Toward the total synthesis of spirastrellolide A. Part 3: Intelligence gathering and preparation of a ring-expanded analogue

Different methods for the formation of the C.25–C.26 bond of spirastrellolide A (1) are evaluated that might qualify for the end game of the projected total synthesis, with emphasis on metathetic ways to forge the macrocyclic frame

Sub-Wavelength Terahertz Spin-Flip Laser Based on a Magnetic Point-Contact Array

We present a novel design for a single-mode, truly sub-wavelength THz disk laser based on a nano-composite gain medium comprising an array of metal/ferromagnetic point contacts embedded in a thin dielectric layer. Stimulated emission of light occurs in the point contacts as a result of spin-flip relaxation of spin-polarized electrons that are injected from the ferromagnetic side of the contacts. Ultra-high electrical current densities in the contacts and a dielectric material with a large refractive index, neither condition being achievable in conventional semiconductor media, allows the thresholds of lasing to be overcome for the lowest-order modes of the disk, hence making single-mode operation possible.Comment: 9 pages,4 figure

Toward the Total Synthesis of Spirastrellolide A. Part 2: Conquest of the Northern Hemisphere

North and South: The unique biological activity of the natural product spirastrellolide A renders it an attractive lead for anticancer agents. The southern hemisphere (C1–C25) and the northern hemisphere (including the chlorinated [5,6,6]-bis-spiroacetal entity and the lateral C42–C47 chain) are prepared by concise and efficient routes. Consequently, the entire carbon framework of this potent phosphatase inhibitor, which contains 21 chiral centers, is prepared in an optically active form, and an important step toward structure determination by total synthesis is achieved

Electrically Switchable Photonic Molecule Laser

We have studied the coherent intercavity coupling of the evanescent fields of the whispering gallery modes of two terahertz quantum-cascade lasers implemented as microdisk cavities. The electrically pumped single-mode operating microcavities allow to electrically control the coherent mode coupling for proximity distances of the cavities up to 30-40 \mu\m. The optical emission of the strongest coupled photonic molecule can be perfectly switched by the electrical modulation of only one of the coupled microdisks. The threshold characteristics of the strongest coupled photonic molecule demonstrates the linear dependence of the gain of a quantum-cascade laser on the applied electric field.Comment: 4 pages, 4 figure

Toward the Total Synthesis of Spirastrellolide A. Part 1: Strategic Considerations and Preparation of the Southern Domain

North and South: The unique biological activity of the natural product spirastrellolide A renders it an attractive lead for anticancer agents. The southern hemisphere (C1–C25) and the northern hemisphere (including the chlorinated [5,6,6]-bis-spiroacetal entity and the lateral C42–C47 chain) are prepared by concise and efficient routes. Consequently, the entire carbon framework of this potent phosphatase inhibitor, which contains 21 chiral centers, is prepared in an optically active form, and an important step toward structure determination by total synthesis is achieved

The use of mid-infrared spectrometry to estimate the ration composition of lactating dairy cows

The composition of cow milk is strongly affected by the feeding regimen. Because milk components are routinely determined using mid-infrared (MIR) spectrometry, MIR spectra could also be used to estimate an animal’s ration composition. The objective of this study was to determine whether and how well amounts of dry matter intake and the proportions of concentrates, hay, grass silage, maize silage, and pasture in the total ration can be estimated using MIR spectra at an individual animal level. A total of 10,200 milk samples and sets of feed intake data were collected from 90 dairy cows at 2 experimental farms of the Agricultural Research and Education Centre in Raumberg-Gumpenstein, Austria. For each run of analysis, the data set was split into a calibration and a validation data set in a 40:60 ratio. Estimated ration compositions were calculated using a partial least squares regression and then compared with the respective observed ration compositions. In separate analyses, the factors milk yield and concentrate intake were included as additional predictors. To evaluate accuracy, the coefficient of determination (R2) and ratio to performance deviation were used. The highest R2 values (for kg of dry matter intake/ for % of ration) for the individual feedstuffs were as follows: pasture, 0.63/0.66; grass silage, 0.32/0.43; concentrate intake, 0.39/0.34; maize silage, 0.32/0.33; and hay, 0.15/0.16. Estimation of groups of feedstuffs (forages, energy-dense feedstuffs) mostly resulted in R2 values >0.50. Including the parameters milk yield or concentrate intake improved R2 values by up to 0.21, with an average improvement of 0.04. The results of this study indicate that not all ration components may be estimated equally accurately. Even if some estimates are good on average, there may be strong deviations between estimated and observed values in individual data sets, and therefore individual estimates should not be overemphasized. Further research including pooled samples (e.g., bulk milk, farm samples) or variations in ration composition is called for

Potenzial der Mid-Infrarot-Spektrometrie bei Kuhmilchproben zur Abschätzung der Rationszusammensetzung

