Gene-based immunotherapy for cancer is limited by the lack of safe, efficient, reproducible, and titratable delivery methods. Direct injection of DNA into tissue, although safer than viral vectors, ...suffers from low gene transfer efficiency. In vivo electroporation, in preclinical models, significantly enhances gene transfer efficiency while retaining the safety advantages of plasmid DNA.
A phase I dose escalation trial of plasmid interleukin (IL)-12 electroporation was carried out in patients with metastatic melanoma. Patients received electroporation on days 1, 5, and 8 during a single 39-day cycle, into metastatic melanoma lesions with six 100-mus pulses at a 1,300-V/cm electric field through a penetrating six-electrode array immediately after DNA injection. Pre- and post-treatment biopsies were obtained at defined time points for detailed histologic evaluation and determination of IL-12 protein levels.
Twenty-four patients were treated at seven dose levels, with minimal systemic toxicity. Transient pain after electroporation was the major adverse effect. Post-treatment biopsies showed plasmid dose proportional increases in IL-12 protein levels as well as marked tumor necrosis and lymphocytic infiltrate. Two (10%) of 19 patients with nonelectroporated distant lesions and no other systemic therapy showed complete regression of all metastases, whereas eight additional patients (42%) showed disease stabilization or partial response.
This report describes the first human trial, to our knowledge, of gene transfer utilizing in vivo DNA electroporation. The results indicated this modality to be safe, effective, reproducible, and titratable.
In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates ...compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR.
Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.
Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients.
A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Telaprevir (TVR), a hepatitis C virus (HCV) NS3/4A protease inhibitor, has been approved to treat genotype 1 HCV. To understand the clinical impact of TVR-resistant variants, we analyzed ...samples from patients in phase 3 clinical trials to determine the frequency and retention of TVR-resistant variants in patients who did not achieve sustained virologic response (SVR). Methods. A total of 1797 patients were treated with TVR. Resistant variants (V36A/G/I/L/M, T54A/S, I132V subtype 1a only, R155G/K/T/M, A156F/N/S/T/V, and D168N) were identified after treatment failure and at visits thereafter, by direct (population) sequencing of the NS3/4A region. Kaplan-Meier analysis was used to determine median time to loss of these variants. Results. Resistant variants were observed in 77% (299/388) of patients who did not achieve SVR. Resistance occurred more commonly in subtype 1a (86%; 232/269) than subtype 1b infections (56%; 67/119). After treatment failure, 355 patients had at least 1 follow-up visit (median follow-up period: 9.6 months). Of patients with resistance at time of failure and at least 1 follow-up visit, 60% (153/254) lost resistance. Kaplan-Meier analysis, including all patients with any sequence data after treatment failure, indicated that median time to wild type was 10.6 months (95% confidence interval CI, 9.47–12.20) in subtype 1a and 0.9 months (95% CI, 0.00–2.07) in subtype 1b infections. Conclusions. After failure to achieve SVR with TVR-based treatment, resistant variants are observed in most patients. However, presumably due to the lower fitness of those variants, they tend to be replaced with wild-type virus over time.
Full text
Available for:
BFBNIB, NUK, PNG, UL, UM, UPUK
The Mars Science Laboratory (MSL) Mars Hand Lens Imager (MAHLI) investigation will use a 2-megapixel color camera with a focusable macro lens aboard the rover, Curiosity, to investigate the ...stratigraphy and grain-scale texture, structure, mineralogy, and morphology of geologic materials in northwestern Gale crater. Of particular interest is the stratigraphic record of a ∼5 km thick layered rock sequence exposed on the slopes of Aeolis Mons (also known as Mount Sharp). The instrument consists of three parts, a camera head mounted on the turret at the end of a robotic arm, an electronics and data storage assembly located inside the rover body, and a calibration target mounted on the robotic arm shoulder azimuth actuator housing. MAHLI can acquire in-focus images at working distances from ∼2.1 cm to infinity. At the minimum working distance, image pixel scale is ∼14 μm per pixel and very coarse silt grains can be resolved. At the working distance of the Mars Exploration Rover Microscopic Imager cameras aboard Spirit and Opportunity, MAHLI’s resolution is comparable at ∼30 μm per pixel. Onboard capabilities include autofocus, auto-exposure, sub-framing, video imaging, Bayer pattern color interpolation, lossy and lossless compression, focus merging of up to 8 focus stack images, white light and longwave ultraviolet (365 nm) illumination of nearby subjects, and 8 gigabytes of non-volatile memory data storage.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Mars Science Laboratory Mast camera and Descent Imager investigations were designed, built, and operated by Malin Space Science Systems of San Diego, CA. They share common electronics and focal ...plane designs but have different optics. There are two Mastcams of dissimilar focal length. The Mastcam‐34 has an f/8, 34 mm focal length lens, and the M‐100 an f/10, 100 mm focal length lens. The M‐34 field of view is about 20° × 15° with an instantaneous field of view (IFOV) of 218 μrad; the M‐100 field of view (FOV) is 6.8° × 5.1° with an IFOV of 74 μrad. The M‐34 can focus from 0.5 m to infinity, and the M‐100 from ~1.6 m to infinity. All three cameras can acquire color images through a Bayer color filter array, and the Mastcams can also acquire images through seven science filters. Images are ≤1600 pixels wide by 1200 pixels tall. The Mastcams, mounted on the ~2 m tall Remote Sensing Mast, have a 360° azimuth and ~180° elevation field of regard. Mars Descent Imager is fixed‐mounted to the bottom left front side of the rover at ~66 cm above the surface. Its fixed focus lens is in focus from ~2 m to infinity, but out of focus at 66 cm. The f/3 lens has a FOV of ~70° by 52° across and along the direction of motion, with an IFOV of 0.76 mrad. All cameras can acquire video at 4 frames/second for full frames or 720p HD at 6 fps. Images can be processed using lossy Joint Photographic Experts Group and predictive lossless compression.
