286 research outputs found
Distinct endocytic pathways identified in tobacco pollen tubes using charged nanogold
In an attempt to dissect endocytosis in Nicotiana tabacum L. pollen tubes, two different probes \u2013 positively or
negatively charged nanogold \u2013 were employed. The destiny of internalized plasma membrane domains, carrying
negatively or positively charged residues, was followed at the ultrastructural level and revealed distinct endocytic
pathways. Time-course experiments and electron microscopy showed internalization of subapical plasmamembrane domains that were mainly recycled to the secretory pathway through the Golgi apparatus and a
second mainly degradative pathway involving plasma membrane retrieval at the tip. In vivo time-lapse experiments using FM4-64 combined with quantitative analysis confirmed the existence of distinct internalization regions. Ikarugamycin, an inhibitor of clathrin-dependent endocytosis, allowed us to further dissect the endocytic process: electron microscopy and time-lapse studies suggested that clathrin-dependent endocytosis occurs in the
tip and subapical regions, because recycling of positively charged nanogold to the Golgi bodies and the consignment
of negatively charged nanogold to vacuoles were affected.
However, intact positively charged-nanogold transport to vacuoles supports the idea that an endocytic pathway that does not require clathrin is also present in pollen tubes
Ultrastructural features of Mimulus aurantiacus (Scrophulariaceae) pollen tubes in vivo
Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.
BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.The authors acknowledge financial support from the UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (and NIHR Clinical Research Facility), and to The University of Cambridge and Cambridge University Hospital NHS Foundation Trust. Cambridge, King’s College London, and Newcastle are Experimental Cancer Medicine Centres.This is the accepted manuscript. The final version is available from http://www.sciencedirect.com/science/article/pii/S0959804914010922
Author Correction: Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer.
The Ground State of Graphene and Graphene Disordered by Vacancies
Graphene clusters consisting of 24 to 150 carbon atoms and hydrogen
termination at the zigzag boundary edges have been studied, as well as clusters
disordered by vacancy(s). Density Function Theory and Gaussian03 software were
used to calculate graphene relative stability, desorption energy, band gap,
density of states, surface shape, dipole momentum and electrical polarization
of all clusters by applying the hybrid exchange-correlation functional
Beke-Lee-Yang-Parr. Furthermore, infrared frequencies were calculated for two
of them. Different basis sets, 6-31g**, 6-31g* and 6-31g, depending on the
sizes of clusters are considered to compromise the effect of this selection on
the calculated results. We found that relative stability and the gap decreases
according to the size increase of the graphene cluster. Mulliken charge
variation increase with the size. For about 500 carbon atoms, a zero HOMO-LUMO
gap amount is predicted. Vacancy generally reduces the stability and having
vacancy affects the stability differently according to the location of
vacancies. Surface geometry of each cluster depends on the number of vacancies
and their locations. The energy gap changes as with the location of vacancies
in each cluster. The dipole momentum is dependent on the location of vacancies
with respect to one another. The carbon-carbon length changes according to each
covalence band distance from the boundary and vacancies. Two basis sets, 6-31g*
and 6-31g**, predict equal amount for energy, gap and surface structure, but
charge distribution results are completely different.Comment: 21 pages, 14 figures, 2 table
Puddle-Induced Resistance Oscillations in the Breakdown of the Graphene Quantum Hall Effect
Observation of the moon shadow using a new reconstruction technique in the CLUE experiment
The CLUE experiment, located in La Palma island at 2200 m a.s.l., is an array of 3Ă—3 telescope, detecting the UV
(190–230 nm) ˇCerenkov light produced by atmospheric showers. Due to the higher atmospheric absorption in the UV range than in the visible one, CLUE cannot apply existing algorithms normally used in IACT experiments to determine primary cosmic ray direction. In this paper we present a new method developed by CLUE. The algorithm performances were evaluated using simulated showers. CLUE experiment collected data in the last two years pointing to AGN sources and to Moon. The preliminary results obtained using the new technique on Crab Nebula and on Markarian 421 were presented in a previous paper. Here, we present the preliminary observation of Moon Shadow employing the new method. As described in the paper, we expect in a near future improvements on AGN sources and on Moon Shadow measurement
Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom
\ua9 The Author(s) 2024.Background: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK. Methods: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG. Results: 132 pts were included. Median age was 56 years (28–91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5–6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts. Conclusion: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience
Interplay between edge states and simple bulk defects in graphene nanoribbons
We study the interplay between the edge states and a single impurity in a
zigzag graphene nanoribbon. We use tight-binding exact diagonalization
techniques, as well as density functional theory calculations to obtain the
eigenvalue spectrum, the eigenfunctions, as well the dependence of the local
density of states (LDOS) on energy and position. We note that roughly half of
the unperturbed eigenstates in the spectrum of the finite-size ribbon hybridize
with the impurity state, and the corresponding eigenvalues are shifted with
respect to their unperturbed values. The maximum shift and hybridization occur
for a state whose energy is inverse proportional to the impurity potential;
this energy is that of the impurity peak in the DOS spectrum. We find that the
interference between the impurity and the edge gives rise to peculiar
modifications of the LDOS of the nanoribbon, in particular to oscillations of
the edge LDOS. These effects depend on the size of the system, and decay with
the distance between the edge and the impurity.Comment: 10 pages, 15 figures, revtex
A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of eribulin mesilate in combination with capecitabine
Background: Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities.
Methods: In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m² days 1–14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics.
Results: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m² day 1 for schedule 1 and 1.4 mg/m² days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m² days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy.
Conclusions: The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC
- …