A phase II trial of dose-dense (biweekly) paclitaxel plus carboplatin as neoadjuvant chemotherapy for operable breast cancer.

The aim of the present study is to investigate the efficacy and safety of dose-dense (biweekly) carboplatin and paclitaxel as a neoadjuvant treatment for operable breast cancer. Patients with previously untreated breast cancer (stages Ic-III) were treated with four cycles of paclitaxel (175 mg/m(2), intravenous drip, D1) and carboplatin (area under the curve of 5, D1). Patients with HER2+ disease simultaneously received trastuzumab (6 mg/kg initial dose with subsequent doses of 4 mg/kg biweekly). The primary endpoint was a pathologically complete response (pCR). Between January 2012 and February 2014, 110 patients were enrolled. The overall pCR rate was 35.45 % (39 of 110). The pCR rates for the different cancer subtypes were as follows: 10.53 % (2 of 19) among the patients with the luminal A subtype, 12.50 % (5 of 40) among the patients with the luminal B (HER2-) subtype, 58.33 % (14 of 24) among the patients with the luminal B (HER2+) subtype, 57.14 % (8 of 14) among the patients with the triple-negative subtype, and 76.92 % (10 of 13) among the patients with the HER2+ subtype. The patients experienced the following toxicity side effects: grade 3/4 neutropenia (N = 27, 24.55 %), grade 3/4 anemia (N = 6, 5.45 %), grade 3/4 thrombocytopenia (N = 2, 1.82 %), grade 3 alanine aminotransferase (ALT) elevation (N = 1, 0.91 %), grade 3 neuropathy (N = 3, 2.73 %), grade 3 pain (N = 2, 1.82 %), and grade 3 fatigue (N = 1, 0.91 %). In total, 19.09 % of the patients experienced treatment delay or discontinuation due to hematological toxicity, and one patient discontinued treatment due to non-hematological toxicity. Neoadjuvant biweekly paclitaxel plus carboplatin is a feasible therapy that achieved high pCR rates in patients with the HER2+, triple-negative, and luminal B (HER2+) cancer subtypes (NCT0205986).

Investigation of snap-through and homoclinic bifurcation of a magnet-induced buckled energy harvester by the Melnikov method.

Snap-through is used to improve the efficiencies of energy harvesters and extend their effective frequency bandwidths. This work uses the Melnikov method to explore the underlying snap-through mechanism and the conditions necessary for homoclinic bifurcations in a magnet-induced buckled energy harvester. First, an electromechanical model of the energy harvester is established analytically using the Euler-Bernoulli beam theory and the extended Hamilton's principle. Second, the Melnikov function of the model is derived, and the necessary conditions for homoclinic bifurcations and chaos are presented on the basis of this model. The analysis reveals that the distance between the magnets and the end-block mass significantly affect the thresholds for chaotic motions and the high-energy solutions. Numerical and experimental studies confirm these analytical predictions and provide guidelines for optimum design of the magnet-induced buckled energy harvester.

Spinal bombesin-recognized neurones mediate more nonhistaminergic than histaminergic sensation of itch in mice.

BACKGROUND: There may be distinct pathways for transmission of histaminergic and nonhistaminergic itch, but all scratching behaviours elicited by histamine-dependent and histamine-independent pruritogens are diminished when spinal bombesin-recognized neurones are ablated. AIM: To investigate whether there is a difference in transmission of spinal itch signals between histamine-induced itch and nonhistamine-induced itch after neurotoxic destruction of spinal bombesin-recognized neurones. METHODS: To ascertain the different relevance of spinal bombesin-recognized neurones in transmission of itch signals between these two classes of pruritogens, we determined the distribution of Fos-positive cells in the dorsal horn of spinal cord after stimulation with histamine (500 µg/site) and chloroquine (200 µg/site) in mice with spinal bombesin-recognized neurones ablated by intrathecal injection of bombesin-saporin (400 ng/5 µL). RESULTS: We found that after stimulation with both histamine and chloroquine, fewer Fos-positive cells were present in mice treated with bombesin-saporin compared with those treated with saporin alone. The reduction in Fos expression was greater with chloroquine than with histamine, and the distribution of Fos-positive cells was also different. We used biotin-labelled isolectin (IB)4, which labels one subset of C-fibres, and found that the percentages of Fos-positive cells in three areas (the dorsal to IB4-labelled region, the IB4-labelled region itself, and the ventral to IB4-labelled region) all changed significantly after intradermal injection of chloroquine, but not histamine, in mice treated with bombesin-saporin. CONCLUSIONS: These results suggest that spinal bombesin-recognized neurones are critical to both the histamine-dependent and histamine-independent pathways for itch, and that they mediate more nonhistaminergic than histaminergic sensation of itch in mice.

