Stable Molecular Metal [ Pd(dddt)2_{\bf 2}] Ag1.54_{\bf 1.54}Br3.50_{\bf 3.50}: Synthesis, Crystal Structure, Transport Properties and Electronic Band Structure

The synthesis, crystal and electronic band structures as well as conducting properties of the new stable molecular metal [ Pd(dddt)$_2$] Ag$_{1.54}$Br$_{3.50}$ (dddt = 5,6-dihydro-1,4-dithiin-2,3-dithiolato) are reported. the crystal structure contains layers of donor cations alternating with layers of silver bromide complex anions along the $a$ axis of the unit cell. The Ag and Br atoms are disordered in the anion layer. The conducting layers contain uniform stacks of the translationally equivalent Pd(dddt)$_2$ cations along the $c$-axis with a Pd$...$Pd distance of 4.157(2) Å. Within the cation layers there are shortened interstack S$...$S contacts (3.49(3) and 3.56(3) Å). The temperature dependence of the resistivity exhibits metallic behaviour down to 1.3 K. The resistivity anisotropy ($\rho_a^*/\rho_{bc}$) at room temperature is about 600 and does not change considerably when decreasing the temperature down to 4.2 K. The origin of the metallic conductivity of [ Pd(dddt)$_2$] Ag$_{1.54}$Br$_{3.50}$ as well as the stability of this salt with respect to metal-to-insulator transitions is explained on the basis of tight binding band structure calculations

Mechanisms of glucosa hypersensitivity in ß-cells from normoglycemic, partially pancreatectomized mice

Increased beta-cell sensitivity to glucose precedes the loss of glucose-induced insulin secretion in diabetic animals. Changes at the level of beta-cell glucose sensor have been described in these situations, but it is not clear whether they fully account for the increased insulin secretion. Using a euglycemic-normolipidemic 60% pancreatectomized (60%-Px) mouse model, we have studied the ionic mechanisms responsible for increased beta-cell glucose sensitivity. Two weeks after Px (Px14 group), Px mice maintained normoglycemia with a reduced beta-cell mass (0.88 +/- 0.18 mg) compared with control mice (1.41 +/- 0.21 mg). At this stage, the dose-response curve for glucose-induced insulin release showed a significant displacement to the left (P < 0.001). Islets from the Px14 group showed oscillatory electrical activity and cytosolic Ca2+ ([Ca2+]i) oscillations in response to glucose concentrations of 5.6 mmol/l compared with islets from the control group at 11.1 mmol/l. All the above changes were fully reversible both in vitro (after 48-h culture of islets from the Px14 group) and in vivo (after regeneration of beta-cell mass in islets studied 60 days after Px). No significant differences in the input resistance and ATP inhibition of ATP-sensitive K+ (K(ATP)) channels were found between beta-cells from the Px14 and control groups. The dose-response curve for glucose-induced MTT (C,N-diphenyl-N''-4,5-dimethyl thiazol 2 yl tetrazolium bromide) reduction showed a significant displacement to the left in islets from the Px14 group (P < 0.001). These results indicate that increased glucose sensitivity in terms of insulin secretion and Ca2+ signaling was not due to intrinsic modifications of K(ATP) channel properties, and suggest that the changes are most likely to be found in the glucose metabolism

Defining the optimal sequence for the systemic treatment of metastatic breast cancer

Metastatic breast cancer is a heterogeneous disease that presents in varying forms, and a growing number of therapeutic options makes it difficult to determine the best choice in each particular situation. When selecting a systemic treatment, it is important to consider the medication administered in the previous stages, such as acquired resistance, type of progression, time to relapse, tumor aggressiveness, age, comorbidities, pre- and post-menopausal status, and patient preferences. Moreover, tumor genomic signatures can identify different subtypes, which can be used to create patient profiles and design specific therapies. However, there is no consensus regarding the best treatment sequence for each subgroup of patients. During the SABCC Congress of 2014, specialized breast cancer oncologists from referral hospitals in Europe met to define patient profiles and to determine specific treatment sequences for each one. Conclusions were then debated in a final meeting in which a relative degree of consensus for each treatment sequence was established. Four patient profiles were defined according to established breast cancer phenotypes: pre-menopausal patients with luminal subtype, post-menopausal patients with luminal subtype, patients with triple-negative subtype, and patients with HER2-positive subtype. A treatment sequence was then defined, consisting of hormonal therapy with tamoxifen, aromatase inhibitors, fulvestrant, and mTOR inhibitors for pre- and post-menopausal patients; a chemotherapy sequence for the first, second, and further lines for luminal and triple-negative patients; and an optimal sequence for treatment with new antiHER2 therapies. Finally, a document detailing all treatment sequences, that had the agreement of all the oncologists, was drawn up as a guideline and advocacy tool for professionals treating patients with this disease

