A multicenter, randomized phase 2 study to establish combinations of CBP501, cisplatin and nivolumab for ≥3rd-line treatment of patients with advanced pancreatic adenocarcinoma.

BACKGROUND: There is no standard of care for ≥ 3rd-line treatment of metastatic pancreatic adenocarcinoma (PDAC). CBP501 is a novel calmodulin-binding peptide that has been shown to enhance the influx of platinum agents into tumor cells and tumor immunogenicity. This study aimed to (1) confirm efficacy of CBP501/cisplatin/nivolumab for metastatic PDAC observed in a previous phase 1 study, (2) identify combinations that yield 35% 3-month progression-free survival rate (3MPFS) and (3) define the contribution of CBP501 to the effects of combination therapy. METHODS: CBP501 16 or 25 mg/m2 (CBP(16) or CBP(25)) was combined with 60 mg/m2 cisplatin (CDDP) and 240 mg nivolumab (nivo), administered at 3-week intervals. Patients were randomized 1:1:1:1 to (1) CBP(25)/CDDP/nivo, (2) CBP(16)/CDDP/nivo, (3) CBP(25)/CDDP and (4) CDDP/nivo, with randomization stratified by ECOG PS and liver metastases. A Fleming two-stage design was used, yielding a one-sided type I error rate of 2.5% and 80% power when the true 3MPFS is 35%. RESULTS: Among 36 patients, 3MPFS was 44.4% in arms 1 and 2, 11.1% in arm 3% and 33.3% in arm 4. Two patients achieved a partial response in arm 1 (ORR 22.2%; none in other arms). Median PFS and OS were 2.4, 2.1, 1.5 and 1.5 months and 6.3, 5.3, 3.7 and 4.9 months, respectively. Overall, all treatment combinations were well tolerated. Most treatment-related adverse events were grade 1-2. CONCLUSIONS: The combination CBP(25)/(16)/CDDP/nivo demonstrated promising signs of efficacy and a manageable safety profile for the treatment of advanced PDAC. CLINICAL TRIAL REGISTRATION: NCT04953962.

A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood.

BACKGROUND: The lack of an accurate blood biomarker in neuroendocrine tumor (NET) disease has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy-liquid biopsy-to facilitate real-time management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD). PATIENTS AND METHODS: A systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified ten original scientific papers that met the inclusion criteria. These were assessed by qualitative analysis and thereafter meta-analysis. Data were pooled and a median [95% confidence interval (CI)] diagnostic odds ratio (DOR), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and area under the curve (AUC) data. RESULTS: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. The meta-analysis identified the diagnostic accuracy of the NETest to be 95%-96% with a mean DOR of 5 853, +LR of 195, and -LR of 0.06. The NETest was 84.5%-85.5% accurate in differentiating stable disease from progressive disease. As a marker of natural history, the accuracy was 91.5%-97.8%. As an interventional/response biomarker, the accuracy was 93.7%-97.4%. The pooled AUC for the NETest was 0.954 ± 0.005, with a z-statistic of 175.06 (P < 0.001). CONCLUSIONS: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of this as a biomarker provides information relevant to NET management consistent with observations regarding utility of liquid biopsies in other oncological disciplines.

Lack of phototoxicity potential with delafloxacin in healthy male and female subjects: comparison to lomefloxacin.

AIMS: Delafloxacin is a fluoroquinolone antibiotic recently approved by the FDA for treatment of acute bacterial skin and skin structure infections (ABSSSI). Delafloxacin was assessed for phototoxicity potential compared with a known phototoxic fluoroquinolone. METHODS: A Phase 1, investigator-blind, placebo/active-controlled, randomized, parallel-group study was conducted in 52 healthy male and female volunteers who received 200 or 400 mg of oral delafloxacin, 400 mg oral lomefloxacin or placebo once daily for 6 days. This study evaluated the photosensitizing potential and possible wavelength dependency of delafloxacin by comparing the response of the skin to ultraviolet A (UVA), ultraviolet B (UVB) and visible radiation prior to and during administration of delafloxacin, lomefloxacin as a positive control, or placebo. Adverse events were monitored throughout the study. RESULTS: Forty-seven subjects completed six days of dosing, and no evidence of phototoxicity was seen with delafloxacin. Delafloxacin at 200 and 400 mg day-1 and placebo did not demonstrate differences in percent change from baseline in minimal erythema dose at all tested wavelengths (295-430 nm) by monochromator and solar simulator. Lomefloxacin, the positive control, had statistically significant differences (p < 0.05) at UVA wavelengths of 335 and 365 ± 30 nm 24 hours after radiation exposure (maximum response). The phototoxic index results were significantly higher for lomefloxacin at 335 nm and 365 nm compared to placebo and delafloxacin. CONCLUSIONS: 200 and 400 mg of delafloxacin administered for 6 days were well tolerated in healthy adult volunteers. Delafloxacin and placebo failed to demonstrate a phototoxic effect but lomefloxacin, the positive control, demonstrated moderate phototoxicity.