Culture of chicken embryo in interspecific surrogate egg white.

The effect of interspecific egg white on the development of chicken embryos was investigated in a surrogate eggshell culture system. Egg yolks were separated from fertile White Leghorn chicken eggs and cultured in different egg whites from turkey (group TK), guineafowl (group GF), and duck (group DK), and chicken (group CK) was used as control. The viability of chicken embryos in groups CK, TK, GF, and DK after 3 d culture in system II was 98.3, 90.2, 96.1, and 91.1%. The whole contents (egg yolk and surrogate egg white) were further transferred into an eggshell from a 1.5 times heavier chicken egg with air space (system III), and incubated for further 16 d, before moving them to a hatcher. No significant difference between the 4 groups was found in their viabilities, which ranged between 72.9 and 81.3%, until 14 d postincubation (P > 0.05). After 21 d, the viability decreased to 60.4, 57.4, 50.0, and 27.7% in groups CK, TK, GF, and DK. The viability in group DK was significantly lower than in the other groups (P < 0.05). Weight loss in system III was approximately 12% in all the 4 groups without significant difference (P > 0.05). Hatchability of the chicken embryo was 60.4, 55.3, 47.9, and 19.1% in groups CK, TK, GF, and DK, respectively, and that in group DK was significantly lower than in the other groups (P < 0.05). There was no difference between the other groups (P > 0.05). These results show that chicken embryos can develop to hatch in duck, guineafowl, and turkey egg whites. However, the hatchability decreases according to the phylogenetic distance. The present study will provide a tool for manipulation of avian embryos and eventual conservation of endangered wild birds.

MiR-133b inhibits MPP+-induced apoptosis in Parkinson's disease model by inhibiting the ERK1/2 signaling pathway.

OBJECTIVE: The aim of this study was to explore the effect of micro ribonucleic acid (miR)-133b on 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis in the Parkinson's disease (PD) model. MATERIALS AND METHODS: PC12 cells were induced by different concentrations of MPP+ to establish the PD cell model. Subsequently, the survival rate of PC12 cells was detected using Cell Counting Kit-8 (CCK-8) assay. Quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of miR-133b in the PD model induced by different concentrations of MPP+. Next, PC12 cells were transfected with miR-133b mimic and miR-negative control (NC), and divided into MPP+ group, MPP+ + miR-NC group and MPP+ + miR-133b mimic group. Transfection efficiency was verified using qRT-PCR. The apoptosis of cells was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphorylated (p)-ERK1/2 were determined using Western blotting. RESULTS: After MPP+ treatment, the survival rate of PC12 cells significantly declined (p<0.05). MPP+ exhibited toxicity against PC12 cells in a concentration-dependent manner. Meanwhile, cell survival rate decreased remarkably with the increase of MPP+ concentration (p<0.05). With increased concentration of MPP+, the expression of miR-133b in the PD cell model declined significantly (p<0.05). The apoptosis of PC12 cells was remarkably inhibited by overexpression of miR-133b in the PD cell model (p<0.05). In addition, the protein expression of p-ERK1/2 in PC12 cells was notably reduced after overexpression of miR-133b in the PD cell model (p<0.05). CONCLUSIONS: MiR-133b is lowly expressed in the PD cell model. Furthermore, overexpression of miR-133b inhibits cell apoptosis in the PD cell model by regulating the ERK1/2 signaling pathway.

[Multimodal analgesic analgesia in patients with obstructive sleep apnea hypopnea syndrome with multiple planar surgery].

