A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors.

BACKGROUND: Tivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination. PATIENTS AND METHODS: Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360 mg capsules) in combination with gemcitabine (1000 mg/m(2) weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration). RESULTS: Twenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120 mg b.i.d. (n = 4), 240 mg b.i.d. (n = 6) and 360 mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360 mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine. CONCLUSION: The combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma. CLINICALTRIALSGOV IDENTIFIER: NCT00874042.

Author Correction: Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution.

Guinea pigs (Cavia spp.) have a long association with humans. From as early as 10,000 years ago they were a wild food source. Later, domesticated Cavia porcellus were dispersed well beyond their native range through pre-Columbian exchange networks and, more recently, widely across the globe. Here we present 46 complete mitogenomes of archaeological guinea pigs from sites in Peru, Bolivia, Colombia, the Caribbean, Belgium and the United States to elucidate their evolutionary history, origins and paths of dispersal. Our results indicate an independent centre of domestication of Cavia in the eastern Colombian Highlands. We identify a Peruvian origin for the initial introduction of domesticated guinea pigs (Cavia porcellus) beyond South America into the Caribbean. We also demonstrate that Peru was the probable source of the earliest known guinea pigs transported, as part of the exotic pet trade, to both Europe and the southeastern United States. Finally, we identify a modern reintroduction of guinea pigs to Puerto Rico, where local inhabitants use them for food. This research demonstrates that the natural and cultural history of guinea pigs is more complex than previously known and has implications for other studies regarding regional to global-scale studies of mammal domestication, translocation, and distribution.

Classical swine fever in Victorian domestic pigs: evidence of disease freedom.

OBJECTIVE: Australia is currently regarded as free of classical swine fever (CSF), a highly contagious disease of pigs caused by a pestivirus. This study aimed to provide additional evidence that the Victorian domestic pig population is free of CSF. DESIGN: A structured representative sero-prevalence survey of Victorian domestic pigs at slaughter. METHOD: Three-hundred and ninety-one pigs from 23 holdings were sampled at the time of slaughter between March 2016 and October 2017. RESULTS: All samples were negative for CSF virus Ab on ELISA. Because of uncertainty in the sensitivity of the CSF Ab ELISA, estimates of the true prevalence of CSF were calculated using Bayesian methods. The median and upper bound of the 95% credible intervals for the true prevalence of CSF was zero when the diagnostic sensitivity of the CSF Ab ELISA was assumed to range from 0.75 to 0.95. CONCLUSION: These results provide evidence that the population of domestic pigs in Victoria in 2016-2017 was free of CSF.

Purification, crystallization and preliminary crystallographic analysis of porcine aldose reductase.

Large crystals of porcine aldose reductase have been grown from polyethylene glycol solutions. The crystals are triclinic, space-group P1, with a = 81.3 A, b = 85.9 A, c = 56.6 A, alpha = 102.3 degrees, beta = 103.3 degrees and gamma = 79.0 degrees. The crystals grow within ten days to dimensions of 0.6 mm x 0.4 mm x 0.2 mm and diffract to at least 2.5 A. There are four molecules in the unit cell related by a set of three mutually perpendicular non-crystallographic 2-fold axes.

Stress resistance and longevity in selected lines of Drosophila melanogaster.

Five independent populations (lines) of Drosophila melanogaster were selected for female starvation resistance. Females and males from the selected lines were relatively starvation resistant when compared to flies from five control lines. Moreover, flies from selected lines were resistant to other stresses: desiccation, acetone fumes, ethanol fumes, and paraquat (a source of oxygen radicals). Data from a variety of previous studies indicate an association between stress resistance and longevity. In this context, the present study addressed the question of whether flies from the stress-resistant lines were relatively long-lived. Replicate population cages from each selected and control line were used to assess longevity. Neither females nor males from the selected lines were relatively long-lived. In at least some cases, stress resistance may be necessary, but not sufficient, for longevity.

Antimicrobial activity of chicken and turkey heterophil peptides CHP1, CHP2, THP1, and THP3.

