Strategies for patients with recurrent nasopharyngeal carcinoma involved internal carotid artery who are intolerant to embolization.

BACKGROUND: The surgical treatment of recurrent nasopharyngeal carcinoma (rNPC) involving the internal carotid artery (ICA) is challenging, as the massive bleeding caused by intraoperative rupture of the ICA is life-threatening. We reported that ICA embolization is an effective pretreatment to avoid fatal bleeding, but some patients cannot tolerate the procedure. We used endovascular vascular protection (ICA stents), vascular sacrifice (bypass grafting) and extravascular vascular protection (transcervical external stent placement) of the ICA to provide alternative options for these patients. METHODOLOGYy: This study enrolled patients with rNPC adjacent to or invading the ICA who were unsuitable for ICA embolization from January 2015 to June 2020. ICA pretreatment combined with endoscopic nasopharyngectomy (ENPG) was performed for the 30 patients. We report the survival outcome and incidence of complications after ICA pretreatment. RESULTS: ICA pretreatment was performed for the 30 enrolled patients, among whom 8 underwent endoscopic-assisted transcervical protection of the parapharyngeal ICA combined with ENPG, 6 underwent bypass grafting, and 16 underwent ICA stent implantation followed by ENPG. After pretreatment, at a median follow-up of 43 months (range, 2-80 months), the 3-year locoregional overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 62.9%, 61.3%, 70.2%, and 71.4%, respectively. CONCLUSIONS: ICA pretreatment combined with salvage ENPG enables the feasible and effective resection of rNPC lesions involving the ICA in patients who cannot tolerate ICA embolization. Therefore, this treatment may be an effective method for improving outcomes. Multidisciplinary therapy is needed to reduce operation-related complications.

[The efficacy and safety of linagliptin in elderly patients with type 2 diabetes: a pooled analysis of eight placebo-controlled clinical trials].

Objective: To evaluate the efficacy and safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects aged 60 years or older with type 2 diabetes mellitus (T2DM). Methods: Data from eight 24-week, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies were analyzed. Patients aged 60 years or older with T2DM were received oral linagliptin (5 mg/d) or placebo in combination with metformin, or metformin plus sulfonylurea. Efficacy was assessed by the changes in glycosylated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) from baseline to 24 weeks of treatment. Safety endpoint included the frequency and intensity of adverse events. Results: A total of 1 421 patients (placebo 429, linagliptin 992) were included in the full analysis set (FAS). Mean ages of the subjects were (67.4±5.6) years in the linagliptin group and (66.7±5.6) years in the placebo group. Baseline HbA1c was (8.0±0.8) % in the linagliptin group and (8.1±0.9) % in the placebo group. At the end of 24-week, placebo-adjusted reduction in HbA1c in subjects with linagliptin was (0.7±0.1)% (95%CI 0.6-0.8, P<0.000 1), and placebo-adjusted reduction in FPG in subjects with linagliptin was (0.88±0.12) mmol/L(95%CI 0.65-1.11, P<0.000 1). Overall safety and tolerability in the two groups were similar. Adverse events occurred in 57.1% of patients in the placebo group and 61.1% of patients in the linagliptin group, and the incidence of adverse events leading to discontinuation was 3.2% in the placebo group and 3.8% in the linagliptin group. Serious adverse events occurred in 1.6% of patients in the placebo group and 2.8% of patients in the linagliptin group. Investigator-defined hypoglycaemia occurred in 7.3% of patients in the placebo group and 11.9% of patients in the linagliptin group. Among them, most were mild or moderate hypoglycaemia, and severe hypoglycaemia only occurred in 0.2% of patients in the placebo and 0.5% in the linagliptin groups. Overall incidence of hypoglycaemia in linagliptin group was slightly higher than that in placebo group, which might be due to the fact that more patients were taking sulfonylureas in linagliptin group than in placebo group (26.8% linagliptin; 18.4% placebo). No difference could be viewed in hypoglycaemia between the two groups in patients without sulfonylureas (1.2% linagliptin, 1.1% placebo). Moreover, no severe hypoglycaemia was reported in subjects without sulfonylureas. The incidences of other adverse events were similar in both groups. Conclusion: Linagliptin was efficacious in lowering glucose with a safety profile similar to placebo in type 2 diabetic patients aged 60 years or older.

