A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates ...(ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety.
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Metamorphic Testing for Cybersecurity Tsong Yueh Chen; Fei-Ching Kuo; Wenjuan Ma ...
Computer (Long Beach, Calif.),
2016-June, 2016-Jun, 2016-6-00, 20160601, Volume:
49, Issue:
6
Journal Article
Peer reviewed
Open access
Metamorphic testing (MT) can enhance security testing by providing an alternative to using a test oracle, which is often unavailable or impractical. The authors report how MT detected previously ...unknown bugs in real-world critical applications such as code obfuscators, giving evidence that software testing requires diverse perspectives to achieve greater cybersecurity.
Abstract
Background
Data on cellular immune responses in persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection following vaccination are limited. The evaluation of these ...patients with SARS-CoV-2 breakthrough infections may provide insight into how vaccinations limit the escalation of deleterious host inflammatory responses.
Methods
We conducted a prospective study of peripheral blood cellular immune responses to SARS-CoV-2 infection in 21 vaccinated patients, all with mild disease, and 97 unvaccinated patients stratified based on disease severity.
Results
We enrolled 118 persons (aged 50 years SD 14.5 years, 52 women) with SARS-CoV-2 infection. Compared to unvaccinated patients, vaccinated patients with breakthrough infections had a higher percentage of antigen-presenting monocytes (HLA-DR+), mature monocytes (CD83+), functionally competent T cells (CD127+), and mature neutrophils (CD10+); and lower percentages of activated T cells (CD38+), activated neutrophils (CD64+), and immature B cells (CD127+CD19+). These differences widened with increased disease severity in unvaccinated patients. Longitudinal analysis showed that cellular activation decreased over time but persisted in unvaccinated patients with mild disease at 8-month follow-up.
Conclusions
Patients with SARS-CoV-2 breakthrough infections exhibit cellular immune responses that limit the progression of inflammatory responses and suggest mechanisms by which vaccination limits disease severity. These data may have implications for developing more effective vaccines and therapies.
Clinical Trials Registration. NCT04401449.
The cellular immune signature found in vaccinated patients with breakthrough infections shows more favorable myeloid and lymphoid compartments that limit inflammatory responses associated with disease severity and may lead to a better control of viral replication and less immune activation.
Graphical Abstract
Graphical Abstract
The catalytic properties of various metal nanoparticles have led to their use in environmental remediation. Our aim is to develop and apply an efficient bioremediation method based on in situ ...biosynthesis of bio-Pd nanoparticles and hydrogen. C. pasteurianum BC1 was used to reduce Pd(II) ions to form Pd nanoparticles (bio-Pd) that primarily precipitated on the cell wall and in the cytoplasm. C. pasteurianum BC1 cells, loaded with bio-Pd nanoparticle in the presence of glucose, were subsequently used to fermentatively produce hydrogen and to effectively catalyze the removal of soluble Cr(VI) via reductive transformation to insoluble Cr(III) species. Batch and aquifer microcosm experiments using C. pasteurianum BC1 cells loaded with bio-Pd showed efficient reductive Cr(VI) removal, while in control experiments with killed or viable but Pd-free bacterial cultures no reductive Cr(VI) removal was observed. Our results suggest a novel process where the in situ microbial production of hydrogen is directly coupled to the catalytic bio-Pd mediated reduction of chromate. This process offers significant advantages over the current groundwater treatment technologies that rely on introducing preformed catalytic nanoparticles into groundwater treatment zones and the costly addition of molecular hydrogen to above ground pump and treat systems.
Adherence to oral anticoagulant (OAC) agents is important for patients with nonvalvular atrial fibrillation (NVAF) to prevent potentially severe adverse events.
To compare real-world adherence rates ...and time to discontinuation for rivaroxaban versus other OACs (apixaban, dabigatran, and warfarin) among patients with NVAF using claims-based data.
Health care claims from the IMS Health Real-World Data Adjudicated Claims database (July 2012-June 2015) were analyzed. Adherence rate was defined as the percentage of patients with proportion of days covered (PDC) ≥ 0.80 and ≥ 0.90. Discontinuation was defined as a gap of more than 30 days between the end of a dispensing days of supply and the start date of the next fill, if any. Patients were included if they had ≥ 2 dispensings of rivaroxaban, apixaban, dabigatran, or warfarin at least 180 days apart (the first was considered the index date), had > 60 days of supply, had ≥ 6 months of pre-index eligibility, had ≥ 1 atrial fibrillation (AF) diagnosis pre-index or at index date, and had no valvular involvement. A logistic regression model was used to evaluate adherence to OAC therapy, while a Cox model was used to compare time to discontinuation; both models adjusted for baseline confounders.