Milk composition of dairy animals is influenced by the composition of the ration fed. The objective of this study was to determine if the percentages and absolute amounts of hay, grass silage, pasture, maize silage and concentrate in the feed ration can be estimated using MIR spectrometry of milk. A total of 10200 milk samples from 90 dairy cows were collected, and the intakes of all ration components were measured. Using partial least squares regression (PLS), equations were developed to estimate ration compositions corresponding to each milk sample. To evaluate accuracy, the correlation between observed and estimated values (R) and ratio to performance (RPD) were used. Notable R values (for kg/for %) were observed for the ration proportion of pasture (0.85/0.87), maize silage (0.74/0.75) and concentrate intake (0.75/0.73). Estimation of groups of feedstuffs (all forages, energy-dense feedstuffs) resulted in R values of >0.8. Including the parameters milk yield and/or concentrate intake into PLS improved R values by up to 0.08. The results indicate a potential use of MIR spectra as a promising predictor for ration composition of dairy cows

Gemcitabine and carboplatin in intensively pretreated patients with metastatic breast cancer

Background: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. Patients and Methods: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. Results: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombo-cytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. Conclusion: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2). Copyright (c) 2008 S. Karger AG, Basel

Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study

Abemaciclib; Adjuvant; Early breast cancerAbemaciclib; Adjuvant; Càncer de mama precoçAbemaciclib; Adyuvante; Cáncer de mama precozBackground Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. Patients and methods This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. Results At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Conclusion Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.This work was supported by the sponsor (Eli Lilly and Company) and designed together with the study Executive Committee (no grant number)

HLA-J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer

The human leukocyte antigen (HLA) genes are cell-surface proteins, essential for immune cell interaction. HLA-G is known for their high immunosuppressive effect and its potential as predictive marker in breast cancer. However, nothing is known about the HLA-J and its immunosuppressive, prognostic and predictive features, as it is assumed to be a pseudogene by in silico sequence interpretation. HLA-J, ESR1, ERBB2, KRT5 and KRT20 mRNA expression were analysed in 29 fresh frozen breast cancer biopsies and their corresponding resectates obtained from patients treated with neoadjuvant chemotherapy (NACT). mRNA was analysed with gene specific TaqMan-based Primer/Probe sets and normalized to Calmodulin 2. All breast cancer samples did express HLA-J and frequently increased HLA-J mRNA levels after NACT. HLA-J mRNA was significantly associated with overexpression of the ESR1 mRNA status (Spearman ρ 0,5679; p = 0.0090) and KRT5 mRNA (Spearman ρ 0,6121; p = 0.0041) in breast cancer core biopsies and dominated in luminal B subtype. Kaplan Meier analysis revealed that an increase of HLA-J mRNA expression after NACT had worse progression free survival (p = 0,0096), indicating a counterreaction of tumor tissues presumably to prevent elimination by enhanced immune infiltration induced by NACT. This counterreaction is associated with worse prognosis. To our knowledge this is the first study identifying HLA-J as a new predictive marker in breast cancer being involved in immune evasion mechanisms.Humane Leukozyten-Antigene (HLA) sind Proteine auf der Zelloberfläche, die essenziell für die Immunzellinteraktion sind. HLA-G ist für seine hohe immunosuppressive Wirkung sowie als potenzieller prädikativer Marker für Brustkrebs bekannt. Dagegen ist kaum etwas über HLA-J und seine immunosuppressiven, prognostischen und prädiktiven Eigenschaften bekannt, da es basierend auf In-silico-Sequenzanalysen als „Pseudogen“ interpretiert wurde. Die Expression von HLA-J, ESR1, ERBB2, KRT5 und KRT20 mRNA wurde in 29 frisch gefrorenen Brustkrebsbiopsien analysiert und mit den klinisch-pathologischen Daten von Patientinnen, welche mit neoadjuvanter Chemotherapie behandelt wurden, verglichen. Die mRNA-Expression wurde mit genspezifischen TaqMan-basierten Primer/Probe-Sets analysiert und auf Calmodulin 2 normalisiert. Alle Gewebeproben von Patientinnen mit Brustkrebs exprimierten HLA-J, und der HLA-J-mRNA-Spiegel war nach NACT oft erhöht. In den Brustkrebsstanzbiopsien war die HLA-J-mRNA-Expression signifikant mit der Überexpression von ESR1-mRNA (Spearmans ρ 0,5679; p = 0,0090) und KRT5-mRNA (Spearmans ρ 0,6121; p = 0,0041) assoziiert und dominierte im Luminal-B-Subtyp. Die Kaplan-Meier-Analyse zeigte, dass ein Anstieg der HLA-J-mRNA-Expression nach NACT mit einem schlechteren progressionsfreien Überleben einhergeht (p = 0,0096), womöglich als Gegenreaktion des Tumorgewebes, um eine Eliminierung durch tumorinfiltrierende Lymphozyten, welche durch eine NACT induziert wurden, zu verhindern. Diese Gegenreaktion ist mit einer schlechteren Prognose assoziiert. Soweit uns bekannt, handelt es sich hierbei um die erste Studie, die HLA-J als neuen prädiktiven Marker im Brustkrebs identifiziert hat und möglicherweise zur Immunevasion beiträgt