The number and position of unsaturated bonds in aliphatic aldehydes affect the cysteine-glucose Maillard reaction: Formation mechanism and comparison of volatile compounds.

Nonanal, (E)-2-nonenal, (E,E)-2,4-nonadienal, and (E,Z)-2,6-nonadienal were used to reveal the effect of the number and position of unsaturated bond in aliphatic aldehydes on Maillard reaction for the generation of 88 stewed meat-like volatile compounds. The results showed that (E,E)-2,4-nonadienal and (E,Z)-2,6-nonadienal exhibited greater inhibition of the cysteine reaction with glucose than nonanal and (E)-2-nonenal. However, the positions of the unsaturated bonds in aliphatic aldehydes in the Maillard reaction stage were similar. A carbohydrate module labeling approach was used to present the formation pathways of 34 volatile compounds derived from the Maillard reaction with aliphatic aldehyde systems. The number and position of unsaturated bonds in aliphatic aldehydes generate multiple pathways of flavor compound formation. 2-Propylfuran and (E)-2-(2-pentenyl)furan resulted from aliphatic aldehydes. 5-Butyldihydro-2(3H)-furanone and 2-methylthiophene were produced from the Maillard reaction. 2-Furanmethanol, 2-thiophenecarboxaldehyde, and 5-methyl-2-thiophenecarboxaldehyde were derived from the interaction of aliphatic aldehydes and the Maillard reaction. In Particular, the addition of aliphatic aldehydes changed the formation pathway of 2-propylthiophene, thieno[3,2-b]thiophene, and 2,5-thiophenedicarboxaldehyde. Heatmap and PLS-DA analysis could discriminate volatile compound compositions of the five systems and screen the marker compounds differentiating volatile compounds.

A proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation or gene silencing.

Novel modalities such as PROTAC and RNAi have the ability to inadvertently alter the abundance of endogenous proteins. Currently available in vitro secondary pharmacology assays, which evaluate off-target binding or activity of small molecules, do not fully assess the off-target effects of PROTAC and are not applicable to RNAi. To address this gap, we developed a proteomics-based platform to comprehensively evaluate the abundance of off-target proteins. First, we selected off-target proteins using genetics and pharmacology evidence. This process yielded 2813 proteins, which we refer to as the "selected off-target proteome" (SOTP). An iterative algorithm was then used to identify four human cell lines out of 932. The 4 cell lines collectively expressed ~ 80% of the SOTP based on transcriptome data. Second, we used mass spectrometry to quantify the intracellular and extracellular proteins from the selected cell lines. Among over 10,000 quantifiable proteins identified, 1828 were part of the predefined SOTP. The SOTP was designed to be easily modified or expanded, owing to the rational selection process developed and the label free LC-MS/MS approach chosen. This versatility inherent to our platform is essential to design fit-for-purpose studies that can address the dynamic questions faced in investigative toxicology.

Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia.

Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG 553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 expression analysis and in vitro and in vivo studies were leveraged to evaluate the nonclinical safety of AMG 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence of CAR T-cell-mediated toxicity, expansion, or persistence, likely due to restricted cell surface FLT3 protein expression in healthy animals. This highlights the limited value of such in vivo studies for safety assessment of the CAR T-cell modality when directed against a target with restricted expression. To complement these studies and directly evaluate the potential toxicities of eliciting T-cell-mediated cytotoxicity against cells with surface expression of FLT3 protein in vivo, data from cynomolgus monkey toxicology studies with 2 bispecific T-cell engager molecules targeting FLT3 were leveraged; findings were consistent with the targeted killing of bone marrow cells expressing cell surface FLT3. Potential AMG 553-induced cytotoxicity was assessed against a wide range of normal human primary cells and cell lines; cytotoxicity was observed against FLT3-positive AML cell lines and a percentage of primary bone marrow CD34+ cells. In conclusion, the nonclinical safety data suggest that AMG 553 can target FLT3 protein on AML cells, whereas only affecting a percentage of normal hematopoietic stem and progenitor cells, supporting clinical development.

