Synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal-free and solvent-free conditions for minimizing waste generation

Brønsted acidic ionic liquid was found to be an efficient and recyclable catalyst for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones. The reactions proceeded smoothly with a broad scope of substrates providing the expected products in good to excellent yields under an atom-economical pathway. The low-cost recyclable catalyst, metal- and solvent-free conditions, and the ease of product isolation are the highlighted advantages in solving the issue of trace metal contamination in synthesized pharmaceuticals.

A facile, efficient, and atom-economic method for preparing benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal- and solvent-free condition has been developed.     

Quantitative and qualitative changes in anti-Neu5Gc antibody response following rabbit anti-thymocyte IgG induction in kidney allograft recipients

Antibodies of non-human mammals are glycosylated with carbohydrate antigens, such as galactose-α-1-3-galactose (α-Gal) and N-glycolylneuraminic acid (Neu5Gc). These non-human carbohydrate antigens are highly immunogenic in humans due to loss-of-function mutations of the key genes involved in their synthesis. Such immunogenic carbohydrates are expressed on therapeutic polyclonal rabbit anti-human T-cell IgGs (anti-thymocyte globulin; ATG), the most popular induction treatment in allograft recipients. To decipher the quantitative and qualitative response against these antigens in immunosuppressed patients, particularly against Neu5Gc, which may induce endothelial inflammation in both the graft and the host. We report a prospective study of the antibody response against α-Gal and Neu5Gc-containing glycans following rabbit ATG induction compared to controls. We show a drop in the overall levels of anti-Neu5Gc antibodies at 6 and 12 months post-graft compared to the pre-existing levels due to the major early immunosuppression. However, in contrast, in a cross-sectional study there was a highly significant increase in anti-Neu5Gc IgGs levels at 6 months post-graft in the ATG-treated compared to non-treated patients(P = 0.007), with a clear hierarchy favouring anti-Neu5Gc over anti-Gal response. A sialoglycan microarray analysis revealed that the increased anti-Neu5Gc IgG response was still highly diverse against multiple different Neu5Gc-containing glycans. Furthermore, some of the ATG-treated patients developed a shift in their anti-Neu5Gc IgG repertoire compared with the baseline, recognizing different patterns of Neu5Gc-glycans. In contrast to Gal, Neu5Gc epitopes remain antigenic in severely immunosuppressed patients, who also develop an anti-Neu5Gc repertoire shift. The clinical implications of these observations are discussed.     

Clinical characteristics and prognostic factors of sinonasal undifferentiated carcinoma: a multicenter study

Background

Sinonasal undifferentiated carcinoma (SNUC) is a very rare entity with a poor prognosis. Due to the lack of studies on the subject, evidence is lacking concerning its management.

Methods

A multicenter collaborative study was conducted to assess treatment strategy, oncological outcome, and prognostic factors.

Results

Definitive analyses focused on 54 patients with a majority of advanced stage; the 3‐year overall survival (OS) and 3‐year recurrence‐free survival (RFS) rates were, respectively, 62.4% and 47.8%. During the follow‐up, 18 patients (33.3%) died, 10 (18.5%) developed metastases, 7 had lymph‐node involvement (13%), and 12 (22.2%) showed recurrence or local progression. In univariate analyses, treatment modalities associated with improved RFS were induction chemotherapy (p = 0.02) and intensity‐modulated radiotherapy (p = 0.007). In the multivariate analyses, only induction chemotherapy (p = 0.047, hazard ratio [HR] = 0.39) was significantly associated with improved RFS.

Conclusion

Multimodal therapies including induction chemotherapy and intensity‐modulated radiotherapy may improve the prognosis of SNUC; surgery might improve local control. Further multicenter studies are required.

     

Interferon gamma signals via a high-affinity multisubunit receptor complex that contains two types of polypeptide chain.

Signaling by interferon gamma (IFN-gamma) requires two structurally related cell surface proteins: a ligand-binding polypeptide, known as the IFN-gamma receptor (IFN-gamma R), and an accessory factor. However, it is not known whether IFN-gamma forms a ternary complex with the IFN-gamma R and accessory factor to initiate signaling. Here we demonstrate complex formation between IFN-gamma and the two proteins, both in solution and at the cell surface. We observe complexes containing ligand, two molecules of IFN-gamma R (designated the IFN-gamma R alpha chain), and one or two molecules of accessory factor (designated the IFN-gamma R beta chain). Transfected cells expressing both IFN-gamma R chains bind IFN-gamma with higher affinity than do cells expressing alpha chain alone. Anti-beta-chain antibodies prevent the beta chain from participating in the ligand-receptor complex, reduce the affinity for IFN-gamma, and block signaling. Soluble alpha- or beta-chain extracellular domains also inhibit function. These results demonstrate that IFN-gamma signals via a high-affinity multisubunit complex that contains two types of receptor chain and suggest a potential approach to inhibiting specific actions of IFN-gamma by blocking the association of receptor subunits.     

Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States

Hepatitis C virus (HCV) RNA status and HCV genotype have become important tools in the diagnosis and monitoring of therapy in chronic HCV infection. To establish a database with respect to HCV genotype and serum HCV RNA concentrations in chronic hepatitis C patients in the United States, we analysed 6807 chronic hepatitis C patients who had HCV RNA and HCV genotype tests conducted at a central laboratory. The HCV RNA concentration cut-off for the lower 25th percentile of this population (low titre) was 0.9 × 10⁶ copies ml^–1. The median HCV RNA concentration was 3.5 × 10⁶ copies ml^–1 and the cut-off for the upper 25th percentile (high titre) was 5 × 10⁶ copies ml^–1. Male patients had a median HCV RNA concentration of 3.9 × 10⁶ copies ml^–1, which was significantly higher than the median HCV RNA level for females (2.75 × 10⁶ copies ml^–1; P  < 0.001). HCV genotype 1 was detected in 73% of patients; genotype 2 in 14%; genotype 3 in 8%; mixed genotype in 4%; and genotypes 4, 5 and 6 with a frequency of < 1%. Patients from the Northeast, Southeast and Midwest had significantly ( P  < 0.001) more infections with genotype 1 than patients from the Western and Southern regions. African–American patients were more likely to be infected with genotype 1 when compared with Caucasian, Hispanic or Asian Pacific Islanders ( P  < 0.001). Patients infected with HCV genotype 1 and mixed HCV genotypes had significantly higher serum HCV RNA concentrations when compared with HCV genotypes 2 and 3 ( P  < 0.001 for all comparisons).     

20S small nuclear ribonucleoprotein U5 shows a surprisingly complex protein composition.

U5 small nuclear ribonucleoprotein (snRNP), purified from HeLa nuclear extracts (splicing extracts), shows a complex protein composition. In addition to the snRNP proteins B', B, D, D', E, F, and G, which are present in each of the major snRNPs U1, U2, U4/U6, and U5, U5 snRNP contains a number of unique proteins characterized by apparent molecular masses of 40, 52, 100, 102, 116, and 200 (mostly a double band) kDa. The latter set of proteins may be regarded as U5-specific for the following reasons. They are not only eluted specifically, together with snRNP particles, from anti-2,2,7-trimethylguanosine immunoaffinity columns by 7-methylguanosine, they also cofractionate with U5 snRNP during chromatography and, most importantly, in glycerol gradient centrifugation. These U5 snRNP particles show a high sedimentation constant of about 20S. U5 snRNPs that lack the U5-specific proteins are also found in nuclear extracts but have (in comparison) a lower sedimentation value of only 8-10S. Autoimmune sera from patients with systemic lupus erythematosus were identified that, on immunoblots with purified U5 snRNP proteins, reacted selectively with the 100- or 200-kDa proteins. This indicates that at least the high molecular mass U5-specific proteins are structurally distinct and not derived one from the other by proteolytic degradation. The existence of so many unique proteins in the U5 snRNP suggests that this snRNP particle may exert its function during splicing mainly by virtue of its protein components.     

Spinal muscular atrophy type 1: management and outcomes

Our objectives were to describe survival, hospitalization, speech, and outcomes related to respirator needs for spinal muscular atrophy type 1 (SMA1) patients, using noninvasive or tracheostomy ventilation. From 65 SMA patients referred to our clinic since 1996, we chose 56 SMA1 patients who developed respiratory failure before age 2 years. Patients either had tracheostomy tubes (group A), or used noninvasive ventilation and assisted coughing; a previously reported extubation protocol (group B) was used as needed.Sixteen patients underwent tracheostomy at 10.8 +/- 5.0 months of age, 33 were in group B, and 7 others died without life-support interventions. Compared to group B, group A patients had fewer hospitalizations until age 3 years, but more after age 5, and 15 of 16 lost all spontaneous breathing tolerance posttracheostomy and could not speak. One group A patient died at 16 months of age, and the others were 73.8 +/- 57 months of age (the oldest was 19 years old). Two group B patients died at 6 and 13 months, respectively, whereas the other 31 were 41.8 +/- 26.0 months (and up to 8.3 years) old. Three of 31 in group B required high-span positive inspiratory pressure plus positive end-expiratory pressure (PIP + PEEP) continuously with minimal tolerance for breathing on their own, and 4 could not communicate verbally.In conclusion, SMA type 1 children can survive beyond 2 years of age when offered tracheostomy or noninvasive respiratory support. The latter is associated with fewer hospitalizations after age 5 years, freedom from daytime ventilator use, and the ability to speak.     

Growth hormone and insulin-like growth factor-I stimulate hormonal function and proliferation of thymic epithelial cells.

We have investigated the role of GH and insulin-like growth factor-I (IGF-I) in controlling the secretion of thymulin, a hormone produced by thymic epithelial cells (TEC). Thymulin plasma concentrations (mean +/- SD) were increased in 21 patients with acromegaly compared to those in 30 controls, as assessed by bioassay (4.24 +/- 0.97 vs. 2.67 +/- 0.87; P less than 0.001) and RIA (561 +/- 241 vs. 315 +/- 113 pg/L; P less than 0.01). Good correlations were observed between plasma levels of thymulin and IGF-I (P less than 0.001). In vitro experiments demonstrated that both recombinant human GH and IGF-I significantly increased thymulin production in culture supernatants of normal human TEC and a rat TEC line. In parallel, IGF-I also significantly stimulated the proliferation of human TEC, as measured by bromodeoxyuridine incorporation. Additionally, the stimulatory effect of GH on thymulin production was abrogated by both an anti-IGF-I antibody and an anti-IGF-I receptor antibody. These results support a role for GH and IGF-I in the control of thymic hormonal function in man and suggest that the effect of GH may be mediated by local secretion of IGF-I within the thymus.