Mechanical and physiological examination of barefoot and shod conditions in female runners.

Barefoot running and running using minimalist footwear have become increasingly popular in recent years. Footwear choice may affect running mechanics and the metabolic cost of running. To investigate these factors, 8 well-trained, female distance runners (mean age=20.1±1.4 years) were recruited to participate in the study. Following orientation to testing procedures, subjects completed 3 running economy tests on separate days. Treatment order (barefoot, minimalist footwear and running shoe) was counter-balanced. Each testing session consisted of a 5-min warm-up at 2.24 m · s(-1), followed by the 7-min RE test at 3.13 m · s(-1). Biomechanical data were collected at the 3-min mark for 10 s, and expired gases were collected from minutes 5-7. One-way repeated measures ANOVA revealed a statistically significant difference for running economy (p=0.04), expressed as relative oxygen uptake per km in the barefoot condition (running shoe: 204.51±2.84; minimalist footwear: 198.21±3.04; barefoot: 193.26±3.62 ml · kg(-1)· km(-1)) vs. running shoe. The other physiological and biomechanical variables were not statistically significant (p>0.05). However, moderate to large effect sizes suggested there were biomechanical changes that ensured between conditions. It should be further evaluated whether these mechanical adjustments and the running economy trend would translate into improved distance race performance while running barefoot or with minimalist footwear.

Torsional electromechanical systems based on carbon nanotubes.

Carbon nanotubes (CNTs) are among the most highly studied nanomaterials due to their unique (and intertwined) mechanical and electrical properties. Recent advances in fabrication have allowed devices to be fabricated that are capable of applying a twisting force to individual CNTs while measuring mechanical and electrical response. Here, we review major results from this emerging field of study, revealing new properties of the material itself and opening possibilities for advances in future devices.

Abundance and bionomics of Ochlerotatus j. japonicus in two counties in southwestern Virginia.

Movement of Ochlerotatus japonicus japonicus into virus-endemic areas in the USA has raised concern about its vector potential and prompted monitoring of its spread. The abundance and seasonal distribution of Oc. japonicus in southwestern Virginia was measured in 2003 and 2004 using gravid traps. In 2003, collections were made over 192 trap-nights from June to August yielding 5,879 mosquitoes of which only 24 were Oc. japonicus. In 2004, 12,151 mosquitoes were trapped from June to September over 160 trap-nights. Ochlerotatus japonicus was the second most abundant mosquito species and the dominant Ochlerotatus species collected in gravid traps. Ochlerotatus japonicus was collected in low numbers in June, but the abundance increased significantly in July and remained consistent throughout the rest of the season. Of the other major mosquito species collected in this study, only Aedes albopictus exhibited a similar seasonal pattern as Oc. japonicus. Other biological similarities of Oc. japonicus and Ae. albopictus are discussed.

Electron beam induced structural transformations of SWNTs and DWNTs grown on Si3N4/Si substrates.

Electron beam induced structural transformations are investigated in single-wall carbon nanotubes (SWNTs), double-wall carbon nanotubes (DWNTs) and crossed nanotube junctions. The nanotubes studied here are synthesized by the chemical vapor deposition method. The response of the nanotubes to an electron beam is found to be influenced by the presence of coatings of amorphous carbon, graphene fragments and structural defects on the tube surface. The dependence of structural modifications on electron beam irradiation dose is measured. While nanotubes with amorphous carbon, graphene fragment coverage and/or defects undergo rapid transformation leading to structure disintegration, those without such coverage or defects are more resistant to beam damage. In addition, it is shown that the amorphous carbon coverage on the double-wall nanotubes can be transformed into graphene layers during electron beam irradiation of coated nanotubes. Finally, the relative stability of nanotube side-wall and end-walls are investigated through sub-threshold energy and above threshold energy irradiation of a model system, C60-filled nanotubes (Peapods). The data indicates that electron beams could be used to join nanotubes end-to-end without damaging the side-walls.

Electrochemical olefin epoxidation employing an iron(IV)porphyrin/trisbipyridineruthenium(III) polymer catalyst.