Four avian heterophil antimicrobial cationic peptides (Chicken Heterophil Peptides 1 and 2, and Turkey Heterophil Peptides 1 and 3) were evaluated for in vitro microbicidal activity against selected avian pathogens and human pathogens which are harbored by birds. At concentrations of 16-2 micrograms/ml, all four avian peptides effected a greater than 90% reduction in the survival of Candida albicans, Salmonella enteriditis, and Campylobacter jejuni. None of the peptides, including the known antimicrobial peptide protamine (used as a positive control), were able to reduce the survival of Pasteurella multocida by 90% at the maximum peptide concentration (16 micrograms/ml) tested. At 16 micrograms/ml, the turkey peptide THP3 did not effect a 90% reduction in survival of Bordetella avium, Escherichia coli, or Salmonella typhimurium, while all of the other peptides tested were effective at this concentration or less. This peptide, THP3, does not share the same homologous amino acid sequence shared by the other three peptides. Under our experimental conditions, none of the peptides neutralized Infectious Bronchitis Virus, an enveloped coronavirus of chickens.

Hearing rehabilitation using the BAHA bone-anchored hearing aid: results in 40 patients.

OBJECTIVE: This study evaluates the U.S. experience with the first 40 patients who have undergone audiologic rehabilitation using the BAHA bone-anchored hearing aid. STUDY DESIGN: This study is a multicenter, nonblinded, retrospective case series. SETTING: Twelve tertiary referral medical centers in the United States. PATIENTS: Eligibility for BAHA implantation included patients with a hearing loss and an inability to tolerate a conventional hearing aid, with bone-conduction pure tone average levels at 60 dB or less at 0.5, 1, 2, and 4 kHz. INTERVENTION: Patients who met audiologic and clinical criteria were implanted with the Bone-Anchored Hearing Aid (BAHA, Entific Corp., Gothenburg, Sweden). MAIN OUTCOME MEASURES: Preoperative air- and bone-conduction thresholds and air-bone gap; postoperative BAHA-aided thresholds; hearing improvement as a result of implantation; implantation complications; and patient satisfaction. RESULTS: The most common indications for implantation included chronic otitis media or draining ears (18 patients) and external auditory canal stenosis or aural atresia (7 patients). Overall, each patient had an average improvement of 32+/-19 dB with the use of the BAHA. Closure of the air-bone gap to within 10 dB of the preoperative bone-conduction thresholds (postoperative BAHA-aided threshold vs. preoperative bone-conduction threshold) occurred in 32 patients (80%), whereas closure to within 5 dB occurred in 24 patients (60%). Twelve patients (30%) demonstrated 'overclosure' of the preoperative bone-conduction threshold of the better hearing ear. Complications were limited to local infection and inflammation at the implant site in three patients, and failure to osseointegrate in one patient. Patient response to the implant was uniformly satisfactory. Only one patient reported dissatisfaction with the device. CONCLUSIONS: The BAHA bone-anchored hearing aid provides a reliable and predictable adjunct for auditory rehabilitation in appropriately selected patients, offering a means of dramatically improving hearing thresholds in patients with conductive or mixed hearing loss who are otherwise unable to benefit from traditional hearing aids.

Risk factors for gastric ulcers in Australian pigs at slaughter.

The stomachs of pigs (n=15,741) originating from 136 herds from the Australian states of Queensland, Western Australia, Victoria and New South Wales were examined at slaughter for the presence of oesophago-gastric ulcers (OGUs). Stomachs were categorised as being normal, hyperkeratotic, eroded, ulcerated, or having strictures. A questionnaire was distributed to piggery owners to identify factors associated with an above-average herd prevalence of OGU. Thirty percent of all pigs examined had OGU (median within-herd prevalence of 17%). The median within-herd prevalence in Victoria (53%) was significantly higher than in Western Australia (30%) or Queensland (7%). The prevalence of OGU in culled breeding animals was significantly higher than in porkers or baconers from the same herds. There was no difference between the prevalence of OGU in male and female pigs sampled from the same Western Australian herds. The relationship between OGU and herd and pig risk factors was assessed by random effects logistic-regression analysis. Herds with a high prevalence of OGU were more likely to feed ad libitum (OR=13.7), use automated feeding systems (OR=7.8), feed a pelleted ration (OR=384) and get water from a dam rather than from a bore or river (OR=3.8). Furthermore, for every change in the ration formulation for finisher pigs, the risk of OGU increased 1.5 times.

