Effects of different stocking densities on organ development, blood biochemical indices, and antioxidative status of breeder pigeons during the rearing period.

The present experiment was conducted to investigate the effect of different stocking densities on the organ development, blood biochemical indices, and antioxidative status of breeder pigeons during the rearing period. A total of 280 (half male and half female) 40-day-old young pigeons were allocated into 4 groups, including 3 experimental groups (in compartments of the flying room): the high stocking density (HSD) (0.308 m3/bird), standard stocking density (SD) (0.616 m3/bird), and low stocking density (LSD) (1.232 m3/bird) and a caged control (0.04125 m3/bird). The results showed that the contents of corticosterone and heat shock protein 70 in males and the corticosterone content in females were higher in the control than in the other groups. The relative weight of liver, lung, and gizzard in males of the HSD group was the highest among the 4 treatments, whereas the abdominal fat index in the control group was higher than those in the other 3 treatments. Body weight and the relative weight of liver and abdominal fat in female pigeons in HSD group increased significantly. The levels of serum urea nitrogen and uric acid in pigeons of LSD group increased significantly, while the concentration of total cholesterol and the activity of alanine aminotransferase were higher in the control group. Ion (K+, Ca2+, and Na+) concentrations in female pigeon serum were also elevated in the control. The activity of antioxidant enzymes, including the total antioxidant capacity, superoxide dismutase, and glutathione peroxidase in pigeon breast muscle and liver had different degrees of inhibition when the space room was crowded. Moreover, the level of malondialdehyde in the liver of male caged pigeons was higher than that in the other treatments. In summary, rearing in cages or at a high density caused stress responses in the breeder pigeons. The stocking density of breeder pigeons during the rearing period should be ranged from 0.616 m3/bird to 1.232 m3/bird.

Dynamic changes in protein concentrations of keratins in crop milk and related gene expression in pigeon crops during different incubation and chick rearing stages.

1. The objective of this study was to examine the keratin composition of crop milk, the variation of epithelial thickness and keratin (K) gene expression in samples from young pigeon during incubation and chick rearing.2. Crop milk was collected from 1-, 3- and 5-day-old squab crops for keratin content analysis. Results showed that K4 accounted for the highest proportion of all detected keratins.3. In total, 42 pairs of adult pigeons were allocated to seven groups according to different stages to collect crop samples. Gene expression studies showed that the K3 gene expression was maximised at rearing Day 15 (15) and R1 in males and females, respectively. K6a gene level was the greatest at R15 in females, whereas it peaked at incubation Day 4 (I4) in males. The K12, K13, K23 and K80 gene levels were inhibited at the peak period of crop milk formation in comparison with I4. In females, K cochleal expression peaked at I10, whereas it was the greatest at R25 in males. K4 and K14 gene expression was the highest at I10 in females, while K4 and K14 were minimised at I17 and R7 in males, respectively. Gene expressions of K5, K8, K19 and K20 in males and K19 in females were maximised at R1. The K5, K20 and K75 gene levels in females peaked at R7. K75 and K8 expressions in males and females reached a maximum value at R25 and I17, respectively.4. The epithelial thickness of male and female crops reached their greatest levels at R1 and had the highest correlation with K19.5. These results emphasised the importance of keratinisation in crop milk formation, and different keratins probably play various roles during this period. The K19 was probably a marker for pigeon crop epithelium development. The sex of the parent pigeon affected keratin gene expression profiles.

Lipid accumulation and oxidative stress in the crop tissues of male and female pigeons during incubation and chick-rearing periods.