A porphyrin molecule containing four meso-appended 2,2'-bipyridyl ligands has been prepared. Each bipyridine is attached to the porphyrin core at the 4-position (pseudo-para to one of the pyridine nitrogens). Subsequently, each of the four bipyridines was complexed with a RuL2(2+) moiety and iron coordinated in the porphyrin core. When L = 4-vinyl-4'-methyl-2,2'-bipyridine, reduction of the ruthenium centers resulted in the formation of robust electroactive polymer films which deposited on the electrode surface. In the presence of aqueous acid, these films electrocatalytically epoxidize cyclohexene at positive potentials from the formal iron(IV) oxidation state. Although product analysis has only been conducted for cyclohexene, the catalytic activity extends to a large variety of olefins including ethylene and propylene.

Controlled switching of optical emission energies in semiconducting single-walled carbon nanotubes.

We present scanning photoluminescence (PL) microscopy of freely suspended single-walled carbon nanotubes grown by chemically assisted vapor deposition (CVD) across micron-sized open apertures. Scans of the PL emission versus excitation position show unusual "holes"having subwavelength spatial features associated with abrupt blue shifts of the emission energy. By varying the excitation polarization, energy, intensity, and position, we demonstrate that optical switching in some nanotubes is controllable in a highly nonlinear manner by adjusting the nonequilibrium carrier density in the nanotube. Technologically important attributes include large spectral contrast between on/off states at room temperature, a dramatic response to small changes in light intensity near threshold, and the possibility that electrical charge injection could also be used to control emission energies.

A fast, convenient and rugged procedure for characterizing the selectivity of alkyl-silica columns.

Previous work has shown that the selectivity of reversed-phase columns for HPLC can be described by means of five column parameters: H (hydrophobicity), S* (steric resistance), A (hydrogen-bond acidity), B (hydrogen-bond basicity) and C (cation-exchange capacity). Values of H, S*, etc. can be determined by carrying out retention measurements for 18 test solutes under standardized conditions. The reproducibility of the latter procedure has been evaluated by comparison testing in four different laboratories and found acceptable. An alternative 10-solute test procedure which is more reproducible and convenient (but somewhat less accurate), requires only 2-3 h per column.

Habitat preferences and phenology of Ochlerotatus triseriatus and Aedes albopictus (Diptera: Culicidae) in southwestern Virginia.

Recently, the number of reported human cases of La Crosse encephalitis, an illness caused by mosquito-borne La Crosse virus (LAC), has increased in southwestern Virginia, resulting in a need for better understanding of the virus cycle and the biology of its vectors in the region. This study examined the spatial and temporal distributions of the primary vector of LAC, Ochlerotatus triseriatus (Say), and a potential secondary vector, Aedes albopictus (Skuse). Ovitrapping surveys were conducted in 1998 and 1999 to determine distributions and oviposition habitat preferences of the two species in southwestern Virginia. Mosquitoes also were collected for virus assay from a tire dump and a human La Crosse encephalitis case site between 1998 and 2000. Oc. triseriatus and Ae. albopictus were collected from all ovitrap sites surveyed, and numbers of Oc. triseriatus eggs generally were higher than those of Ae. albopictus. Numbers of Oc. triseriatus remained high during most of the summer, while Ae. albopictus numbers increased gradually, reaching a peak in late August and declining thereafter. In Wise County, relative Ae. albopictus abundance was highest in sites with traps placed in open residential areas. Lowest numbers of both species were found in densely forested areas. Ovitrapping during consecutive years revealed that Ae. albopictus was well established and overwintering in the area. An oviposition comparison between the yard and adjacent forest at a human La Crosse encephalitis case site in 1999 showed that Ae. albopictus preferentially oviposited in the yard surrounding the home, but Oc. triseriatus showed no preference. LAC isolations from larval and adult collections of Oc. triseriatus females from the same case site indicated the occurrence of transovarial transmission.

Pharmacokinetics, metabolism and excretion of an inhibitor of inducible nitric oxide synthase, L-NIL-TA, in dog.