A total of 13,645 rivaroxaban, 6,304 apixaban, 3,360 dabigatran, and 13,366 warfarin patients were identified. A significantly higher proportion of rivaroxaban users (80.1%) was adherent to therapy (PDC ≥ 0.80 at 6 months) versus apixaban (75.8%), dabigatran (69.2%), and warfarin users (64.5%). After adjustment, the proportion of patients adherent to therapy remained significantly higher for rivaroxaban users versus apixaban (absolute difference AD = 5.8%), dabigatran (AD = 9.5%), and warfarin users (AD = 13.6%; all P < 0.001). More pronounced differences were found with a PDC ≥0.90. In addition, rivaroxaban users were significantly less likely to discontinue therapy compared with other OACs after adjustments (all P < 0.05).
Among NVAF patients, rivaroxaban was associated with significantly higher adherence rates relative to other OACs whether using either a PDC of > 0.80 or > 0.90. Such differences in adherence could translate into improved patient outcomes and lower health care costs.
This research was funded by Janssen Scientific Affairs. Ashton, Crivera, and Schein are employees and stockholders of Janssen Scientific Affairs. Laliberté, Germain, Wynant, and Lefebvre are employees of Analysis Group, a consulting company that received research grants from Janssen Scientific Affairs in connection with this study. McHorney is an employee of Evidera, a consulting company that received research grants from Janssen Scientific Affairs in connection with this study. Peterson received research grants from Janssen Scientific Affairs in connection with this study. All authors contributed to concept and design. The data were collected by Germain, Wynant, Laliberté, and Lefebvre and interpreted primarily by McHorney and Peterson, with the assistance of Lefebvre, Laliberté, Ashton, Crivera, and Schein. The manuscript was written primarily by Laliberté, Germain, and Lefebvre, with the assistance of Wynant. Revisions were made primarily by Ashton, Crivera, McHorney, Schein, and Peterson.
The aim of the study was to compare which test is most sensitive in identifying stress urinary incontinence (SUI) in women with pelvic organ prolapse using urodynamics (UDS) as the criterion ...standard: cough stress test (CST) or pyridium pad test.
This was a prospective study of women with pelvic organ prolapse stage II or greater who desired surgical management for prolapse. Each patient underwent preoperative urinary testing: UDS, CST, and a 24-hour pyridium pad test.
A total of 84 patients were analyzed. Using UDS as the criterion standard, both the CST and the pyridium pad test showed a fair agreement with UDS outcomes (κ = 0.27 for both tests). There was no statistically significant difference between the CST and the pyridium pad test, with estimated sensitivities of 34.4% versus 40.6% (P = 0.791), specificities of 90.4% versus 84.6% (P = 0.508). The pyridium pad test was found to have a statistically significant difference in identifying the subjective complaint of SUI (38.6%, P = 0.003) compared with other tests. Patients with occult incontinence were identified 42.5%, 17.5%, and 10% of the time during UDS, CST, and pyridium pad testing, respectively.
Our data suggest that the sensitivities of the CST and pyridium pad test for stress incontinence and occult stress incontinence in patients with pelvic organ prolapse are low when compared with UDS as the criterion standard. Urodynamics has an important role in preoperative identification of occult SUI.
The International Potato Center (CIP) genebank conserves and facilitates access to highly diverse germplasm of potato, sweetpotato, and Andean roots and tubers as a global public good for food ...security. While it is generally understood that material from the CIP genebank has played an important role in the release of many CIP-related varieties grown by smallholder farmers in lower-income countries, the contribution has not been evaluated in quantitative terms. By applying the relative contribution of provenance based on pedigree data, we apportion the CIP genebank contribution of two released potato varieties: Pallay Poncho and Victoria. The estimated contribution of the CIP genebank to Pallay Poncho and Victoria is 35% and 72%, respectively. We then used an economic surplus approach to measure Victoria’s benefits in Uganda by attributing and valuing productivity gains. The gross benefit of Victoria in Uganda is estimated at USD $1.04 billion (2016 value), which exceeds the annual operating cost of the entire genebank over its lifetime. Seventy-two percent of the economic benefits corresponding to germplasm of Victoria are due to the CIP genebank contribution. Our findings demonstrate the magnitude of economic benefits generated by the use of conserved germplasm provided by the CIP genebank in crop improvement, which is only one of the several components of its total economic value. These results show that the availability of diverse germplasm is perhaps one of the most important elements in varietal development.
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