Lapatinib Plus Capecitabine in Women with HER-2–Positive Advanced Breast Cancer: Final Survival Analysis of a Phase III Randomized Trial

The article presents final analyses of overall survival from a phase III trial of lapatinib and capecitabine in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer that progressed following prior therapy including trastuzumab

Extra-osseous osteochondroma-like soft tissue mass of the patello-femoral space

BACKGROUND: Extraskeletal cartilaginous tumors are uncommon. Osteochondromas usually arise from the metaphyseal region of the growing skeleton. CASE PRESENTATION: A 53 year old man presented with a three years history of anterior knee pain and inability to flex his knee more than 90°. Clinical examination and imaging studies revealed a nodular calcific mass in the anterior portion of the knee, displacing the medial portion of the patellar tendon. Following excision, histopathology confirmed the diagnosis of extra-osseous osteochondroma-like soft tissue mass, with no recurrence 24 months after surgery. CONCLUSION: An integrated clinical-pathologic diagnosis helps to clarify the nature of extraskeletal cartilaginous tumors that can arise at unusual anatomic site. Complete local surgical excision is the management of choice

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs were performed. The calculated values agree well with the available experimental data, and the main contribution to the free energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle distributions, which fall within the narrow range of −140° to −90° for all investigated compounds. The corresponding ensemble average of the coupling constants 3J(C4,H1′) is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the relative binding affinities to FtsZ, indicating their dominant contribution

The effect of hexose ratios on metabolite production in Saccharomyces cerevisiae strains obtained from the spontaneous fermentation of mezcal

Mezcal from Tamaulipas (Me´xico) is produced by spontaneous alcoholic fermentation using Agave spp. musts, which are rich in fructose. In this study eight Saccharomyces cerevisiae isolates obtained at the final stage of fermentation from a traditional mezcal winery were analysed in three semisynthetic media. Medium M1 had a sugar content of 100 g l-1 and a glucose/fructose (G/F) of 9:1. Medium M2 had a sugar content of 100 g l-1 and a G/F of 1:9. Medium M3 had a sugar content of 200 g l-1 and a G/F of 1:1. In the three types of media tested, the highest ethanol yield was obtained from the glucophilic strain LCBG-3Y5, while strain LCBG-3Y8 was highly resistant to ethanol and the most fructophilic of the mezcal strains. Strain LCBG-3Y5 produced more glycerol (4.4 g l-1) and acetic acid (1 g l-1) in M2 than in M1 (1.7 and 0.5 g l-1, respectively), and the ethanol yields were higher for all strains in M1 except for LCBG-3Y5, -3Y8 and the Fermichamp strain. In medium M3, only the Fermichamp strain was able to fully consume the 100 g of fructose l-1 but left a residual 32 g of glucose l-1. Regarding the hexose transporters, a high number of amino acid polymorphisms were found in the Hxt1p sequences. Strain LCBG-3Y8 exhibited eight unique amino acid changes, followed by the Fermichamp strain with three changes. In Hxt3p, we observed nine amino acid polymorphisms unique for the Fermichamp strain and five unique changes for the mezcal strains