1. The pharmacokinetics, metabolism and excretion of L-NIL-TA, an inducible nitric oxide synthase inhibitor, were investigated in dog. 2. The dose of [14C]L-NIL-TA was rapidly absorbed and distributed after oral and intravenous administration (5 mg kg-1), with Cmax of radioactivity of 6.45-7.07 microg equivalents g-1 occurring at 0.33-0.39-h after dosing. After oral and intravenous administration, radioactivity levels in plasma then declined with a half-life of 63.1 and 80.6-h, respectively. 3. Seven days after oral and intravenous administrations, 46.4 and 51.5% of the radioactive dose were recovered in urine, 4.59 and 2.75% were recovered in faeces, and 22.4 and 22.4% were recovered in expired air, respectively. The large percentages of radioactive dose recovered in urine and expired air indicate that [14C]L-NIL-TA was well absorbed in dogs and the radioactive dose was cleared mainly through renal elimination. The mean total recovery of radioactivity over 7 days was approximately 80%. 4. Biotransformation of L-NIL-TA occurred primarily by hydrolysis of the 5-aminotetrazole group to form the active drug L-N6-(1-iminoethyl)lysine (NIL or M3), which was further oxidized to the 2-keto acid (M5), the 2-hydroxyl acid (M1), an unidentified metabolite (M2) and carbon dioxide. The major excreted products in urine were M1 and M2, representing 22.2 and 21.2% of the dose, respectively.

Tissue factor pathway inhibitor does not influence inflammatory pathways during human endotoxemia.

Activation of coagulation induces a proinflammatory response in in vitro and animal experiments. Inhibition of the tissue factor-dependent pathway of coagulation inhibits cytokine release and prevents death in gram-negative sepsis models in primates. This study investigated the influence of blocking the coagulation system by tissue factor pathway inhibitor (TFPI) on endotoxin-induced inflammatory responses in healthy humans. Eight men were studied in a double-blind, randomized, placebo-controlled cross-over study. They received a bolus intravenous injection of 4 ng/kg of endotoxin, followed by a 6-h continuous infusion of either TFPI (0.2 mg/kg/h after a bolus of 0.05 mg/kg) or placebo. Endotoxin induced-activation of coagulation was prevented completely by TFPI. In contrast, TFPI did not influence leukocyte activation, chemokine release, endothelial cell activation, or the acute phase response. Thus, complete prevention of coagulation activation by TFPI does not influence activation of inflammatory pathways during human endotoxemia.

Pharmacokinetics of celecoxib after oral administration in dogs and humans: effect of food and site of absorption.

Celecoxib pharmacokinetics was evaluated after single and multiple oral dosing; after dosing in a solution and as a solid; with and without food; and after administration into different sites of the GI tract using dog. After oral dosing in a solution, celecoxib was rapidly absorbed and reached maximum concentrations by 1 h; absorption was delayed another 1 to 2 h when administered as a solid. The absolute bioavailability of celecoxib was higher when given as a solution (64--88%) compared with capsule (22--40%). The absorption of celecoxib given in a capsule was delayed by food, although systemic exposure increased by 3- to 5-fold. The systemic availability of celecoxib given intragastrically in solution was similar to that obtained following direct instillation into the duodenum, jejunum, or colon through a chronic intestinal access port. Collectively, these data suggest that celecoxib is a highly permeable drug that can be absorbed throughout the GI tract and that dissolution may be a rate-limiting factor for absorption from solid dosage forms. Unlike dogs, celecoxib given to humans with a high fat meal exhibits only a slight increase in AUC(0--infinity) (11%) that is not clinically significant with regard to safety or efficacy. In humans, a lower dose and a longer GI residence time may promote the opportunity for absorption of a poorly soluble drug such as celecoxib that can be absorbed throughout the GI tract. This would minimize the effect of food on absorption; as such, patients with arthritis can be given celecoxib with or without food.

Low proliferative rate of invasive node-negative breast cancer predicts for a favorable outcome: a prospective evaluation of 669 patients.

This study was designed to compare outcome in terms of disease-free survival (DFS) in women with histologically negative axillary lymph nodes and documented low proliferative rate cancer to other well-defined prognostic factors including type of adjuvant treatment. Between 1988 and 1998, we studied 669 patients with invasive node-negative breast cancer up to 5 cm in size and low proliferative rate measured by flow cytometry to determine S-phase fraction (SPF) or by histochemistry (Ki67/MIB1). At a median follow-up of 53 months, 5-year DFS for the entire group was 94% and did not differ significantly by type of systemic adjuvant treatment: none (133 patients, 95% DFS), tamoxifen (441 patients, 94% DFS), or chemotherapy with doxorubicin and cyclophosphamide (95 patients, 92% DFS). In a multivariate prognostic factor analysis, only tumor size was significant; 5-year DFS was 96% for T1N0 cancer versus 89% for T2N0 cancer (P = 0.01). We have prospectively confirmed that a low rate of proliferation as measured by SPF or MIB1 determination confers an excellent prognosis in invasive node-negative breast cancer up to 5 cm in size, regardless of adjuvant treatment.

Characterization of metabolites of Celecoxib in rabbits by liquid chromatography/tandem mass spectrometry.

