Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small-cell lung cancer.

BACKGROUND: Antibiotic (ABX) use can reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics. The effect for patients treated with targeted therapies, namely, small-molecule tyrosine kinase inhibitors (TKIs), is less known. PATIENTS AND METHODS: Retrospective data were analysed for TKI-treated patients with advanced melanoma and non-small-cell lung cancer (NSCLC) between January 2015 and April 2017 at The Christie NHS Foundation Trust. Data on demographics, disease burden, lactate dehydrogenase (LDH) level, presence of brain metastases, ECOG performance status (PS) and ABX use were collected. Progression-free survival (PFS) and overall survival (OS) were compared between the ABX+ group (ABX within 2 weeks of TKI initiation-6 weeks after) and the ABX- group (no ABX during the same period). RESULTS: A total of 168 patients were included; 89 (53%) with NSCLC and 79 (47%) with melanoma. 55- (33%) patients received ABX. On univariable analysis, ABX+ patients demonstrated shorter PFS (208 versus 357 days; P = 0.008) and OS (294 versus 438 days; P = 0.024). Increased age, poorer PS and higher LDH were associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.05-2.34, P = 0.028] and OS (HR 2.19, 95% CI 1.44-3.32, P = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with PS of ≥2 (HR 3.82, 95% CI 1.18-12.36, P = 0.025). CONCLUSION: For patients treated with TKIs, ABX use is independently associated with reduced PFS and OS and judicious use is warranted, particularly in patients with poorer PS.

Comparison of propofol and the combination of propofol and alfentanil during bronchoscopy: a randomized study.

BACKGROUND: propofol is an excellent sedative agent for use in patients undergoing bronchoscopy. The addition of an opioid to propofol can be advantageous because of the antitussive effect of the opioid and the possible improvement in sedation quality. However, it may increase the risk of hypoxaemia. To investigate the effect of the addition of alfentanil to propofol, we performed a prospective study to compare propofol-only sedation with propofol-alfentanil combination sedation in patients undergoing bronchoscopy. METHODS: patients were randomly assigned either to the propofol-only (group P, n=32) or to the propofol-alfentanil combination group (group PA, n=32). The average peripheral oxygen saturation (SpO(2) ) and the lowest SpO(2) during the sedation were compared. Patient and bronchoscopist satisfaction as well as the degree of coughing were compared using a 100 mm visual analogue scale, where 0 indicated the least and 100 indicated the most satisfied. RESULTS: group P had the higher average SpO(2) (%) during the procedure than group PA (97.8 ± 1.6 and 96.4 ± 1.1, P<0.01) as well as the lowest SpO(2) (%) (95.4 ± 2.7 and 94.0 ± 2.4, P<0.05). Patient satisfaction (92.2 ± 13.5 and 92.3 ± 18.2), bronchoscopist satisfaction (76.6 ± 18.1 and 72.8 ± 19.1), and degree of cough (73.4 ± 22.7 and 72.2 ± 18.5; group P and group PA, respectively) were not different between the groups. CONCLUSIONS: the combination of propofol and alfentanil resulted in a greater respiratory depression than propofol alone; furthermore, the addition of an opioid did not improve the quality of sedation. In conclusion, we do not recommend sedation with propofol and alfentanil during bronchoscopy.

Photoluminescent properties of (la(1-x)Y(x))(0.94)Tb(0.06)PO4 phosphor powders prepared by ultrasonic spray pyrolysis.

The calculated crystallite sizes of (La(1-x)Y(x))(0.94)Tb(0.06)PO4 (0 < or = x < or = 1.0) phosphors ranged from 37-39 nm. Annealed (La(1-x)Y(x))(0.94)Tb(0.06)PO4 (0 < or = x < or = 1.0) phosphors showed a smooth, regular, and spherical morphology. Strong excitation peaks were appeared at 226 and 270 nm for all the phosphors. These were caused by the crystal splitting of 7D and 9D of 4f75d1 configuration in Tb3+, respectively. The characteristic emission peaks were observed at 489, 543, 585, and 621 nm, which were caused by the 5D4-7F(j) (j = 6-3) transitions of Tb3+, respectively. The emission intensity at 543 nm increased with an increase in Y content up to 0.5 and then decreased for a higher Y content.