Key Points
The Mars Descent Imager, an f/3 9.7 mm, 2 M pixel color camera operated autonomously during landing taking a descent video at 4 frames/second
Mastcam‐34 f/8, 34 mm camera takes <1600 × 1200 pixel images in broad and narrowband color over a field 20° × 15° at a scale of 218 μrad/pixel
Mastcam‐100 f/10, 100 mm, f/10 takes <1600 × 1200 pixel images in broad and narrowband color over a field 6.8° × 5.1° at 74 μrad/pixel scale
Plain Language Summary
Paper describes the Mast cameras and Descent Imager on the Mars Science Laboratory Curiosity rover. Cameras take 2 megapixel color images that can be compressed in both JPEG lossy and predictive lossless format. One of the two Mastcams has a 34 mm lens, equivalent to a consumer camera 35 mm lens, and the other has a 100 mm lens, similar to consumer camera telephoto lens. The descent imager has a very wide angle lens (~90°) and takes wide angle pictures. The Mast cameras are mounted on an azimuth elevation mast so they can scan around the rover and into the sky. The Descent camera always points down. The Mast cameras have different filters to allow for scientific color imaging as well as standard color imaging as performed by consumer cameras.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In response to infection or immunization, antibodies are produced that provide protection against re-exposure with the same pathogen. These antibodies can persist at high titers for decades and are ...maintained by bone marrow-resident long-lived plasma cells (LLPC). However, the durability of antibody responses to immunization varies amongst vaccines. It is unknown what factors contribute to the differential longevity of serum antibody responses and whether heterogeneity in LLPC contributes to this phenomenon. While LLPC differentiation has been studied extensively in mice, little is known about this population in humans or non-human primates (NHP). Here, we use multi-omic single-cell profiling to identify and characterize the LLPC compartment in NHP. We identify LLPC biomarkers including the marker CD102 and show that CD102 in combination with CD31 identifies LLPC in NHP bone marrow. Additionally, we find that CD102 is expressed by LLPC in mouse and humans. These results further our understanding of the LLPC compartment in NHP, identify biomarkers of LLPC, and provide tissue-specific single cell references for future studies.
PURPOSETo compare the safety and efficacy of travoprost 0.004% without benzalkonium chloride (BAC) to that of the marketed formulation of travoprost 0.004% in patients with open-angle glaucoma or ...ocular hypertension.
METHODSThe study was a double-masked, randomized, parallel group, multicenter, noninferiority design. Adult patients with open-angle glaucoma or ocular hypertension with qualifying intraocular pressure (IOP) on 2 eligibility visits received either travoprost 0.004% with BAC (n=346), or travoprost 0.004% without BAC (n=344) dosed once-daily each evening. Patients were followed for a period of 3 months. IOP measurements at 8 AM, 10 AM, and 4 PM were taken at study visits on week 2, week 6, and month 3.
RESULTSMean IOP reductions, across all 9 study visits and times ranged from 7.3 to 8.5 mm Hg for travoprost 0.004% without BAC and from 7.4 to 8.4 mm Hg for travoprost 0.004% with BAC. Statistical equivalence was also demonstrated for the comparison of mean IOP changes; 95% confidence limits were within ±0.8 mm Hg at 9 of 9 study visits and times in both the per protocol and intent-to-treat data sets. Adverse events and the number of patients discontinued owing to adverse events were similar for both treatment groups. Adverse events due to hyperemia occurred in 6.4% and 9.0% of patients treated with travoprost 0.004% without BAC and travoprost 0.004% with BAC, respectively.
CONCLUSIONTravoprost 0.004% without BAC is equivalent to travoprost 0.004% with BAC in both safety and efficacy.