Molecular Identification and Characterization of Tomato zonate spot virus in Tobacco in Guangxi, China.

In Guangxi Province of southwest China, diseases caused by Tospoviruses (family Bunyaviridae) pose a serious threat to tobacco (Nicotiana tobacum) production. During surveys conducted annually at Xinrong Village in Jingxi County from 2008 to 2010, more than 130 ha of fields were found to have 10 to 50% of plants exhibiting symptoms similar to spotted wilt caused by Tomato spotted wilt virus (TSWV). During this period, disease symptoms at similar prevalence and incidence were also found at Fushan, Debao County in most of the cultivars produced in these areas, including Yunyan 85, 87, 92, 97, and K326. Symptoms on tobacco varied but commonly included dwarfing, midrib browning, distorted apical buds, and concentric ringspots that coalesced to form large areas of dead leaf tissue. Mechanical inoculation from diseased tobacco leaves with concentric ringspots back to tobacco cv. Yunyan 85 or 87, resulted in 12 of 16 plants with symptoms similar to those observed in the field. No symptoms on plants developed following inoculation with buffer only. Symptoms found in the field resembled those caused by TSWV. However, testing using TSWV-specific antiserum was shown to be negative by double-antibody sandwich-ELISA (Agdia, Elkhart, IN). Total RNA was extracted from 27 diseased tobacco plants collected from different regions in Guangxi using Trizol reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions. RNA extracts were amplified by reverse transcription (RT)-PCR using the degenerate primers T2740 (ATGGGDATNTTTGATTTCATG) and T3920c (TCATGCTCATSAGRTAAATYTCTCT) designed to target the partial RNA-dependent RNA polymerase (RdRp) sequence of members in the genus Tospovirus (3). Amplification was performed at 42°C for 60 min, followed by 35 cycles of PCR (30 s denaturation at 94°C, 45 s annealing at 55°C, and 30 s extension at 72°C) and a 7-min final extension at 72°C. A PCR product of approximately 1.2 kb was amplified from 21 diseased plants. RT-PCR amplicons were cloned into the pUC19-T Simple Vector (TaKaRa, Dalian, China) and sequenced in both directions. Sequences were assembled and analyzed by DNAStar 5.01 (DNASTAR, Madison, WI). Sequences of representative isolates were deposited in GenBank (Accession Nos. JN020022 to JN020027). The 1.2-kb partial RdRp sequences of these isolates were shown to have 94.4 to 95.3% nucleotide identity and 96.5 to 97.5% amino acids identity to Tomato zonate spot virus (TZSV) (GenBank Accession No. NC_010491) (1). Among these TZSV isolates from Guangxi, the partial RdRp sequences have 98.0 to 99.4% nucleotide identity and 98.8 to 100% amino acids identity with each other. The presence of TZSV was further confirmed in diseased tobacco plants by indirect ELISA using antiserum of TZSV (provided by Prof. Zhongkai Zhang, Agricultural Academy of Yunnan, China). TZSV has been characterized as a novel tospovirus on various hosts including tobacco in Yunnan province (1,2). To our knowledge, this is the first report of TZSV-associated disease on tobacco in Guangxi Province, southwest China. Further work is necessary to study the epidemiology and management of the disease. References: (1) J. Dong et al. Arch. Virol. 153:855, 2008. (2) J. Dong et al. J. Insect Sci. 10:166, 2010. (3) Y. Lin. Master Thesis. National Chung Hsing University, Taichung, Taiwan, Republic of China, 2007.