Production of monoclonal antibodies to the Bordetella avium 41-kilodalton surface protein and characterization of the hemagglutinin.

Production of monoclonal antibodies (MAbs) to Bordetella avium surface proteins led to further characterization of the hemagglutinin. Proteins obtained by homogenization of whole-cell B. avium were used to immunize mice for the production of monoclonal antibodies. Immunoprecipitation and Western blot techniques were used to determine the specificity of three MAbs, which all recognized the B. avium 41-kilodalton (kd) surface protein. In addition, all of the MAbs inhibited hemagglutination (HA) of guinea pig erythrocytes by B. avium. The 41-kd protein recognized by the MAbs was observed by the indirect immunofluorescence test and sodium dodecyl sulfate-polyacrylamide gel electrophoresis to bind to guinea pig erythrocytes. When HA-positive isolates of B. avium were treated with periodic acid, which cleaves carbohydrates from proteins, the isolates became HA-negative. Likewise, treatment of HA-positive B. avium isolates with proteinase K, which would also remove carbohydrates associated with proteins on the surface of the bacterium, inhibited HA. Considering these data, we suggest that the B. avium hemagglutinin is a carbohydrate closely associated with the 41-kd surface protein.

Reticuloendotheliosis virus (REV) long terminal repeats incorporated in the genomes of commercial fowl poxvirus vaccines and pigeon poxviruses without indication of the presence of infectious REV.

Because of reticuloendotheliosis virus (REV) contamination in commercial poultry vaccines, polymerase chain reaction (PCR) assays have been described to increase the sensitivity of biological assays used to detect REV in vaccines. The PCR assay designed to amplify the long terminal repeat (LTR) region of REV identified REV LTRs in many of the commercial fowl poxvirus (FPV) vaccines evaluated. These commercial vaccines were not thought to be contaminated with replicating REV because of the lack of REV outbreaks, the lack of in vitro amplification, and lack of a serologic response to REV. As previously described, the FPV S vaccine strain is known to carry infectious integrated proviral REV, whereas FPV M vaccine strain and its derivatives carry integrated LTRs or remnants of REV proviral DNA inserted into the FPV genome. Another PCR assay designed to amplify the envelope gene of REV was used to verify that the envelope proviral gene was not present in REV LTR PCR-positive samples. Southern blot analysis with REV LTR probes hybridized to the 9-kb EcoRI genomic fragment of all FPV and pigeon poxviruses evaluated, whereas the envelope probe did not hybridize to any poxvirus genome. Sequence analysis of the 9-kb EcoRI fragment indicated that an integrated REV LTR exists in the 9-kb EcoRI of some poxvirus genomes. A new PCR assay designed to amplify integrated REV LTRs in the 9-kb EcoRI fragment identified complete and incomplete integrated REV LTRs in all FPV and pigeon poxvirus genomes evaluated.

Bordetella avium hemagglutination and motility mutants: isolation, characterization, and pathogenicity.

Transposon mutagenesis was used to produce Bordetella avium mutants, which were screened for the lack of potential virulence factors, including a hemagglutinin, flagella, pili, and toxins. A mini-Tn10 transposon containing a kanamycin-resistance gene was introduced into the chromosomal DNA of the virulent 002/S isolate by electroporation. A hemagglutination-negative (HA-) mutant and a motility-negative mutant were obtained. Southern blot analysis showed that only the motility-negative mutant contained the transposon, whereas the HA- mutant was a spontaneous kanamycin-resistant mutant. Both mutants were stable in vitro and in vivo. Following inoculation of 2-week-old poults, the HA- mutant was determined to be less virulent than the 002/S parent, whereas the motility-negative mutant was similar in virulence to the 002/S parent. These results indicate that the hemagglutinin of B. avium is a virulence factor, but motility does not appear to contribute to virulence.

