Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma

Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity

Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published.Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina.Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

A Cerium M-Edge X-ray Absorption Study of the CeM₂ Compounds, Where M Is Mg, Al, Fe, Co, Ni, Ru and Rh

The cerium valence in the CeM2 compounds, where M is magnesium, aluminum, iron, cobalt, nickel, ruthenium and rhodium, has been measured at room temperature by X-ray absorption at the cerium M-edge. The observed valencies, which agree with previous more limited measurements made at the cerium LIII-edge, extend the study to additional compounds and lead to the conclusion that the relationship between the cerium volume and its valence in the CeM2 compounds is not straightforward. The results show a clear linear increase in the cerium valence with the atomic number of the metal M and indicate that the increase in the cerium valence from 3.05 in CeMg2 to 3.24 in CeRh2 results from an increase in the hybridization between the cerium 4f orbitals and the highest occupied M orbitals

Cerium M-Edge X-ray Absorption and an Iron L-Edge Magnetic Circular Dichroism Study of the Ce₂Fe₁₇₋ₓMₓ Solid Solutions, Where M Is Al and Si

The cerium M-edge X-ray absorption spectra and the iron L-edge magnetic circular dichroism spectra of the Ce2Fe17-xMx solid solutions, where M is aluminum and silicon, were measured at room temperature. The cerium M-edge spectra was used to determine the variation in the valence of cerium in the solid solutions. The resulting values, which range from 3.20 in Ce2Fe16.8Si0.2 to 3.02 in Ce2Fe6Al11, decrease linearly with x in both series, but the decrease is twice as large in Ce2Fe17-xSix. Interestingly, the resulting valencies are quantitatively different from those determined using cerium L-edge X-ray absorption data, but the qualitative trends in the valence with metalloid substitution is the same using either the cerium L- or M-edge data. The cerium valencies also correlate linearly with the cerium Wigner-Seitz cell volumes, but with a positive slope for the silicon and a negative slope for the aluminum solid solutions. This difference results because of the more extensive cerium-silicon covalent bonding interaction in Ce2Fe17-xSix as compared to the cerium-aluminum interaction in Ce2Fe17-xAlx. The iron L-edge magnetic circular dichroism spectra indicate that a non-zero iron orbital moment is coupled parallel to the iron spin moment. The orbital moments range from 0.0 to 0.2 µB and reveal that the orbital moments are probably independent of x and are ca. 0.07 µB for both series of solid solutions. The cerium M-edge magnetic circular dichroism spectra reveal no dependence upon the relative orientation of the magnetization or the photon helicity, indicating that there is no 4f magnetic moment associated with cerium in these solid solutions

Epidermal Notch1 recruits ROR gamma(+) group 3 innate lymphoid cells to orchestrate normal skin repair

Notch has a well-defined role in controlling cell fate decisions in the embryo and the adult epidermis and immune systems, yet emerging evidence suggests Notch also directs non-cell-autonomous signalling in adult tissues. Here, we show that Notch1 works as a damage response signal. Epidermal Notch induces recruitment of immune cell subsets including RORg gamma+ ILC3s into wounded dermis; ROR gamma+ ILC3s are potent sources of IL17F in wounds and control immunological and epidermal cell responses. Mice deficient for ROR gamma+ ILC3s heal wounds poorly resulting from delayed epidermal proliferation and macrophage recruitment in a CCL3-dependent process. Notch1 upregulates TNF alpha and the ILC3 recruitment chemokines CCL20 and CXCL13. TNF alpha, as a Notch1 effector, directs ILC3 localization and rates of wound healing. Altogether these findings suggest that Notch is a key stress/injury signal in skin epithelium driving innate immune cell recruitment and normal skin tissue repair