Objective:To observe the value of multimodal analgesia in patients with OSAHS undergoing multiplanar surgery.Method: A total number of 90 patients with obstructive sleep apnea hypopnea syndrome with tongue hypertrophy or hyperplasia of the root lymphoid tissue were collected. All patients underwent improved uvulatopharyngeal angioplasty (H-UPPP) and tongue root partial resection, or simultaneous tongue ablation at the same time, and they were randomly divided into two groups,45 patients in each group.In multi-modal analgesic group, the parrixibub sodium 40 mg were given intravenously 0.5 h before surgery, and oxygen budesonide aerosol inhalation therapy was given after surgery.Besides,sodium aescinate 10 mg was given intravenously 24, 48, 72 h after surgery,respectively.The control group did not do the above treatment. Both groups received 40 mg paradoxes sodium hydrostatic Bid for 4 days.To perform VAS on two groups of patients, uvula swelling time and first time to eat were recorded，and the symptoms of postoperative nausea and vomiting were observed.Result: The general conditions of the two groups of patients, including age, sex, body mass index, intraoperative blood loss, and operative time, were not statistically significant(all of the P>0.05). The scores of 24, 48, 72, 96 h VAS in multi-mode analgesic group were lower than those in control group after the operation of multi-mode analgesia, and the difference was statistically significant（P<0.05）.The duration of the swelling time of the uvula in the multi-mode analgesic group was significantly shorter than that in the control group, and the difference was statistically significant (5.44±0.88) d compared with (7.68±0.89) d (t=12.01, P<0.01);(30.1±7.3)h compared with (36.5±7.0) h,(t=4.25, P<0.01). Conclusion: Multi-mode analgesia is effective for OSAHS patients after multi-planar surgery. It effectively reduces postoperative pain, shortened postoperative swelling time, and improves the surgical compliance and safety.

Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl-p53 pathway.

PURPOSE: Macrophages play critical roles in inflammation and wound healing and can be divided into two subtypes: classically activated (M1) and alternatively activated (M2) macrophages. Macrophages also play important roles in regulating iron homeostasis, and intracellular iron accumulation induces M1-type macrophage polarization which provides a potential approach to tumor immunotherapy through M2 tumor-associated macrophage repolarization. However, the mechanisms underlying iron-induced M1 polarization remain unclear. METHODS: Western blotting, qRT-PCR, and flow cytometry were used to detect the polarization indexes in RAW 264.7 murine macrophages treated with iron, and Western bloting and qRT-PCR were used to detect p21 expression. The compound 2,7-dichlorofluorescein diacetate was used to measure reactive oxygen species (ROS) levels in macrophages after iron or N-acetyl-l-cysteine (NAC) treatment. The p300/CREB-binding protein (CBP) inhibitor C646 was used to inhibit p53 acetylation, and Western bloting, qRT-PCR, and immunofluorescence were used to detect p53 expression and acetylation. BALB/c mice were subcutaneously injected with H22 hepatoma cells, and macrophage polarization status was investigated after tail intravenous injection of iron. Immunohistochemical staining was used to evaluate the protein expression of cluster of differentiation 86 (CD86) and EGF-like module-containing mucin-like hormone receptor-like 1 (F4/80) in the subcutaneous tumors. RESULTS: Iron overload induced M1 polarization by increasing ROS production and inducing p53 acetylation in RAW cells, and reduction in ROS levels by NAC repressed M1 polarization and p53 acetylation. Inhibition of acetyl-p53 by a p300/CBP inhibitor prevented M1 polarization and inhibited p21 expression. These results showed that high ROS levels induced by iron overload polarized macrophages to the M1 subtype by enhancing p300/CBP acetyltransferase activity and promoting p53 acetylation.

[Sclerotherapy for faciocervical lymphatic malformations under digital subtraction angiography in children].

