Aromatase inhibitor strategies in metastatic breast cancer

Despite ongoing therapeutic innovations, metastatic breast cancer (MBC) remains a treatable but incurable disease. In the developed world, a diagnosis of MBC without a preceding diagnosis of early stage disease is a rare event. However, approximately one-third of women with early stage breast cancer ultimately experience a distant recurrence. Because the majority of breast cancers express estrogen and/or progesterone receptors and are accordingly considered hormone-sensitive, therapeutic strategies that interfere with hormone-mediated tumorigenesis have been a cornerstone of the breast cancer management paradigm for decades. Historically, the selective estrogen receptor modulator tamoxifen has been the most extensively studied and widely used hormone maneuver in breast cancer. However, a recent therapeutic innovation, namely the successful development of third-generation aromatase inhibitors (AIs), has had a dramatic impact on the treatment paradigm for women with hormone-sensitive MBC. Because of the demonstrated efficacy in postmenopausal breast cancer patients, the generally favorable side-effect profile, and the convenience of oral administration, AIs are now in widespread clinical use. Currently, there are three clinically available third-generation AIs: two reversible, nonsteroidal AIs, letrozole and anastrozole; and one irreversible, steroidal AI, exemestane. All three agents are at least as efficacious as tamoxifen as monotherapy for postmenopausal women with hormone-sensitive MBC. Current clinical research aims to improve upon existing strategies by evaluating AIs in combination with systemic chemotherapy regimens and/or novel targeted agents. It is hoped that these therapeutic innovations will lead to ongoing improvements in quality of life parameters and ideally survival for women with hormone-sensitive MBC

Synaptic tagging and capture : differential role of distinct calcium/calmodulin kinases in protein synthesis-dependent long-term potentiation

Weakly tetanized synapses in area CA1 of the hippocampus that ordinarily display long-term potentiation lasting ~3 h (called early-LTP) will maintain a longer-lasting change in efficacy (late-LTP) if the weak tetanization occurs shortly before or after strong tetanization of an independent, but convergent, set of synapses in CA1. The synaptic tagging and capture hypothesis explains this heterosynaptic influence on persistence in terms of a distinction between local mechanisms of synaptic tagging and cell-wide mechanisms responsible for the synthesis, distribution, and capture of plasticity-related proteins (PRPs). We now present evidence that distinct CaM kinase (CaMK) pathways serve a dissociable role in these mechanisms. Using a hippocampal brain-slice preparation that permits stable long-term recordings in vitro for >10 h and using hippocampal cultures to validate the differential drug effects on distinct CaMK pathways, we show that tag setting is blocked by the CaMK inhibitor KN-93 (2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) that, at low concentration, is more selective for CaMKII. In contrast, the CaMK kinase inhibitor STO-609 [7H-benzimidazo(2,1-a)benz(de)isoquinoline-7-one-3-carboxylic acid] specifically limits the synthesis and/or availability of PRPs. Analytically powerful three-pathway protocols using sequential strong and weak tetanization in varying orders and test stimulation over long periods of time after LTP induction enable a pharmacological dissociation of these distinct roles of the CaMK pathways in late-LTP and so provide a novel framework for the molecular mechanisms by which synaptic potentiation, and possibly memories, become stabilized

Bifurcated Dacron patch for simultaneous superficial femoroplasty and profundoplasty: a case report

<p>Abstract</p> <p>Introduction</p> <p>Common femoral endarterectomy and/or profundoplasty are procedures commonly performed on patients with functional or critical limb ischaemia.</p> <p>Case presentation</p> <p>A 61-year-old Caucasian British man was referred to our unit with recent onset of severe left calf and thigh claudication and rest pain in his left foot. Magnetic resonance angiography revealed occlusive disease of the left common femoral artery, proximal superficial and profunda femoral arteries.</p> <p>These findings were confirmed intraoperatively and an endarterectomy was subsequently performed from the left common femoral onto the proximal superficial femoral artery and then onto the proximal profunda femoris artery. The arteriotomy was closed with a Dacron patch and its distal end was bisected into two to patch the profunda femoris and superficial femoral arteries. The patient made an uneventful recovery with a full clinical improvement of his left leg.</p> <p>Conclusion</p> <p>A Dacron patch that was bisected distally to make a bifurcated patch for simultaneous patching of the profunda femoris artery and the superficial femoral artery was used to treat our patient's occlusions. This technique has not been previously described in the published literature and we have found it easy to do with little time added to conventional operation.</p