Laboratory selection for an accelerated mosquito sexual development rate

<p>Abstract</p> <p>Background</p> <p>Separating males and females at the early adult stage did not ensure the virginity of females of <it>Anopheles arabiensis </it>(Dongola laboratory strain), whereas two years earlier this method had been successful. In most mosquito species, newly emerged males and females are not able to mate successfully. For anopheline species, a period of 24 h post-emergence is generally required for the completion of sexual maturation, which in males includes a 180° rotation of the genitalia. In this study, the possibility of an unusually shortened sexual maturity period in the laboratory-reared colony was investigated.</p> <p>Methods</p> <p>The effect of two different sex-separation methods on the virginity of females was tested: females separated as pupae or less than 16 h post-emergence were mated with males subjected to various doses of radiation. T-tests were performed to compare the two sex-separation methods. The rate of genitalia rotation was compared for laboratory-reared and wild males collected as pupae in Dongola, Sudan, and analysed by Z-tests. Spermatheca dissections were performed on females mated with laboratory-reared males to determine their insemination status.</p> <p>Results</p> <p>When the sex-separation was performed when adults were less than 16 h post-emergence, expected sterility was never reached for females mated with radio-sterilized males. Expected sterility was accomplished only when sexes were separated at the pupal stage. Observation of genitalia rotation showed that some males from the laboratory strain Dongola were able to successfully mate only 11 h after emergence and 42% of the males had already completed rotation. A small proportion of the same age females were inseminated. Wild males showed a much slower genitalia rotation rate. At 17 h post-emergence, 96% of the laboratory-reared males had completed genitalia rotation whereas none of the wild males had.</p> <p>Conclusion</p> <p>This colony has been cultured in the laboratory for over one hundred generations, and now has accelerated sexual maturation when compared with the wild strain. This outcome demonstrates the kinds of selection that can be expected during insect colonization and maintenance, particularly when generations are non-overlapping and similar-age males must compete for mates.</p

Convulsant Doses of a Dopamine D1 Receptor Agonist Result in Erk-Dependent Increases in Zif268 and Arc/Arg3.1 Expression in Mouse Dentate Gyrus

Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30–45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory

Color afterimages in autistic adults

It has been suggested that attenuated adaptation to visual stimuli in autism is the result of atypical perceptual priors (e.g., Pellicano and Burr in Trends Cogn Sci 16(10):504–510, 2012. doi:10.​1016/​j.​tics.​2012.​08.​009). This study investigated adaptation to color in autistic adults, measuring both strength of afterimage and the influence of top-down knowledge. We found no difference in color afterimage strength between autistic and typical adults. Effects of top-down knowledge on afterimage intensity shown by Lupyan (Acta Psychol 161:117–130, 2015. doi:10.​1016/​j.​actpsy.​2015.​08.​006) were not replicated for either group. This study finds intact color adaptation in autistic adults. This is in contrast to findings of attenuated adaptation to faces and numerosity in autistic children. Future research should investigate the possibility of developmental differences in adaptation and further examine top-down effects on adaptation

Proteolysis-Dependent Remodeling of the Tubulin Homolog FtsZ at the Division Septum in \u3ci\u3eEscherichia coli\u3c/i\u3e

During bacterial cell division a dynamic protein structure called the Z-ring assembles at the septum. The major protein in the Z-ring in Escherichia coli is FtsZ, a tubulin homolog that polymerizes with GTP. FtsZ is degraded by the two-component ATP-dependent protease ClpXP. Two regions of FtsZ, located outside of the polymerization domain in the unstructured linker and at the C-terminus, are important for specific recognition and degradation by ClpXP. We engineered a synthetic substrate containing green fluorescent protein (Gfp) fused to an extended FtsZ C-terminal tail (residues 317–383), including the unstructured linker and the C-terminal conserved region, but not the polymerization domain, and showed that it is sufficient to target a non-native substrate for degradation in vitro. To determine if FtsZ degradation regulates Z-ring assembly during division, we expressed a full length Gfp-FtsZ fusion protein in wild type and clp deficient strains and monitored fluorescent Z-rings. In cells deleted for clpX or clpP, or cells expressing protease-defective mutant protein ClpP(S97A), Z-rings appear normal; however, after photobleaching a region of the Z-ring, fluorescence recovers ~70% more slowly in cells without functional ClpXP than in wild type cells. Gfp-FtsZ(R379E), which is defective for degradation by ClpXP, also assembles into Z-rings that recover fluorescence ~2-fold more slowly than Z-rings containing Gfp-FtsZ. In vitro, ClpXP cooperatively degrades and disassembles FtsZ polymers. These results demonstrate that ClpXP is a regulator of Z-ring dynamics and that the regulation is proteolysis-dependent. Our results further show that FtsZ-interacting proteins in E. coli fine-tune Z-ring dynamics