Luminescence properties of Ca(Y(0.915-x)Gd(x)Al0.025Eu0.06)BO4 phosphors under VUV irradiation.

The major phase of post-treated Ca(Y(0.915-x)Gd(x)A10.025Eu0.06)BO4 (0 < or = x < or = 0.3) phosphors was solid solutions of the constituent oxides, which had an orthorhombic warwickite-like structure. The calculated crystallite size of the Ca(Y(0.915-x)Gd(x)Al0.025Eu0.06)BO4 phosphors was approximately 36 nm. The Gd additive significantly enhanced both the charge transfer (CT) transition of O2(-) -Eu3+ and the absorption of the host materials, thereby resulting in an increase in emission intensity. The Ca(Y(0.715)Gd0.2Al0.025Eu0.06)BO4 phosphor showed the highest emission intensity at 593 nm, which was over five times as strong as that of a Gd-free Ca(Y0.915Al0.025Eu0.06)BO4 phosphor. The addition of Gd was desirable for improving the photoluminescent properties of red-emitting Ca(Y0.915Al0.025Eu0.06)BO4 phosphors.

Characterization and molecular genetic mapping of microsatellite loci in pepper.

Microsatellites or simple sequence repeats are highly variable DNA sequences that can be used as informative markers for the genetic analysis of plants and animals. For the development of microsatellite markers in Capsicum, microsatellites were isolated from two small-insert genomic libraries and the GenBank database. Using five types of oligonucleotides, (AT)(15), (GA)(15), (GT)(15), (ATT)(10) and (TTG)(10), as probes, positive clones were isolated from the genomic libraries, and sequenced. Out of 130 positive clones, 77 clones showed microsatellite motifs, out of which 40 reliable microsatellite markers were developed. (GA)(n) and (GT)(n) sequences were found to occur most frequently in the pepper genome, followed by (TTG)(n) and (AT)(n). Additional 36 microsatellite primers were also developed from GenBank and other published data. To measure the information content of these markers, the polymorphism information contents (PICs) were calculated. Capsicum microsatellite markers from the genomic libraries have shown a high level of PIC value, 0.76, twice the value for markers from GenBank data. Forty six microsatellite loci were placed on the SNU-RFLP linkage map, which had been derived from the interspecific cross between Capsicum annuum "TF68" and Capsicum chinense "Habanero". The current "SNU2" pepper map with 333 markers in 15 linkage groups contains 46 SSR and 287 RFLP markers covering 1,761.5 cM with an average distance of 5.3 cM between markers.

Altered calcium homeostasis in cerebellar Purkinje cells of leaner mutant mice.

The leaner (tg(la)) mouse mutation occurs in the gene encoding the voltage-activated Ca(2+) channel alpha(1A) subunit, the pore-forming subunit of P/Q-type Ca(2+) channels. This mutation results in dramatic reductions in P-type Ca(2+) channel function in cerebellar Purkinje neurons of tg(la)/tg(la) mice that could affect intracellular Ca(2+) signaling. We combined whole cell patch-clamp electrophysiology with fura-2 microfluorimetry to examine aspects of Ca(2+) homeostasis in acutely dissociated tg(la)/tg(la) Purkinje cells. There was no difference between resting somatic Ca(2+) concentrations in tg(la)/tg(la) cells and in wild-type (+/+) cells. However, by quantifying the relationship between intracellular Ca(2+) elevations and depolarization-induced Ca(2+) influx, we detected marked alterations in rapid calcium buffering between the two genotypes. Calcium buffering values (ratio of bound/free ions) were significantly reduced in tg(la)/tg(la) (584 +/- 52) Purkinje cells relative to +/+ (1,221 +/- 80) cells. By blocking the endoplasmic reticulum (ER) Ca(2+)-ATPases with thapsigargin, we observed that the ER had a profound impact on rapid Ca(2+) buffering that was also differential between tg(la)/tg(la) and +/+ Purkinje cells. Diminished Ca(2+) uptake by the ER apparently contributes to the reduced buffering ability of mutant cells. This report constitutes one of the few instances in which the ER has been implicated in rapid Ca(2+) buffering. Concomitant with this reduced buffering, in situ hybridization with calbindin D28k and parvalbumin antisense oligonucleotides revealed significant reductions in mRNA levels for these Ca(2+)-binding proteins (CaBPs) in tg(la)/tg(la) Purkinje cells. All of these results suggest that alterations of Ca(2+) homeostasis in tg(la)/tg(la) mouse Purkinje cells may serve as a mechanism whereby reduced P-type Ca(2+) channel function contributes to the mutant phenotype.