Protein crystal growth and the International Space Station.

Protein structural information plays a key role in understanding biological structure-function relationships and in the development of new pharmaceuticals for both chronic and infectious diseases. The Center for Macromolecular Crystallography (CMC) has devoted considerable effort studying the fundamental processes involved in macromolecular crystal growth both in a 1-g and microgravity environment. Results from experiments performed on more than 35 U.S. space shuttle flights have clearly indicated that microgravity can provide a beneficial environment for macromolecular crystal growth. This research has led to the development of a new generation of pharmaceuticals that are currently in preclinical or clinical trials for diseases such as cutaneous T-cell lymphoma, psoriasis, rheumatoid arthritis, AIDS, influenza, stroke and other cardiovascular complications. The International Space Station (ISS) provides an opportunity to have complete crystallographic capability on orbit, which was previously not possible with the space shuttle orbiter. As envisioned, the x-ray Crystallography Facility (XCF) will be a complete facility for growing protein crystals; selecting, harvesting, and mounting sample crystals for x-ray diffraction; cryo-freezing mounted crystals if necessary; performing x-ray diffraction studies; and downlinking the data for use by crystallographers on the ground. Other advantages of such a facility include crystal characterization so that iterations in the crystal growth conditions can be made, thereby optimizing the final crystals produced in a three month interval on the ISS.

Creating a Web-accessible, point-of-care, team-based information system (PointTIS): the librarian as publisher.

The Internet has created new opportunities for librarians to develop information systems that are readily accessible at the point of care. This paper describes the multiyear process used to justify, fund, design, develop, promote, and evaluate a rehabilitation prototype of a point-of-care, team-based information system (PoinTIS) and train health care providers to use this prototype for their spinal cord injury and traumatic brain injury patient care and education activities. PoinTIS is a successful model for librarians in the twenty-first century to serve as publishers of information created or used by their parent organizations and to respond to the opportunities for information dissemination provided by recent technological advances.

Identification of amino acids involved in a serotype and neutralization specific epitope within the s1 subunit of avian infectious bronchitis virus.

Localization of neutralizing, serotype specific epitopes of infectious bronchitis virus has been difficult because these epitopes are conformationally dependent. We identified amino acids involved in a serotype specific, conformationally dependent epitope by analysis of the S1 gene of 13 monoclonal antibody-neutralization-resistant mutants. Substitutions in the predicted amino acid sequence of these mutants were located at residues 304 and/or 386. Most of the substitutions at residue 304 were from threonine to isoleucine, whereas the substitutions at residue 386 were from arginine to proline, histidine, cysteine, or tryptophan. Based on this data, it appears that AA residues at 304 and 386 on the S1 glycoprotein are involved in a virus neutralizing serotype specific epitope.

Contact laser or conventional cholecystectomy: a controlled trial.

There have been claims that the use of lasers in surgery is associated with reduced operative blood loss, trauma, postoperative pain and improved postoperative mobility. With the development of sapphire probes capable of transmitting neodymium yttrium aluminium garnet (Nd: YAG) laser light, it is now feasible to perform direct-contact low-power laser surgery. In a small randomized controlled trial, we have compared cholecystectomy performed by conventional methods (n = 11) with the same operation performed by contact laser (n = 10). Operative time, blood loss, operative stability, analgesic requirement, mobility and response to the trauma of surgery were compared. The only differences between the two groups were a significantly increased wound infection rate (P = 0.051) in the laser surgery group and a significantly increased length of operating time (P = 0.001). Thus, the laser did not confer any advantage over conventional surgery.

Binding of hippocampal CA1 neural activity to multiple reference frames in a landmark-based navigation task.