Optimum superimposition of protein structures: ambiguities and implications.

BACKGROUND: Techniques for comparison and optimum superimposition of protein structures are indispensable tools, providing the basis for statistical analysis, modeling, prediction and classification of protein folds. Observed similarity of structures is frequently interpreted as an indication of evolutionary relatedness. A variety of advanced techniques are available, but so far the important issue of uniqueness of structural superimposition has been largely neglected. We set out to investigate this issue by implementing an efficient algorithm for structure superimposition enabling routine searches for alternative alignments. RESULTS: The algorithm is based on optimum superimposition of structures and dynamic programming. The implementation is tested and validated using published results. In particular, an automatic classification of all protein folds in a recent release of the protein data bank is performed. The results obtained are closely related to published data. Surprisingly, for many protein pairs alternative alignments are obtained. These alignments are indistinguishable in terms of number of equivalent residues and root mean square error of superimposition, but the respective sets of equivalent residue pairs are completely distinct. Alternative alignments are observed for all protein architectures, including mixed alpha/beta folds. CONCLUSIONS: Superimposition of protein folds is frequently ambiguous. This has several implications on the interpretation of structural similarity with respect to evolutionary relatedness and it restricts the range of applicability of superimposed structures in statistical analysis. In particular, studies based on the implicit assumption that optimum superimposition of structures is unique are bound to be misleading.

A differential geometric treatment of protein structure comparison.

The technique of model-building a protein of known sequence but unknown tertiary structure from the structures of homologous proteins is probably so far the most reliable means of mapping from primary to tertiary structure. A key step towards the realization of the aim is to develop ways of aligning three-dimensional structures of homologous proteins, thereby deriving the rules useful for protein modelling. We have developed a generalized differential-geometric representation of protein local conformation for use in a protein comparison program which aligns protein sequences on the basis of their sequence and conformational knowledge. Because the differential-geometric distance measure between local conformations is independent of the coordinate frame and remains chirality information, the comparison program is easily implemented, relatively rational and reasonably fast. The utility of this program for aligning closely and distantly related homologous proteins is demonstrated by multiple alignment of globins, serine proteinases and aspartic proteinase domains. Particularly, the method has reached the rational alignment between the mammalian and microbial serine proteinases as compared with many published alignment programs.

Relationship between naturally occurring human antibodies to casein and autologous antiidiotypic antibodies: implications for the network theory.

Previous studies on human autologous antiidiotypes have been based largely upon analyses of autoimmune disease. We have previously described polyclonal, naturally occurring human autoantibodies directed against antibodies with specificity toward bovine casein in the sera of IgA-deficient humans. In order to define this system more exactly we have not produced two murine monoclonal antibodies directed against bovine milk kappa-casein to use as clonal tools to identify specific antiidiotypes in these human sera. Kappa-casein is an important part of the casein micelle in milk and cheese; in addition to being an important immunogen for man, kappa-casein is known to have conserved amino acid sequence and two antigenic epitopes. Data presented here show that the serum of up to 74% of IgA-deficient and 10% of normal humans have specific autologous antiidiotypes in their serum which bind to monoclonal antibodies directed to bovine kappa-casein. These human antibodies [intact or F(ab)'2] can be blocked from binding to the monoclonal anti-kappa-caseins by pure bovine kappa-casein or the kappa-casein peptide fragment. In contrast to previous studies in autoimmune disease, serum levels of the autoantiidiotypes were directly proportional to the level of IgG antibody to bovine kappa-casein. These observations suggest that continual exposure to a ubiquitous dietary antigen may produce an antigen driven system in which stimulation of both Ab1 and Ab2 occurs in concert.

[Anti-inflammatory effect of cyproheptadine].