Supraspinal involvement in the production of mechanical allodynia by spinal nerve injury in rats.

This study examined whether or not the production of mechanical allodynia in a rat model of neuropathic pain required an involvement of supraspinal site(s). To this aim, we assessed the effect of spinal cord section at the L1 segment level on the mechanical allodynia sign (i.e. tail flick/twitch response), which was elicited by innocuous von Frey hair stimulation of the tail after unilateral transection of the tail-innervating nerve superior caudal trunk (SCT) at the level between the S3 and S4 spinal nerves. Cord transection or hemisection of the cord ipsilateral to the injured SCT drastically (though not completely) blocked the behavioral sign of mechanical allodynia (leaving noxious pinprick-elicited tail withdrawal reflex intact), whereas sham section or contralateral hemisection of the cord was without effect. These results suggest that the generation of mechanical allodynia following partial peripheral nerve injury involves transmission of the triggering sensory signal to a site(s) rostral to the L1 segment via an ipsilateral pathway(s).

Ventricular premature beat-driven intermittent restoration of coronary blood flow reduces the incidence of reperfusion-induced ventricular fibrillation in a cat model of regional ischemia.

With a cat model of regional cardiac ischemia, we examined whether the incidence of reperfusion-induced ventricular fibrillation (VF) could be reduced by ventricular premature beat (VPB)-driven intermittent reperfusion. In addition, we assessed whether the effect of the intermittent reperfusion was comparable with that of ischemic preconditioning in suppressing the VF. Of 15 cats subjected to uninterrupted reperfusion after 20-minute occlusion of the left anterior descending coronary artery, 13 (86.70%) had VF, whereas only 1 (7.1%) of 14 cats subjected to the VPB-driven intermittent reperfusion had VF. This incidence of VF was significantly lower than that of the animal group subjected to uninterrupted reperfusion. However, it was not statistically different from that (3 of 15) of the group subjected to a 10-minute episode of the coronary artery occlusion before the 20-minute occlusion (i.e., "ischermic preconditioning"). Our results suggest that the VPB-driven intermittent reperfusion (i.e., "postconditioning") is very effective in preventing reperfusion-induced VF and as good as, if not better than, ischemic preconditioning.

Mechanical allodynia is more strongly manifested in older rats in an experimental model of peripheral neuropathy.

Partial peripheral nerve injury often leads to chronic neuropathic pain characterized by symptoms such as allodynia. In the present study, employing a rat model of experimental neuropathy produced by partial denervation of the tail, we examined whether peripheral nerve injury-induced mechanical and thermal allodynia were affected by the animal's age at the time of the injury. The motive of this study was the demonstration in other neuropathy models of the age effects on the manifestation of neuropathic pain symptoms following partial peripheral nerve injury. We compared two groups of young (n = 23, 7-8 weeks old, 150-200 g) and old rats (n = 14, 16-18 months old, 550-800 g). We found that the older rats exhibited more vigorously the behavioral signs of mechanical allodynia during the first week after the nerve injury. With respect to thermal (cold or warm) allodynia, however, we detected no significant difference between young and old rat groups. The results of the present study, as those of previous studies, support the idea that the age at the time of partial peripheral nerve injury affects the severity of certain neuropathic pain symptoms appearing after the injury. However, the present results argue against the suggestion from previous studies that younger subjects are more vulnerable to partial peripheral nerve injury-induced neuropathic pain symptoms.