounds are measured, and the velocity dependent crack opening propagation energy at the interface is calculated. Silicone elastomers show a good agreement between the measured work of adhesion and the predicted results, but carbon black filled hydrogenated nitrile butadiene rubber compounds reveal that strain softening at the crack tip may play an important role in determining the work of adhesion. Additionally, adhesion measurement under submerged conditions in distilled water and water + soap solutions are also performed: a strong reduction in the work of adhesion is measured for the silicone elastomers submerged in water, and a complete elimination of adhesion is found for the water + soap solution attributed to an osmotic repulsion between the negatively charged surface of the glass and the elastomer.

Acute outcome of chronic total occlusion (CTO) recanalizsation in the elderly

Objectives: Percutaneous coronary intervention (PCI) of total chronic total occlusion (CTO) still remains a major challenge in interventional cardiology. There is only insignificant knowledge reported in the literature about age differences in CTO recanalization. We analyzed in this study the issue of the impact of age on procedural characteristics, complications and short-term outcome. Methods: Between 2012-2016 we included 440 patients. They underwent PCI for at least one CTO. Antegrade and retrograde CTO techniques were applied. The retrograde approach was used only after failed antegrade intervention. Continuous data are presented as the mean ± standard deviation; categorical data are presented as numbers and percentages unless otherwise specified. We used Twosamplet- t-test with equal variance to test the significant differences of the variables between the two cohorts. Results: Procedural success proved independently of age. There was no significant interaction between age and procedural success (p=0.5). Complication rates were low in both groups (2.7% vs. 4%; p=0,4) with no difference in statistical significance. Conclusions: Our study suggests that in an aging society patients with severe coronary artery disease and chronical total occlusions an interventional therapy should be used more intensively. It can be performed safe and feasible.

Erratum: Higgs Boson Pair Production in Gluon Fusion at Next-to-Leading Order with Full Top-Quark Mass Dependence [Phys. Rev. Lett. 117, 012001 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.117.012001.

Higgs Boson Pair Production in Gluon Fusion at Next-to-Leading Order with Full Top-Quark Mass Dependence.

We present the calculation of the cross section and invariant mass distribution for Higgs boson pair production in gluon fusion at next-to-leading order (NLO) in QCD. Top-quark masses are fully taken into account throughout the calculation. The virtual two-loop amplitude has been generated using an extension of the program GoSam supplemented with an interface to Reduze for the integral reduction. The occurring integrals have been calculated numerically using the program SecDec. Our results, including the full top-quark mass dependence for the first time, allow us to assess the validity of various approximations proposed in the literature, which we also recalculate. We find substantial deviations between the NLO result and the different approximations, which emphasizes the importance of including the full top-quark mass dependence at NLO.

Asymmetric ring structure of Vps4 required for ESCRT-III disassembly.

The vacuolar protein sorting 4 AAA-ATPase (Vps4) recycles endosomal sorting complexes required for transport (ESCRT-III) polymers from cellular membranes. Here we present a 3.6-Å X-ray structure of ring-shaped Vps4 from Metallosphera sedula (MsVps4), seen as an asymmetric pseudohexamer. Conserved key interface residues are shown to be important for MsVps4 assembly, ATPase activity in vitro, ESCRT-III disassembly in vitro and HIV-1 budding. ADP binding leads to conformational changes within the protomer, which might propagate within the ring structure. All ATP-binding sites are accessible and the pseudohexamer binds six ATP with micromolar affinity in vitro. In contrast, ADP occupies one high-affinity and five low-affinity binding sites in vitro, consistent with conformational asymmetry induced on ATP hydrolysis. The structure represents a snapshot of an assembled Vps4 conformation and provides insight into the molecular motions the ring structure undergoes in a concerted action to couple ATP hydrolysis to ESCRT-III substrate disassembly.

Renormalization scheme dependence of the two-loop QCD corrections to the neutral Higgs-boson masses in the MSSM.

