Paradoxical response in a patient with non-small cell lung cancer who received nivolumab followed by anti-Mycobacterium tuberculosis agents

Anti-programmed cell death-1 (PD-1) agents enhance the antitumor immunoresponse. A number of reports have indicated that patients with malignancies who receive anti-PD-1 agents are at risk for tuberculosis (TB) infection. In this report, we present a patient with non-small cell lung cancer who developed pulmonary tuberculosis while receiving the anti-PD-1 agent nivolumab, and who subsequently demonstrated a paradoxical response (PR) 10 days after initiation of anti-MTB treatment. We suggest that anti-PD-1 agents not only induce the development of pulmonary TB, but also development of PR after anti-MTB treatment, through upregulation of the immune response. Furthermore, based on their radiological and immunological similarity, we speculate that the schema of development of PR closely resembles that of pseudoprogression in non-small cell lung cancer patients after anti-PD-1 treatment.     

Lack of effect of running training at two intensities on cardiac myosin isozyme composition in rats

Little information is available regarding the influence of the intensity of endurance training over biochemical profiles in cardiac muscle. We assessed the effect of running training at two different intensities on cardiac myosin isozyme composition in rats. Male Sprague-Dawley rats (4 weeks old) were divided into four groups: sedentary control (SC), trained at 20 m/min (T20), trained at 40 m/min (T40), and weight-matched sedentary control (WMSC) groups. The T20 and T40 group rats were trained by treadmill running for 60 min/d, 5 d/week at 20 or 40 m/min, respectively, for 11 to 12 weeks. In both groups the left ventricle was significantly heavier than in WMSC animals. The ratio of left ventricle weight to body weight was significantly greater in T40 rats than in either the untrained (SC and WMSC) or trained T20 rats. Thus the extent of exercise-induced cardiac hypertrophy appears to be influenced by the intensity of running training. However, neither of the training programs (1) induced a change in cardiac myosin isozyme composition or (2) had any effect on myocardial succinate dehydrogenase or citrate synthase activity. These results suggest that although the intensity of running training may play an important role in cardiac morphological adaptation, it does not modulate the cardiac biochemical adaptation to running training.     

Novel synthetic approach to poly(p-benzenesulfonamide): Self-polycondensation of active p-aminobenzenesulfonic acid derivatives under mild conditions

Three active p-aminobenzenesulfonic acid derivatives, 1-(p-aminobenzenesulfonyl)imidazole ( 4a ), 1-(p-aminobenzenesulfonyloxy)benzotriazole ( 4b ), and 2-phenyl-4-(p-aminobenzenesulfonyl)-1,3,4-oxadiazoline-5-thione ( 4c ) were synthesized by reacting p-isocyanatobenzenesulfonyl chloride ( 1 ) with stoichiometrical quantities of water in the presence of dibutyltin didodecanoate and subsequently with imidazole, 1-hydroxybenzotriazole and 2-phenyl-1,3,4-oxadiazoline-5-thione, respectively. The self-polycondensation of 4a–c , leading to poly(p-benzenesulfonamide) ( 7 ), was carried out in solution using polar aprotic solvents, N-methyl-2-pyrrolidone (NMP) and hexamethylphosphoric triamide (HMPA), and acidic media, dimethyl sulfoxide (DMSO) and m-cresol, with or without an appropriate acid catalyst or acid acceptor under mild conditions. Poly(p-benzenesulfonamide) having the highest reduced viscosity of 0,14 dl·^?1 was obtained almost quantitatively from 4c by using m-cresol as a solvent without any acid catalyst and acid acceptor at 25°C. The polymers are soluble in polar aprotic solvents such as NMP, HMPA and DMSO and in aqueous sodium hydroxide. These poly(p-benzenesulfonamide)s are less thermally stable than completely aromatic polyamides, because the initial weight-loss started at 250–350°C. Aminolysis of three benzenesulfonic acid derivatives, 1-benzenesulfonylimidazole ( 5a ), 1-benzenesulfonyloxybenzotriazole ( 5b ), and 2-phenyl-4-benzenesulfonyl-1,3,4-oxadiazoline-5-thione ( 5c ), with the same leaving groups was also carried out as a model reaction of self-polycondensation to determine the reaction conditions.     