The behavioral correlates of rat hippocampal CA1 cells were examined in a spatial navigation task in which two cylindrical landmarks predicted the location of food. The landmarks were maintained at a constant distance from each other but were moved from trial to trial within a large arena surrounded by static background cues. On each trial, the rats were released from a box to which they returned for additional food after locating the goal. The box also was located variably from trial to trial and was moved to a new location while the animals were searching for the goal site. The discharge characteristics of multiple, simultaneously recorded cells were examined with respect to the landmarks, the static background cues, and the box in which each trial started and ended. Three clear categories of cells were observed: (1) cells with location-specific firing (place cells); (2) goal/landmark-related cells that fired in the vicinity of the goal or landmarks, regardless of their location in the arena; and (3) box-related cells that fired either when the rat was in the box or as it was leaving or entering the box, regardless of its location in the arena. Disjunctive cells with separate firing fields in more than one reference frame also were observed. These results suggest that in this task a subpopulation of hippocampal cells encodes location in the fixed spatial frame, whereas other subpopulations encode location with respect to different reference frames associated with the task-relevant, mobile objects.

Sequence comparison of avian infectious bronchitis virus S1 glycoproteins of the Florida serotype and five variant isolates from Georgia and California.

The infectious bronchitis virus (IBV) spike glycoprotein S1 subunit is required to initiate infection and contains virus-neutralizing and serotype-specific epitope(s). Reported are the S1 gene nucleotide and predicted amino acid sequences for the Florida 18288 strain and isolates GA-92, CV-56b, CV-9437, CV-1686, and 1013. These sequences were compared with previously published gene sequences of IBV strains, and phylogenetic relationships are reported. The S1 amino acid sequence of Florida 18288 was 94.9% similar to the Connecticut strain, and GA-92 was 92.8% similar to the Arkansas 99 strain. S1 amino acid sequences of the California variants, CV-56b, CV-9437, and CV-1686, were 97.6-99.3% similar to one another and only 76.6%-76.8% similar to the Arkansas-type strains. Isolate 1013, also from California, was 84.0% similar to Ark DPI and 77.9% similar to CV-56b. When comparing 19 viruses isolated from the United States, sequence variations were observed between amino acids 55-96, 115-149, 255-309, and 378-395. Similar regions are reported to be involved in virus-neutralizing and/or serotype-specific epitopes. These data demonstrate that variant IBV strains continue to emerge, and unique variants may circulate among poultry in geographically isolated areas.

Carbon and nitrogen stable isotopic signatures of human dietary change in the Georgia Bight.

Measurement of carbon and nitrogen stable isotope ratios (delta 13C and delta 15N) in samples of human bone collagen (n = 93) from a temporal series of four prehistoric (early preagricultural, late preagricultural, early agricultural, late agricultural) and two historic (early contact, late contact) periods from the Georgia Bight, a continental embayment on the southeastern U.S. Atlantic coast, reveals a general temporal trend for less negative delta 13C values and less positive delta 15N values. This trend reflects a concomitant decrease in emphasis on marine resources and increased reliance on C4-based resources, especially maize. This dietary reorientation is most apparent for the early agricultural sample (AD 1150-1300), coinciding with the Mississippian fluorescence in the eastern United States. There is, however, a shift toward the use of C3 (non-maize) foods during the last prehistoric period (AD 1300-1450), which is likely related to environmental stress and social disruption. A heavier use of maize and terrestrial resources in general after the establishment of mission centers on barrier islands is indicated. A reduced dietary breadth during the mission period may have contributed to the extinction of these populations in the eighteenth century.

Crystallization and preliminary structure determination of porcine aldehyde reductase from two crystal forms.

Aldehyde reductase from porcine kidney has been crystallized from buffered ammonium sulfate solutions. Two crystal forms are monoclinic, space group P2(1), with a = 56.2, b = 98.1, c = 73.2 A, beta = 112.5 degrees and a = 92.4, b = 62.1, c = 59.0 A, beta = 94.6 degrees. A third crystal form is hexagonal with a = b = 166.0, c = 66.0 A, alpha = beta = 90.0 degrees and gamma = 120.0 degrees. Molecular-replacement structure solutions have been successfully obtained for the two monoclinic crystal forms. The crystallographic R factor at 8-2.8 A resolution for the two monoclinic crystal forms is currently 0.23 and 0.25, respectively. There are two molecules per asymmetric unit related by a non-crystallographic twofold axis. The aldehyde reductase models are supported by the arrangement of the molecules in their respective unit cells and by electron densities corresponding to amino-acid side chains not included in the search structures.