artcat: Sample-size calculation for an ordered categorical outcome

We describe a new command, artcat, that calculates sample size or power for a randomized controlled trial or similar experiment with an ordered categorical outcome, where analysis is by the proportional-odds model. artcat implements the method of Whitehead (1993, Statistics in Medicine 12: 2257–2271). We also propose and implement a new method that 1) allows the user to specify a treatment effect that does not obey the proportional-odds assumption, 2) offers greater accuracy for large treatment effects, and 3) allows for noninferiority trials. We illustrate the command and explore the value of an ordered categorical outcome over a binary outcome in various settings. We show by simulation that the methods perform well and that the new method is more accurate than Whitehead’s method

miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia

Cell-type-specific optogenetic stimulation of the locus coeruleus induces slow-onset potentiation and enhances everyday memory in rats

Memory formation is typically divided into phases associated with encoding, storage, consolidation, and retrieval. The neural determinants of these phases are thought to differ. This study first investigated the impact of the experience of novelty in rats incurred at a different time, before or after, the precise moment of memory encoding. Memory retention was enhanced. Optogenetic activation of the locus coeruleus mimicked this enhancement induced by novelty, both when given before and after the moment of encoding. Optogenetic activation of the locus coeruleus also induced a slow-onset potentiation of field potentials in area CA1 of the hippocampus evoked by CA3 stimulation. Despite the locus coeruleus being considered a primarily noradrenergic area, both effects of such stimulation were blocked by the dopamine D1/D5 receptor antagonist SCH 23390. These findings substantiate and enrich the evidence implicating the locus coeruleus in cellular aspects of memory consolidation in hippocampus.</p

Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.

Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies

Has the Universe always expanded ?

We consider a cosmological setting for which the currently expanding era is preceded by a contracting phase, that is, we assume the Universe experienced at least one bounce. We show that scalar hydrodynamic perturbations lead to a singular behavior of the Bardeen potential and/or its derivatives (i.e. the curvature) for whatever Universe model for which the last bounce epoch can be smoothly and causally joined to the radiation dominated era. Such a Universe would be filled with non-linear perturbations long before nucleosynthesis, and would thus be incompatible with observations. We therefore conclude that no observable bounce could possibly have taken place in the early universe if Einstein gravity together with hydrodynamical fluids is to describe its evolution, and hence, under these conditions, that the Universe has always expanded.Comment: 11 pages, LaTeX-ReVTeX, no figures, submitted to PR

Caltech Faint Galaxy Redshift Survey. XI. The Merger Rate to Redshift 1 from Kinematic Pairs

The rate of mass accumulation due to galaxy merging depends on the mass, density, and velocity distribution of galaxies in the near neighborhood of a host galaxy. The fractional luminosity in kinematic pairs combines all of these effects in a single estimator that is relatively insensitive to population evolution. Here we use a k-corrected and evolution-compensated volume-limited sample having an R-band absolute magnitude of M^(k,e)_R ≤ -19.8 + 5 log h mag drawing about 300 redshifts from the Caltech Faint Galaxy Redshift Survey and 3000 from the Canadian Network for Observational Cosmology field galaxy survey to measure the rate and redshift evolution of merging. The combined sample has an approximately constant comoving number and luminosity density from redshift 0.1 to 1.1 (Ω_M = 0.2, Ω_Λ = 0.8); hence, any merger evolution will be dominated by correlation and velocity evolution, not density evolution. We identify kinematic pairs with projected separations less than either 50 or 100 h^(-1) kpc and rest-frame velocity differences of less than 1000 km s^(-1). The fractional luminosity in pairs is modeled as f_L(Δv, r_p, M^(k,e)_τ)(1 + z)^(m,L), where [f_L, m_L] are [0.14 ± 0.07, 0 ± 1.4] and [0.37 ± 0.7, 0.1 ± 0.5] for r_p ≤ 50 and 100 h^(-1) kpc, respectively (Ω_M = 0.2, Ω_Λ = 0.8). The value of mL is about 0.6 larger if Λ = 0. To convert these redshift-space statistics to a merger rate, we use the data to derive a conversion factor to a physical space pair density, a merger probability, and a mean in-spiral time. The resulting mass accretion rate per galaxy (M_1, M_2 ≥ 0.2M*) is 0.02 ± 0.01(1 + z)^(0.1±0.5)M* Gyr^(-1). Present-day high-luminosity galaxies therefore have accreted approximately 0.15M* of their mass over the approximately 7 Gyr to redshift 1. Since merging is likely only weakly dependent on the host mass, the fractional effect, δM/M 0.15M*/M, is dramatic for lower mass galaxies but is, on the average, effectively perturbative for galaxies above 1M*