Clinical effect analysis of microscopic surgery for epiglottis cysts with coblation.

This study aims to explore the effects and advantages of coblation combined with microscopy to treat epiglottis cysts. Ninety patients with epiglottis cysts were randomly assigned to three groups: the first group: marsupialisation + electric coagulation group, n = 30; the second group: marsupialisation + coblation, n = 30; and the third group: marsupialisation + coblation + microsurgery, n = 30. To compare the cure rate, intraoperative bleeding volume, postoperative pain, operation time and postoperative complications were investigated among these three groups. The comparison among three procedures showed a significant difference for intraoperative bleeding volume, operation time and postoperative pain (P < 0.05), whereas no significant difference was observed for cure rate (P > 0.05). These three procedures are effective in treating epiglottis cysts. Microscopic surgery with coblation has the advantages of less bleeding, short procedure duration, less pain and few complications. Thus, microscopic surgery is worthy of clinical application.

Experimental studies on the inhibition of adenovirus-ING4-OSM therapy on nasopharyngeal carcinoma proliferation in vitro and in vivo.

In the present study, the effects of the co-transfer of the tumor growth inhibitor 4 gene (ING4) together with the Oncostatin M (OSM) were investigated on tumor regression and subsequent tumor recurrence. We constructed a recombinant adenovirus carrying ING4 and OSM, which could induce high-level expression of these three genes in NPC CNE-1 cells. Ad-ING4, Ad-OSM and Ad-ING4-OSM infection all inhibited the growth of CNE-1 cells in vitro, while the Ad-ING4-OSM exerted the strongest inhibitory effect. In CNE-1 xenograft tumor models mice, an intratumoral injection of Ad-ING4, Ad-OSM and Ad-ING4-OSM resulted in a reduced tumor burden, compared to normal saline controls. Therefore, we suggested that the introduction of adenovirus-mediated ING4 and OSM genes could synergistically decrease the recurrence or metastases and develop a control of NPC tumors, which advocate a promising therapeutic future in NPC treatment.

[Correlation between allergic rhinitis and childhood obstructive sleep apnea-hypopnea syndrome].

OBJECTIVE: To investigate the correlation between allergic rhinitis and obstructive sleep apnea-hypopnea (OSAHS) syndrome in children. METHOD: (1) According to medical history, physical signs, skin-prick test, serum sIgE, endoscopic examination and polysomnography, the incidence of allergic rhinitis was confirmed in 574 cases of childhood obstructive sleeping apnea-hypopnea syndrome in our hospital between July in 2008 to June in 2010. (2) Effects of anti-allergic drugs were observed on 78 children with OSAHS and allergic rhinitis meanwhile. RESULT: (1) 258 cases of allergic rhinitis were confirmed in 574 cases of OSAHS, accounting for 44.9% of the OSAHS cases and 50.4% of all cases of allergic rhinitis during the same period. Most of them were perennial allergic rhinitis (223 cases, 86.4%), and 72.5% of them were aroused by fungal allergen. Compared with other allergen, statistically significant difference was found (P < 0.05). (2) After receiving anti-allergic drugs regularly for 3 weeks, 40 cases suffering from mild and moderate OSAHS and allergic rhinitis, 3 cases out of 38 cases suffering from serious OSAHS and allergic rhinitis showed satisfactory results, while other cases had little improvement. CONCLUSION: Allergic rhinitis is closely related to childhood OSAHS, and perennial allergic rhinitis dominates. The most common allergen is fungal allergen, the second is house and flour dust mites. So for patients of mild and moderate OSAHS with allergic rhinitis, regular anti-allergic drugs can lighten OSAHS effectively and may make patients avoid surgery. Severe OSAHS cases can receive surgical intervention if prior anti allergic therapy fails. Anti allergic therapy should be adopted routinely after tonsillectomy and adenoidectomy in case of hypopnea due to hypertrophy of inferior turbinate or tubal torus in allergic rhinitis.