To compare 1-year safety and efficacy of anecortave acetate 15 mg with photodynamic therapy (PDT) with verteporfin in patients eligible for initial PDT treatment.
Prospective, masked, randomized, ...multicenter, parallel group, active control, noninferiority clinical trial.
Five hundred thirty patients with predominantly classic subfoveal choroidal neovascularization secondary to age-related macular degeneration were randomized to treatment with either anecortave acetate 15 mg or PDT.
In the anecortave acetate group, the drug was administered under the Tenon's capsule as a periocular posterior juxtascleral depot (PJD) at the beginning of the study and at month 6. Before the first administration of anecortave acetate, patients in this treatment group received a sham PDT treatment, and sham PDT treatments were repeated every 3 months if there was evidence of leakage on fluorescein angiography (FA). Patients assigned to PDT received up to 4 PDT treatments at 3-month intervals, as needed based upon FA, and a sham PJD procedure at the beginning of the study and at month 6. Best-corrected visual acuity was determined at baseline and all follow-up visits. Safety data were regularly reviewed by an independent safety committee.
Percent responders (patients losing <3 lines of vision) at month 12.
Percent responders in the anecortave acetate and PDT groups were 45% and 49%, respectively (not statistically different, P = 0.43). The confidence interval (CI) for the difference ranged from -13.2% favoring PDT to +5.6% favoring anecortave acetate. The month 12 clinical outcome for anecortave acetate was improved in patients for whom reflux was controlled and who were treated within the 6-month treatment window (57% vs. 49%; 95% CI, -4.3% favoring PDT to +21.7% favoring anecortave acetate). No serious adverse events related to the study drug were reported in either treatment group.
The safety and efficacy outcomes in this study demonstrate that the benefits of anecortave acetate for the treatment of choroidal neovascularization outweigh the risks associated with either the drug or the PJD administration procedure.
Veneers and thicker rinds that coat outcrop surfaces and partially cemented fracture fills formed perpendicular to bedding document relatively late stage alteration of ancient sedimentary rocks at ...Meridiani Planum, Mars. The chemistry of submillimeter thick, buff‐colored veneers reflects multiple processes at work since the establishment of the current plains surface. Veneer composition is dominated by the mixing of silicate‐rich dust and sulfate‐rich outcrop surface, but it has also been influenced by mineral precipitation, including NaCl, and possibly by limited physical or chemical weathering of sulfate minerals. Competing processes of chemical alteration (perhaps mediated by thin films of water or water vapor beneath blanketing soils) and sandblasting of exposed outcrop surfaces determine the current distribution of veneers. Dark‐toned rinds several millimeters thick reflect more extensive surface alteration but also indicate combined dust admixture, halite precipitation, and possible minor sulfate removal. Cemented fracture fills that are differentially resistant to erosion occur along the margins of linear fracture systems possibly related to impact. These appear to reflect limited groundwater activity along the margins of fractures, cementing mechanically introduced fill derived principally from outcrop rocks. The limited thickness and spatial distribution of these three features suggest that aqueous activity has been rare and transient or has operated at exceedingly low rates during the protracted interval since outcropping Meridiani strata were exposed on the plains surface.
The 1995 Annual Report of the North American Pediatric Renal Transplant Cooperative Study summarizes data voluntarily collected from 123 centers on 5,197 children and adolescents grouped into three ...cohorts: (1) patients who received renal transplants on or after 1 January 1987 (n = 3,066), (2) patients who were maintained on peritoneal dialysis (PD) or hemodialysis (HD) on or after 1 January 1992 (n = 1,488), and (3) patients treated for chronic renal insufficiency (CRI) on or after 1 January 1994 (n = 643). The transplant and dialysis information update previous registry data whereas the CRI information reflects 1st-year registry data. Three-year graft survival rates were 83% and 66% for living donor grafts and cadaver donor (CD) grafts, respectively. Triple drug maintenance therapy with prednisone, cyclosporine, and azathioprine was used by > 70% of all transplant recipients through 5 years of follow-up. The 2-year CD survival has steadily improved from 65% in 1987 to 82% in 1992. Fifty malignancies have been reported, the majority of which are lymphoproliferative disorders. The 2-year patient survival posttransplantation is 95%. Mortality rates for the youngest patients have drastically improved over the past 2 years. Approximately two-thirds of patients in the dialysis cohort are maintained on PD; automated PD remains the preferred modality. Overall, the peritonitis rate is one infection every 13.3 patient months, the frequency of infection being greatest in the youngest patients. Whereas the primary reason for dialysis modality termination is transplantation approximately 40% of the entire dialysis cohort (PD at HD) were not considered active transplant candidate Baseline CRI data revealed the most common primary diagnoses to be obstructive uropathy (24%) and aplastic/hypoplastic/dysplastic kidneys (19%). The standardized height deficit in the CRI cohort was greatest in the younger patients and those with the most impaired renal function.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