The metabolism of the anti-inflammatory drug Celecoxib in rabbits was characterized using liquid chromatography (LC)/tandem mass spectrometry (MS/MS) with precursor ion and constant neutral loss scans followed by product ion scans. After separation by on-line liquid chromatography, the crude urine samples and plasma and fecal extracts were analyzed with turbo-ionspray ionization in negative ion mode using a precursor ion scan of m/z 69 (CF(3)) and a neutral loss scan of 176 (dehydroglucuronic acid). The subsequent product ion scans of the [M - H] ions of these metabolites yielded the identification of three phase I and four phase II metabolites. The phase I metabolites had hydroxylations at the methyl group or on the phenyl ring of Celecoxib, and the subsequent oxidation product of the hydroxymethyl metabolite formed the carboxylic acid metabolite. The phase II metabolites included four positional isomers of acyl glucuronide conjugates of the carboxylic acid metabolite. These positional isomers were caused by the alkaline pH of the rabbit urine and were not found in rabbit plasma. The chemical structures of the metabolites were characterized by interpretation of their product ion spectra and comparison of their LC retention times and the product ion spectra with those of the authentic synthesized standards.

Tunable resistance of a carbon nanotube-graphite interface.

The transfer of electrons from one material to another is usually described in terms of energy conservation, with no attention being paid to momentum conservation. Here we present results on the junction resistance between a carbon nanotube and a graphite substrate and show that details of momentum conservation also can change the contact resistance. By changing the angular alignment of the atomic lattices, we found that contact resistance varied by more than an order of magnitude in a controlled and reproducible fashion, indicating that momentum conservation, in addition to energy conservation, can dictate the junction resistance in graphene systems such as carbon nanotube junctions and devices.

Students' perceptions of parent-adolescent closeness and communication about sexuality: relations with sexual knowledge, attitudes, and behaviors.

The main goal of this study was to explore how parent-adolescent closeness and communication about sexuality were associated with three aspects of adolescent sexuality (sexual knowledge, attitudes and behaviors). Participants were 157 boys and girls in grades 9 to 12 from two suburban high schools in the Midwest. Canonical correlation analyses revealed two significant combinations of variables. First, younger age and less maternal and paternal communication were related to less sexual behavior and less sexual knowledge. Second, being younger and female and receiving less maternal communication was related to less sexual knowledge and more conservative attitudes. Contrary to expectation, higher levels of parental closeness in conjunction with parental communication did not have a significant influence on these adolescents' sexuality. Given the importance of both age and parental communication in predicting adolescent's sexuality in this study, implications concerning the timing of communication become evident.

Comparison of celecoxib metabolism and excretion in mouse, rabbit, dog, cynomolgus monkey and rhesus monkey.

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit, the EM (extensive) and PM (poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [14C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [14C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.

The influence of reduced liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue factor pathway inhibitor.

OBJECTIVES: Recombinant tissue factor pathway inhibitor (rTFPI) has been shown to be an effective treatment in animal models of sepsis and is under investigation for human use. Reduced liver blood flow during septic shock may substantially alter the pharmacokinetics of rTFPI because clearance of rTFPI approaches liver blood flow. The aim of this study was to examine the effect of exercise-induced reduction in liver blood flow on the pharmacokinetics and pharmacodynamics of rTFPI. METHODS: This was a two-way, open-label, randomized crossover study in eight healthy male volunteers. The subjects in both treatment groups received a continuous intravenous infusion of rTFPI (0.2 mg/kg/h) concurrently with intravenous sorbitol (50 mg/min) for 4 hours. Sorbitol was used as a biomarker for liver blood flow. The subjects were randomized to remain supine or to exercise on a bicycle ergometer for 30 minutes starting at the beginning of the third hour of the infusion. RESULTS: Exercise reduced liver blood flow (mean +/- SEM) from 1.44 +/- 0.06 L/min to 0.40 +/- 0.03 L/min. The average clearance of rTFPI decreased from 0.73 +/- 0.04 L/min in the supine position to 0.25 +/- 0.02 L/min during exercise. This decrease in rTFPI clearance resulted in an 80% (95% confidence interval [CI], 60% to 102%) increase in plasma rTFPI levels during exercise. The average maximal prothrombin time and activated partial thromboplastin time values during exercise were 1.4 (95% CI, 0.4 to 2.5) and 4.4 (95% CI, 2.7 to 6.1) seconds higher compared with the supine steady-state level. CONCLUSIONS: Reduction in liver blood flow by exercise markedly increased rTFPI concentrations and induced a slight but variable prothrombin time and activated partial thromboplastin time increase at the rTFPI dose studied.