High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer

Background: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. Patients and Methods: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles ( 3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. Results: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses ( median cumulative dose 339 mg/m(2)) was administered ( range: 2 - 18). The overall response rate was 48.1% ( 95% CI: 34 - 61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months ( intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. Conclusion: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status. Copyright (C) 2005 S. Karger AG, Basel

Results and Performance Simulations of the Main Linac Design for BERLinPro

The Berlin Energy Recovery Linac Project BERLinPro is designed to develop and demonstrate CW LINAC technology for 100 mA class ERLs. High current operation requires an effective damping of higher ordermodes HOMs of the 1.3 GHz main linac cavities. We have studied elliptical seven cell cavities damped by five waveguides at the adjacent beam tubes. Eigenmode calculations for geometrical figures of merit show that the present design should allow successful cw linac operation at the maximum beam current of 100 mA 77pC bunch charge. In this paper the progress in HOM calculations to avoid beam breakup instabilities for the favored cavity structure is presente

Human iPSC-derived neurons and cerebral organoids establish differential effects of germline NF1 gene mutations

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis

Neurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T\u3eC, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1

Pancreatectomy for metastasis to the pancreas from colorectal cancer and reconstruction of superior mesenteric vein: a case report

<p>Abstract</p> <p>Introduction</p> <p>Tumors of the pancreatic head can infiltrate the superior mesenteric vein. In such cases, the deep veins of the lower limbs can serve as suitable autologous conduits for superior mesenteric vein reconstruction after its resection. Few data exist, however, describing the technique and the immediate patency of such reconstruction.</p> <p>Case report</p> <p>We present the case of a 70-year-old Caucasian man with a metachronous metastasis of colon cancer and infiltration of the uncinate pancreatic process, on the anterior surface of which the tumor was located. <it>En bloc </it>resection of the tumor was performed with resection of the superior mesenteric vein and reconstruction. A 10 cm segment of the superficial femoral vein was harvested for the reconstruction. The superficial femoral vein segment was inter-positioned in an end-to-end fashion. The post-operative conduit patency was documented ultrasonographically immediately post-operatively and after a six-month period. The vein donor limb presented subtle signs of post-operative venous hypertension with edema, which was managed with compression stockings and led to significant improvement after six months.</p> <p>Conclusion</p> <p>In cases of exploratory laparotomies with high clinical suspicion of pancreatic involvement, the potential need for vascular reconstruction dictates the preparation for leg vein harvest in advance. The superficial femoral vein provides a suitable conduit for the reconstruction of the superior mesenteric vein. This report supports the uncomplicated nature of this technique, since few data exist about this type of reconstruction.</p

Generalized model for dynamic percolation

We study the dynamics of a carrier, which performs a biased motion under the influence of an external field E, in an environment which is modeled by dynamic percolation and created by hard-core particles. The particles move randomly on a simple cubic lattice, constrained by hard-core exclusion, and they spontaneously annihilate and re-appear at some prescribed rates. Using decoupling of the third-order correlation functions into the product of the pairwise carrier-particle correlations we determine the density profiles of the "environment" particles, as seen from the stationary moving carrier, and calculate its terminal velocity, V_c, as the function of the applied field and other system parameters. We find that for sufficiently small driving forces the force exerted on the carrier by the "environment" particles shows a viscous-like behavior. An analog Stokes formula for such dynamic percolative environments and the corresponding friction coefficient are derived. We show that the density profile of the environment particles is strongly inhomogeneous: In front of the stationary moving carrier the density is higher than the average density, $\rho_s$, and approaches the average value as an exponential function of the distance from the carrier. Past the carrier the local density is lower than $\rho_s$ and the relaxation towards $\rho_s$ may proceed differently depending on whether the particles number is or is not explicitly conserved.Comment: Latex, 32 pages, 4 ps-figures, submitted to PR

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Isolated communities of Epsilonproteobacteria in hydrothermal vent fluids of the Mariana Arc seamounts

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in FEMS Microbiology Ecology 73 (2010): 538-549, doi:10.1111/j.1574-6941.2010.00910.x.Low-temperature hydrothermal vent fluids represent access points to diverse microbial communities living in oceanic crust. This study examined the distribution, relative abundance, and diversity of Epsilonproteobacteria in 14 low-temperature vent fluids from 5 volcanically active seamounts of the Mariana Arc using a 454 tag sequencing approach. Most vent fluids were enriched in cell concentrations compared to background seawater, and quantitative PCR results indicated all fluids were dominated by bacteria. Operational taxonomic unit (OTU)-based statistical tools applied to 454 data show that all vents from the northern end of the Marian Arc grouped together, to the exclusion of southern arc seamounts, which were as distinct from one another as they were from northern seamounts. Statistical analysis also showed a significant relationship between seamount and individual vent groupings, suggesting that community membership may be linked to geographical isolation and not geochemical parameters. However, while there may be large-scale geographic differences, distance is not the distinguishing factor in microbial community composition. At the local scale, most vents host a distinct population of Epsilonprotoebacteria, regardless of seamount location. This suggests there may be barriers to exchange and dispersal for these vent endemic microorganisms at hydrothermal seamounts of the Mariana Arc.This work was supported by a National Research Council Research Associateship Award and L’Oréal USA Fellowship (J.A.H.), NASA Astrobiology Institute Cooperative Agreement NNA04CC04A (M.L.S.), the Alfred P. Sloan Foundation’s ICoMM field project, and the W. M. Keck Foundation. This publication is [partially] funded by the Joint Institute for the Study of the Atmosphere and Ocean (JISAO) under NOAA Cooperative Agreement No. NA17RJ1232, Contribution #1814