Reductions in bone turnover, mineral, and structure associated with mechanical properties of lumbar vertebra and femur in glucocorticoid-treated growing minipigs

The present study was designed to determine the effects of glucocorticoid (GC) on bone turnover, minerals, structure, and bone mechanical properties in minipigs. Six 8-month-old G?ttingen minipigs were subcutaneously injected with prednisolone (PN, 0.5 mg/kg body wt (BW)/day, 5 days/week for 26 weeks (Group GC)), 6 were treated with vehicle alone (Group VC), and 4 were sacrificed at start of the study for baseline controls (Group BC). The increase in BW was similar in all groups. PN significantly reduced serum osteocalcin and urinary type-1 collagen N-telopeptide levels at 13 weeks and thereafter, compared with baseline and control, and also reduced serum bone specific alkaline phosphatase levels relative to baseline. At 26 weeks, the longitudinal axis of the lumbar bone and length of femur were smaller in Group GC than Group VC. The total cross-sectional area of femur, but not the lumbar bone, in Group GC was significantly different from Group VC. BMD of the femur, but not L2, measured by DXA, was lower in Group GC than in Groups BC and VC. The cortical shell structure measured by 2D-micro-CT deteriorated and age-dependent increases in trabecular bone structure 3D micro-CT were reduced by PN. PN also caused deterioration of the cortical structure of the mid-femur. In L2 and femur, PN significantly reduced the ultimate load and maximum absorption energy of the femur and L2 compared with Group VC. The structural modulus in Group GC was lower than in Group BC. Regression analyses revealed that bone minerals, bone structure, and chemical markers correlated with mechanical properties of L2 and mid-femur. Our results indicate that PN reduced systemic bone formation and resorption and suppressed the age-dependent increases in bone minerals, structure, and mechanical properties of L2 and mid-femur. Reduced bone turnover seemed to be associated with a reduction in mechanical properties. The growing minipig could be a suitable model of GCs-induced osteoporosis in humans.     

Effect of zirconium on immunological reactions of T cells and macrophages in mice

The effects of zirconium (Zr) on T cells and macrophages in mice were studied in vitro using the indexes of immunological reactions, mitogenesis of C3H/HeJ mouse thymocytes induced by PHA and the production of interleukin-1 of C3H/He mouse intraperitoneal macrophages (MIL-1). The mitogenesis of thymocytes induced by PHA when stimulated with Zr solutions at various concentrations or culture supernatants of macrophages stimulated with LPS and Zr, or Zr alone, ware as shown below. 1. The mitogenesis of thymocytes by PHA was enhanced in the presence of Zr at 0.625-2.5 microM, and suppressed in the presence of Zr at 5-10 microM in culture 2. This reaction was enhanced by the addition of supernatants of macrophages stimulated with LPS and Zr. The most activation by LPS and Zr was shown at concentrations of 0.625-1.25 microM in culture, and the degree activated corresponding to 12.5-25 I.U. of MIL-1. 3. On the other hand, this reaction was inhibited by addition of supernatants of macrophages stimulated with Zr alone. From these results, it is suggested that Zr serves various functions such as an activator or inhibitor of T-cell mitogenesis by PHA, and that this may depend upon the Zr concentration in culture. In regard to the effect of Zr on MIL-1 production, Zr may activate this reaction by LPS, and Zr alone may induce MIL-1 production from macrophages.     

Gastric secretion in rats with chronic gastric fistulae and in stomach-perfused, anesthetized rats

A method of establishing chronic gastric fistulae in rats is described. In rats with chronic gastric fistulae, the basal acid output was 48.8 +/- 2.9 microEq/100 g/hr and the basal pepsin output was 543 +/- 28 micrograms tyrosine/100 g/hr. The effects of urethane-induced anesthesia, pyloric ligation, and acute laparotomy on gastric secretion in rats were examined. Both urethane-induced anesthesia and acute laparotomy depressed gastric secretions. In Ghosh-Schild rats, the basal acid output was 3.2 +/- 0.4 microEq/100 g/hr and the basal pepsin output was 70 +/- 13 micrograms tyrosine/100 g/hr. The persistent and very low level of of gastric secretion in these animals appears to result from the combination of both urethane anesthesia and invasive surgery. Because the rats with chronic gastric fistulae do not require anesthesia, invasive surgery, or pyloric ligation, which may play very important roles in the regulation of gastric functions, this kind of preparation is a suitable method for studying the physiology and pharmacology of gastric secretions in the rat.