Objective:To investigate the efficacy and advantages of fluoroscopy sclerotherapy treatment for the faciocervical lymphatic malformations (LMs) under digital subtraction angiography (DSA) in children. Method:Retrospective analysis of 48 cases of lymphatic malfromations who were treated with intratumoral injection of Pingyangmycin and iohexol under DSA and fluoroscopy, and followed up in Kunming children's hospital. Result:Forty-eight cases of children were treated 1 to 5 intratumoral injection of Pingyangmycin and iohexol that carried out under DSA and fluoroscopy. Follow up ranged from 6 to 18 months, 22 cases (45.83%) were cured, 19 cases (39.85%) were markedly effective, 5 cases (10.42%) were effective and 2 cases (4.17%) were ineffective. The total effective rate was 95.83% with no scarring, pigmentation and significant postoperative complications. Conclusion:Intratumoral injection of Pingyangmycin under DSA is an effective and safe method for treatment of lymphatic malformations in children and has the advantages of positioning accuracy, less damage, fewer complication and no influence on apperarence and function.

Concerted proton-electron transfer between ascorbic acid and cytochrome b561.

Ascorbic acid is an essential reductant in biology but its reducing power is paradoxical. At physiological pH the predominant form of ascorbate (the monoanion) is a poor electron donor because it oxidizes to the energetically unfavorable neutral free radical. The ascorbate dianion forms the relatively stable semidehydroascorbate radical anion and is a powerful electron donor but its concentration at neutral pH is insufficient to produce the reaction rates observed. For example, ascorbate rapidly reduces cytochrome b561 from adrenal medullary chromaffin vesicles. This fast reaction rate may be rationalized by a mechanism involving concerted proton-electron transfer rather than electron transfer alone. This would permit reduction of the cytochrome by the abundant ascorbate monoanion but would circumvent formation of unfavorable intermediates. This may be a general mechanism of biological ascorbic acid utilization: enzymes using ascorbic acid may react with the ascorbate monoanion via concerted proton-electron transfer.

Increased reactive oxygen species in familial amyotrophic lateral sclerosis with mutations in SOD1.

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder characterized by degeneration of large motor neurons of the brain and spinal cord. A subset of ALS is inherited (familial ALS, FALS) and is associated with more than 70 different mutations in the SOD1 gene. Here we report that lymphoblast cell lines derived from FALS patients with 16 different mutations in SOD1 gene exhibit significant increase of intracellular reactive oxygen species (ROS) compared with sporadic ALS (SALS) and normal controls (spouses of ALS patients). The ROS generation did not correlate with SOD1 activity. Further, cells incubated with vitamin C, catalase or the flavinoid quercetin significantly reduced ROS in all groups. The catalase inhibitor 3-amino-1,2,4-triazole resulted in a ten-fold increase of ROS in all groups. Neither L-nitroarginine, a nitric oxide synthase inhibitor or vitamin E altered the ROS levels. Thus, these studies suggest that hydrogen peroxide (H(2)O(2)) is a major ROS elevated in FALS lymphoblasts and it may contribute to the degeneration of susceptible cells. Further, we postulate a mechanism by which increased H(2)O(2) could be generated by mutant SOD1.

Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis.

Two new mutations in the gene encoding cytoplasmic Cu,Zn superoxide dismutase (SOD1) have been discovered in patients with familial amyotrophic lateral sclerosis (FALS). These mutations result in the truncation of most of the polypeptide segment encoded by exon 5, one by the formation of a stop codon in codon 126 (L126Z) and the other by inducing alternative splicing in the mRNA (splicing junction mutation). These two mutants of SOD1 result in a FALS phenotype similar to that observed in patients with missense mutations in the SOD1 gene, establishing that exon 5 is not required for the novel toxic functions of mutant SOD1 associated with ALS. These mutant enzymes are present at very low levels in FALS patients, suggesting elevated toxicity compared to mutant enzymes with single site substitutions. This increased toxicity likely arises from the extreme structural and functional changes in the active site channel, beta-barrel fold, and dimer interface observed in the mutant enzymes, including the loss of native dismutase activity. In particular, the truncation of the polypeptide chain dramatically opens the active site channel, resulting in a marked increase in the accessibility and flexibility of the metal ions and side chain ligands of the enzyme active site. These structural changes are proposed to cause a decrease in substrate specificity and an increase in the catalysis of harmful chemical reactions such as peroxidation.