Reaching a theoretical accuracy in the prediction of the lightest MSSM Higgs-boson mass, [Formula: see text], at the level of the current experimental precision requires the inclusion of momentum-dependent contributions at the two-loop level. Recently two groups presented the two-loop QCD momentum-dependent corrections to [Formula: see text] (Borowka et al., Eur Phys J C 74(8):2994, 2014; Degrassi et al., Eur Phys J C 75(2):61, 2015), using a hybrid on-shell-[Formula: see text] scheme, with apparently different results. We show that the differences can be traced back to a different renormalization of the top-quark mass, and that the claim in Ref. Degrassi et al. (Eur Phys J C 75(2):61, 2015) of an inconsistency in Ref. Borowka et al. (Eur Phys J C 74(8):2994, 2014) is incorrect. We furthermore compare consistently the results for [Formula: see text] obtained with the top-quark mass renormalized on-shell and [Formula: see text]. The latter calculation has been added to the FeynHiggs package and can be used to estimate missing higher-order corrections beyond the two-loop level.

Analysis of anabolic androgenic steroids as sulfate conjugates using high performance liquid chromatography coupled to tandem mass spectrometry.

Improvements in doping analysis can be effected by speeding up analysis time and extending the detection time. Therefore, direct detection of phase II conjugates of doping agents, especially anabolic androgenic steroids (AAS), is proposed. Besides direct detection of conjugates with glucuronic acid, the analysis of sulfate conjugates, which are usually not part of the routine doping control analysis, can be of high interest. Sulfate conjugates of methandienone and methyltestosterone metabolites have already been identified as long-term metabolites. This study presents the synthesis of sulfate conjugates of six commonly used AAS and their metabolites: trenbolone, nandrolone, boldenone, methenolone, mesterolone, and drostanolone. In the following these sulfate conjugates were used for development of a fast and easy analysis method based on sample preparation using solid phase extraction with a mixed-mode sorbent and detection by high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Validation demonstrated the suitability of the method with regard to the criteria given by the technical documents of the World Anti-Doping Agency (WADA). In addition, suitability has been proven by successful detection of the synthesized sulfate conjugates in excretion urines and routine doping control samples.

SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef.

HIV-1 Nef and the unrelated mouse leukaemia virus glycosylated Gag (glycoGag) strongly enhance the infectivity of HIV-1 virions produced in certain cell types in a clathrin-dependent manner. Here we show that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and SERINC5 into HIV-1 virions to an extent that correlates with infectivity enhancement. Silencing of both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. The infectivity of nef-deficient virions increased more than 100-fold when produced in double-knockout human CD4(+) T cells that lack both SERINC3 and SERINC5, and re-expression experiments confirmed that the absence of SERINC3 and SERINC5 accounted for the infectivity enhancement. Furthermore, SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. SERINC3 and SERINC5 are highly expressed in primary human HIV-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat HIV/AIDS.

Diffusion chamber system for testing of collagen-based cell migration barriers for separation of ligament enthesis zones in tissue-engineered ACL constructs.

A temporary barrier separating scaffold zones seeded with different cell types prevents faster growing cells from overgrowing co-cultured cells within the same construct. This barrier should allow sufficient nutrient diffusion through the scaffold. The aim of this study was to test the effect of two variants of collagen-based barriers on macromolecule diffusion, viability, and the spreading efficiency of primary ligament cells on embroidered scaffolds. Two collagen barriers, a thread consisting of a twisted film tape and a sponge, were integrated into embroidered poly(lactic-co-caprolactone) and polypropylene scaffolds, which had the dimension of lapine anterior cruciate ligaments (ACL). A diffusion chamber system was designed and established to monitor nutrient diffusion using fluorescein isothiocyanate-labeled dextran of different molecular weights (20, 40, 150, 500 kDa). Vitality of primary lapine ACL cells was tested at days 7 and 14 after seeding using fluorescein diacetate and ethidium bromide staining. Cell spreading on the scaffold surface was measured using histomorphometry. Nuclei staining of the cross-sectioned scaffolds revealed the penetration of ligament cells through both barrier types. The diffusion chamber was suitable to characterize the diffusivity of dextran molecules through embroidered scaffolds with or without integrated collagen barriers. The diffusion coefficients were generally significantly lower in scaffolds with barriers compared to those without barriers. No significant differences between diffusion coefficients of both barrier types were detected. Both barriers were cyto-compatible and prevented most of the ACL cells from crossing the barrier, whereby the collagen thread was easier to handle and allowed a higher rate of cell spreading.