[More exploration on endoscopic rhinoplasty and septoplasty].

OBJECTIVE: Exploring a method of rhinoplasty and septoplasty to get better nasal function and aesthetic effect. METHOD: 1) Using endoscopic rhinoplasty and septoplasty, separating the joint of quadrangular cartilage and the bones around it, resecting vertical and horizontal strip of the deviated septal cartilage and fracturing the deviated septal bones and reconstructing them with three layers (mucosa-cartilage or bone-mucosa), positing the reconstructed septum in the middle between two lateral walls of nasal cavity, proper space between septum and turbinates was maintained. 2) The caudal part of quadrangular cartilage was resected and placed in the columella pocket between the two medial parts of the alar cartilage and the supporting function of the septal cartilage was maintained. RESULT: Compared with traditional nasal septal reconstruction surgery, our method got better functional and aesthetic outcome. CONCLUSION: The anatomic three layers were preserved in our method, thus it is better than the traditional methods. The caudal septal cartilage should be used as the perfect material in rhinoplasty.

[Detection of PD4, CD44, PCNA protein and its clinical significance in human laryngeal carcinoma].

OBJECTIVE: To study the expression of PD4, CD44 and PCNA proteins in laryngeal carcinoma and their relationships with the pathogenesis, development and prognosis of laryngeal carcinoma. METHOD: Immunohistochemistry was used to study 140 cases of laryngeal carcinoma tissues, 25 cases of precarcinoma tissues, 36 cases of vocal cord polyps and 13 cases of normal tissues adjacent to laryngeal carcinoma. RESULT: 1. The positive rates of PD4, CD44 and PCNA were 45.71% (64/140), 64.29% (90/140) and 77.86% (109/140) in laryngeal carcinoma, which were much higher than in non-carcinoma tissues (P < 0.01). 2. The third and fourth stages laryngeal carcinoma express stronger PD4 and CD44 than those of the first and second stages. Laryngeal carcinoma with cervical metastasis had higher expression than those without cervical metastasis. To 3 and 5 years' survival, PD4, CD44 and PCNA positive cases had lower chance than those negative cases(P < 0.01 or 0.05). 3. The over all positive rate of PD4, CD44 and PCNA was 27.86% (39/140) in laryngeal carcinoma tissues and 5.41% (4/74) in non-carcinoma tissues. CONCLUSION: The high expression of PD4, CD44 and PCNA proteins maybe closely related to the pathogenesis, development and prognosis of laryngeal carcinoma.

[Expression of PD4, CD44v6, CD44v9 and its clinical significance in human laryngeal carcinoma].

OBJECTIVE: Study on the role of mycoplasma infection and expression of CD44v6, CD44v9 protein in the pathogenesis, development and prognosis of laryngeal carcinoma (LC). METHOD: Immunohistochemistry was used to study 137 cases of laryngeal carcinoma tissues, 26 cases of precarcinoma tissues, 34 cases of vocal cord polypus and 15 cases of normal tissues adjacent to laryngeal carcinoma. RESULT: The positive rate of PD4 and CD44v6, CD44v9 was 45.3% (62/137), 72.3% (99/137) and 56.2% (77/137) in laryngeal carcinoma, which are much higher than those in non-carcinoma tissues. (2) The positive rate of PD4 and CD44v6. CD44v9 in the third and fourth stages of LC were higher than those in the first and second stages of LC. Laryngeal carcinoma with cervical metastasis had higher expression than those without cervical metastasis (P < 0.01). To 3 and 5 years survival, PD4 and CD44v6, CD44v9 positive cases had lower chance than those negative cases (P < 0.01 [Chinese character: see text] 0.05). (3) The overall positive rate of PD4 and CD44v6, CD44v9 was 27.7% (38/137) in laryngeal carcinoma tissues and 5.3% (4/75) in non-carcinoma tissues. CONCLUSION: These results implicates that the pathogenesis, development and prognosis of laryngeal carcinoma maybe closely related to the high expression of PD4 and CD44v6, CD44v9 protein.