Cyproheptadine, an anti-5-hydroxytryptamine drug, 20 mg/kg ip or 20-40 mg/kg ig markedly inhibited hind paw edema induced by injection of fresh egg white 0.1 ml or 2.5% formaldehyde 0.1 ml in rats. Cyproheptadine 20 mg/kg ip or 40-60 mg/kg ig inhibited hind paw edema produced by local injection of 0.15 ml 1% carrageenin in normal or adrenalectomized rats. It inhibited the proliferation of granuloma induced by cotton pellet after sc 20 mg/kg qd x 7d, the swelling of mouse ear induced by xylene, and the increased vascular permeability induced by 0.7% HAc in mice. Cyproheptadine did not prolong the survival time in adrenalectomized rats and there were no marked effects on adrenal weight or the plasma concentration of cortisol in rats. It decreased the weight of the thymus and the content of prostaglandin E in the inflammatory tissue of rats. These results suggest that the anti-inflammatory activity of cyproheptadine is presumably due to its anti-5-hydroxytryptamine effect and the inhibition of synthesis or release of prostaglandin E.

Production of a monoclonal antibody to bovine kappa-casein.

Caseins (including alpha s1, alpha s2, beta, kappa and gamma casein), a family of phosphoproteins which binds to calcium, are the major proteins in mammalian milk. Kappa-casein, in addition to its calcium binding capacities has an important role in the stabilization of the micelle structure of milk. In the course of studies to investigate the immunologic effects of ingested bovine kappa-casein in IgA deficiency, a hybridoma has been produced that secretes a monoclonal antibody, (IgG1 kappa isotype), which is specific for bovine kappa -casein. The antibody has been characterized by ELISA and it has been shown to bind specifically to bovine kappa -casein. In a sandwich radioimmunoassay, as little as 0.3 x 10(-4) nM/ml of kappa-casein. could be detected. This antibody does not bind to other bovine milk proteins, nor to human casein.

[Anti-inflammatory effect of diethylcarbamazine citrate].

Diethylcarbamazine citrate (DEC) at 180-300 mg/kg ip or 560 mg/kg ig inhibited hind paw swelling induced by sc 0.15 ml of carrageenan in normal and adrenalectomized rats. DEC ip 300 mg/kg also inhibited the same swelling induced by sc 2.5% formaldehyde in rats. The proliferation of granuloma induced by cotton-pellets tended to be inhibited by DEC, although not significantly. It inhibited the swelling of mouse ear induced by xylene and the increased vascular permeability induced by ip 0.7% HAC. DEC neither prolonged the survival time in adrenalectomized rats nor increased the weight of the adrenal or plasma cortisol levels in normal rats. DEC decreased the prostaglandin E content in inflammatory tissue, although less than the extent in the indomethacin group. These results indicate that the anti-inflammatory action of DEC is presumably due to the inhibition of synthesis or the release of prostaglandin E, in addition to a possible action mediated by its leukotriene synthesis inhibitor action.

Analysis of a common inheritable idiotype in IgA-deficient sera using monoclonal antibodies.

In these studies we describe the production of three mAb raised to an idiotype on an IgG anticasein antibody isolated from the serum of one IgA-deficient blood donor. These are IgM kappa and block the binding of casein Ag to anticasein antibody. Sera of unrelated IgA-deficient donors were tested for the presence of the idiotype; 15 of 56 IgA-deficient sera (25%) contain the anticasein idiotype, whereas 1 of 45 normal sera was positive. Anticasein antibodies as a whole were predominantly of the IgG1 and IgG3 subclass; idiotype-positive anticaseins are predominantly of the IgG1 subclass. For IgA-deficient donors, the relative amount of idiotype-positive anticasein antibody was correlated with the level of anticasein present in the serum. Studies were done to investigate the potential inheritance of the idiotype in families; in three of four families the idiotype was inherited in an apparent autosomal dominant pattern. Our data show that a common cross-reactive idiotype can be detected in the sera of IgA-deficient individuals and their family members. This suggests that V region markers may be conserved in this humoral immunodeficiency disease.