The current study aimed to evaluate the changes in lipid accumulation and oxidative status in pigeon crops during different breeding stages. Forty-two pairs of adult pigeons were randomly assigned to 7 groups. Lipid droplet accumulation in pigeon crops was visualized by using oil red O staining from d 17 of incubation (I17) to d 7 of chick rearing (R7). Transmission electron microscopy analysis showed swollen mitochondria with disintegration of cristae and typical characteristics of endoplasmic reticulum stress in crop tissues at R1 compared with those at I4. During the peak of pigeon milk formation, the concentrations of reactive oxygen species, and oxidative damage markers (advanced oxidation protein products, 8-hydroxy-2 deoxyguanosine, and malondialdehyde) and the enzyme activities of total superoxide dismutase and glutathione peroxidase were all elevated significantly (P < 0.05). The protein concentration of B-cell lymphoma-2 associated X in crop tissues was significantly higher at R1, while the level of B-cell lymphoma-2 protein in males was the highest at I4 (P < 0.05). The ratio of B-cell lymphoma-2 associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) in both male and female crops peaked at R1 (P < 0.05). Gene expression of the key enzymes involved in mitochondrial and peroxisomal fatty acid ß-oxidation was investigated in crops. In males, the gene expression of carnitine palmitoyltransferase 1a peaked at R15, and that of carnitine palmitoyltransferase 2 increased significantly from R1 to R15 (P < 0.05). The mRNA abundance of long chain 3-hydroxyacyl-CoA dehydrogenase increased to the maximum value at R1 and I17 in males and females, respectively. From I17 to R7, the mRNA levels of acyl-CoA oxidase 1 and acyl-CoA oxidase 2 were decreased in pigeon crops (P < 0.05). Conclusively, lipid droplet accumulation was found in male and female pigeon crops from the end of incubation to the early stage of chick rearing. Although antioxidant defence and mitochondrial fatty acid ß-oxidation were both mobilized, oxidative stress in crop tissues still occurred during the peak of milk formation.

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Effect of Akt activation on apoptosis-related gene expression in the crop tissues of male and female pigeons (Columba livia).

The current study investigated whether the expression of apoptosis genes in the pigeon crops was affected by the Akt signaling pathway during crop milk formation. First, 78 pairs of adult White King pigeons were randomly assigned to 7 groups, and the expression of apoptosis-related genes and Akt signaling pathway-related proteins in the crop tissues during different breeding stages were examined. The results showed that the mRNA levels of Bak, caspase-3, caspase-6, and caspase-9 in female crops all increased and reached their highest levels at d 17 of incubation (I17). In male crops, the levels of caspase-3 and caspase-9 gene expression peaked at d 1 of chick rearing (R1). The lowest level of Bcl-2 gene expression in females was observed at I17. The expression ratios of p-Akt (Ser473)/Akt and p-Akt (Thr308)/Akt in male crops decreased to their minimum at R1, while it was observed at d 7 of chick rearing (R7) in females. Second, 36 pairs of adult pigeons were divided into 3 groups and were subjected to SC79 injections with dosages of 0, 0.02, or 0.04 mg/kg bodyweight. The SC79 injections resulted in a considerable decrease in growth performance of pigeon squabs. In male crops, the expression ratios of p-Akt (Ser473)/Akt and p-Akt (Thr308)/Akt were significantly elevated in the 0.02 mg/kg SC79 group, while in female crops, they were higher in the 0.04 mg/kg SC79 group (P < 0.05). The SC79 injection inhibited the gene expression of Bak in female crops, but enhanced the gene expression of Bcl-2 in both male and female crops. In the 0.04 mg/kg SC79 group, a 50.7 to 75.7% decrease was observed in the expression of caspase-3, caspase-6, and caspase-9 in male and female pigeon crops. Expression of the caspase-8 gene and total Akt protein in pigeon crops was not changed in different breeding stages or after SC79 injection. In conclusion, the expression of genes related to mitochondria-dependent apoptosis can be regulated by the Akt signaling pathway, which may play a potential role in pigeon milk formation.

microRNA-1205 promotes cell growth by targeting APC2 in lung adenocarcinoma.

OBJECTIVE: An increasing amount of evidence indicates that microRNAs (miRNAs) can be potential diagnostic and prognostic markers for various cancers. In this study, a novel miRNA, miR-1205, was identified in lung adenocarcinoma (LUAD). PATIENTS AND METHODS: First, the expression of miR-1205 in tissues was determined and verified to be correlated with the prognosis of patients. Overexpression and knockdown in LUAD cells were chosen to evaluate the effect of miR-1205 on cell growth in vitro. Luciferase assays, Western blot and rescue assays were performed to screen and confirm potential targets of miR-1205. RESULTS: We demonstrated that miR-1205 was down-regulated in the tissues of LUAD, and that miR-1205 may be a predictor of overall survival of LUAD. The overexpression of miR-1205 promoted cell proliferation and colony formation. Our results indicated that miR-1205 targeted APC2 directly, serving as a vital part in accelerating LUAD cell proliferation. CONCLUSIONS: We showed that miR-1205 could promote LUAD cell growth by targeting APC2 protein expression and provided further proof of miR-1205 as a potential non-invasive biomarker and therapeutic target for LUAD.

Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan Cooperative Oncology Group (TCOG) 1303 Study.

Background: Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation. Patients and methods: This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8-2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66-70 Gy to the involved neck. The primary end point was disease-free survival (DFS). Results: In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm [5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565-0.965; P = 0.0264], after stratified for N3b and LDH, and adjusted for T stage. Conclusion: Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved. Clinical trial information: NCT00201396.

Induction therapy before surgery improves survival in patients with clinical T3N0 esophageal cancer: a nationwide study in Taiwan.

The utility of induction therapy (IT) in patients with resectable esophageal cancer remains controversial, especially when clinical evidence of nodal metastases is lacking. We sought to compare the survival impact of IT versus upfront surgery (US) in patients with cT3N0 esophageal cancer. We searched the Taiwan Cancer Registry for patients with cT3N0 esophageal cancer who underwent US or IT between 2008 and 2013. Multivariate Cox regression analysis was used to analyze the potential benefits of IT in terms of overall survival (OS) and disease-free survival (DFS). Of the 11752 patients with esophageal cancer included in the nationwide database, 762 (6.5%) had cT3N0 disease. Most cases (720 [94.5%]) had a histological diagnosis of squamous cell carcinoma. Of them, 135 received IT (the IT group) and 237 received surgery first (the US group). In the US group, pretreatment clinical staging was accurate in 47.9% of patients. Twenty-one (8.97%) were clinically overstaged (pT1-2N0), whereas 101 (43.17%) were clinically understaged (pT4N0 or pTanyN1-3). The presence of unexpected nodal metastases was identified in 92.1% of clinically understaged patients. In the IT group, 28 (20.74%) patients did not proceed to surgery after IT. The use of IT was associated with higher R0 resection rates and fewer pathological nodal metastases, despite unexpected M1 disease being more common (all P< 0.05). The 5-year OS rate was significantly higher (42%) in the IT group than in the US group (33%, P= 0.032). Similar findings were observed in terms of 5-year DFS (37% in the IT group versus 29% in the US group, P= 0.009). Multivariate analysis identified US (hazard ratio: 1.42, P= 0.03) and non-R0 resection (hazard ratio: 1.58, P= 0.03) as independent adverse prognostic factors. We found that 43.17% of patients with cT3N0 disease undergoing primary surgery had their disease understaged. The use of IT before esophagectomy significantly improves OS and DFS in patients with clinical T3N0 esophageal squamous cell carcinoma.

Matrix metalloproteinase-based photodynamic molecular beacons for targeted destruction of bone metastases in vivo.

The metastatic spread of cancer from the primary site or organ is one of its most devastating aspects, being responsible for up to 90% of cancer-associated mortality. Bone is one of the common sites of metastatic spread, including the vertebrae. Regardless of the treatment strategy, the clinical goals for patients with vertebral metastases are to improve the quality of life by preventing neurologic decline, to achieve durable pain relief and enhance local tumor control. However, in part due to the close proximity of the spinal cord, current treatment options are limited. We propose a novel therapeutic strategy with the use of photodynamic molecular beacons (PMBs) for targeted destruction of spinal metastases, particularly to de-bulk lesions as an adjuvant to vertebroplasty or kyphoplasty in order to mechanically stabilize weak or fractured vertebrae. The PDT efficacy of a matrix metalloproteinase-specific PMB is reported in a metstatic model that recapitulates the clinical features of tumor growth within the bone. We demonstrate that not only does tumor cell destruction occur but also the killing of bone stromal cells. The potential of PMB-PDT to destroy metastatic tumors, disrupt the osteolytic cycle and better preserve critical organs with an increased therapeutic window compared with conventional photosensitizers is demonstrated.

Structure of Bergman-type W-TiZrNi approximants to quasicrystal, analyzed by lattice inversion method.

The combined interatomic pair potentials of TiZrNi, including Morse and Inversion Gaussian, are successfully built by the lattice inversion method. Some experimental controversies on atomic occupancies of sites 6-8 in W-TiZrNi are analyzed and settled with these inverted potentials. According to the characteristics of composition and site preference occupancy of W-TiZrNi, two stable structural models of W-TiZrNi are proposed and the possibilities are partly confirmed by experimental data. The stabilities of W-TiZrNi mostly result from the contribution of Zr atoms to the phonon densities of states in lower frequencies.