Natural and improved natural pastures on the reproductive performance of first-calf beef cows Pastagens naturais e melhoradas no desempenho reprodutivo de vacas de corte primíparas

This work evaluated the reproductive performance of first-calf cows at three years of age, submitted or not to protein supplementation at yearling on natural pastures. After calving, cows were managed on natural or improved pastures. The feeding managements were the following: on natural pastures as yearlings and during pregnancy, post-calving period and breeding season; on natural pastures with protein supplement as yearlings and only natural pasture during pregnancy, post-calving and breeding season; on natural pastures as yearlings and during pregnancy and on improved natural pastures (Lolium multiflorum L., Trifolium repens cv. Yi and Lotus corniculatus cv. São Gabriel) during the post-calving period and breeding season; on natural pastures with protein supplement at yearling, on natural pastures during pregnancy, and on improved natural pasture during post-calving period and breeding season. Cows did not differ on body weight, but from calving to the beginning of breeding season, cows on improved natural pastures presented higher weight gain than those on natural pastures (0.203 vs. 0.109 kg/day). Cows in post-calving on natural pastures lost 1.0 point of body condition score during mating, determinant of the lowest pregnancy rate and later conception in relation to cows on improved natural pasture. Pregnant cows presented higher body weight (440 vs. 413 kg) and body condition score (4.14 vs. 3.66 points) than open cows at the end of the breeding season.<br>O trabalho avaliou o desempenho reprodutivo de vacas primíparas aos três anos de idade, submetidas previamente ou não à suplementação protéica no sobreano sobre pastagens naturais. Após o parto, foram manejadas em pastagens naturais ou naturais melhoradas. Os manejos alimentares foram: em pastagem natural na recria e nos períodos de gestação, pós-parto e reprodutivo; em pastagem natural com suplemento protéico na recria e somente pastagem natural durante os períodos de gestação, pós-parto e reprodutivo; em pastagem natural durante a recria e período de gestação, em pastagem natural melhorada (Lolium multiflorum L., Trifolium repens cv. Yi e Lotus corniculatus L. cv. São Gabriel) nos períodos pós-parto e reprodutivo; em pastagem natural com suplemento protéico na recria, em pastagem natural no período de gestação e em pastagem natural melhorada nos períodos pós-parto e reprodutivo. As vacas não diferiram em peso corporal, porém do parto ao início do acasalamento vacas em pastagem natural melhorada tiveram maiores ganhos de peso do que as vacas mantidas em pastagem natural (0,230 vs 0,109 kg/dia). Vacas no pós-parto em pastagens naturais perderam 1,0 ponto de condição corporal durante o acasalamento, determinante da menor taxa de prenhez e de concepções mais tardias em relação às vacas em pastagem natural melhorada. Vacas que conceberam apresentaram maior peso (440 vs 413 kg) e condição corporal (4,14 vs 3,66 pontos) no final do acasalamento do que as vacas não prenhes

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Background The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. Methods In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2(days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1\u201321) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). Findings Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10\ub74 months (IQR 6\ub75\u201314\ub71) in the ipatasertib group and 10\ub72 months (6\ub70\u201313\ub76) in the placebo group. Median progression-free survival in the intention-to-treat population was 6\ub72 months (95% CI 3\ub78\u20139\ub70) with ipatasertib versus 4\ub79 months (3\ub76\u20135\ub74) with placebo (stratified hazard ratio [HR] 0\ub760, 95% CI 0\ub737\u20130\ub798; p=0\ub7037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6\ub72 months (95% CI 3\ub76\u20139\ub71) with ipatasertib versus 3\ub77 months (1\ub79\u20137\ub73) with placebo (stratified HR 0\ub759, 95% CI 0\ub726\u20131\ub732, p=0\ub718). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. Interpretation Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. Funding F Hoffmann-La Roche