To survive cryopreservation, oocytes, zygotes and embryos must tolerate a sequence of volumetric contractions and expansions. These result as an egg or an embryo is exposed to a permeating ...cryoprotective additive, then to an increase followed by a decrease in the osmolality of its extracellular milieu as water freezes during cooling and then melts during warming, and finally to the dilution of the cryoprotective additive solution. Measurements of the extent to which mouse zygotes and human oocytes undergo osmotic contraction have been made by exposing them to solutions of monosaccharides (fructose, galactose, glucose) or disaccharides (maltose, sucrose, trehalose), ranging in concentration from 0.25 to 1.50 M. Mouse zygotes and human oocytes exhibit very similar responses to these solutions. Their volumes contract linearly as a function of 1/(osmolality) of the solutions, yielding estimates of non-osmotic volumes of 13-23%. Mouse zygotes exposed to 1.5 M concentrations of these solutions for 10 min lose 85% of their cell water. Yet > 75% of treated zygotes develop into hatching blastocysts. Human oocytes also appear to survive such extreme dehydration, based on a vital dye assay. These results suggest that solutions of various non-permeating saccharides can serve as osmotic buffers for the recovery of cryopreserved oocytes, zygotes and embryos.
The emergence of individualized medicine is driven by developments in precision diagnostics, epitomized by molecular testing. Because treatment decisions are being made based on such molecular data, ...data management is gaining major importance. Among data management challenges, creating workflow solutions for timely delivery of molecular data has become pivotal. This study aims to design and implement a scalable process that permits pre-appointment
BRAF
/
KIT
mutation analysis in melanoma patients, allowing molecular results necessary for treatment plans to be available before the patient's appointment. Process implementation aims to provide a model for efficient molecular data delivery for individualized medicine. We examined the existing process of
BRAF/KIT
testing in melanoma patients visiting our institution for oncology consultation. We created five working groups, each designing a specific segment of an alternative process that would allow pre-appointment
BRAF/KIT
testing and delivery of results. Data was captured and analyzed to evaluate the success of the alternative process. Over one year, 35 of 55 (59%) patients had prior
BRAF
/
KIT
testing. The remaining 20 patients went through the new process of pre-appointment testing; results were available at the time of appointment for 12 patients (overall pre-appointment results availability = 85.5%). The overall process averaged 13.4 ± 4.7 days. In conclusion, we describe successful implementation of a scalable workflow solution that permits pre-appointment
BRAF
/
KIT
mutation analysis and result delivery in melanoma patients. This sets the stage for further applications of this model to other conditions, answering an increasing demand for robust delivery of molecular data for individualized medicine.
Provision of Services to First-Responders McWilliams, R; Prezant, D; Wartenberg, D ...
American journal of epidemiology,
06/2006, Letnik:
163, Številka:
suppl_11
Journal Article
Encouraging family forest owners to create early successional habitat is a high priority for wildlife conservation agencies in the northeastern USA, where most forest land is privately owned. Many ...studies have linked regional declines in wildlife populations to the loss of early successional habitat. The government provides financial incentives to create early successional habitat, but the number of family forest owners who actively manage their forests remains low. Several studies have analyzed participation of family forest owners in federal forestry programs, but no study to date has focused specifically on creation of wildlife habitat. The objective of our study was to analyze the experience of a group of wildlife-oriented family forest owners who were trained to create early successional habitat. This type of family forest owners represents a small portion of the total population of family forest owners, but we believe they can play an important role in creating wildlife habitat, so it is important to understand how outreach programs can best reach them. The respondents shared some characteristics but differed in terms of forest holdings, forestry experience and interest in earning forestry income. Despite their strong interest in wildlife, awareness about the importance of early successional habitat was low. Financial support from the federal government appeared to be important in motivating respondents to follow up after the training with activities on their own properties: 84% of respondents who had implemented activities received federal financial support and 47% would not have implemented the activities without financial assistance. In order to mobilize greater numbers of wildlife-oriented family forest owners to create early successional habitat we recommend focusing outreach efforts on increasing awareness about the importance of early successional habitat and the availability of technical and financial assistance.
Oligonucleotides that complement Escherichia coli 16S ribosomal RNA residues 685-696 and 694-705 have been synthesized so as to incorporate antibody-recognizable markers: a 3'-terminal residue of ...N6-delta 2-isopentenyladenosine, a 5'-dinitrophenyl group, or both. Each oligonucleotide is able to bind RNA within the small ribosomal subunit, whether free or in 70S ribosomes. Immune electron microscopy places probes at nucleotides 685, 694 and 705 within a single area, at the tip of the subunit platform, very near the position of the 3'-end of the 16S RNA.
Abstract
Background
Tumor mutational burden (TMB) has been correlated with response to CTLA-4 and PD-(L)1 inhibitors. We explored the association of TMB with outcomes in cohorts A through J of ...KEYNOTE-158, a phase II basket study of pembrolizumab monotherapy for patients (pts) with select advanced solid tumors (NCT02628067).
Methods
Key eligibility criteria were progression on or intolerance to ≥ 1 line of standard therapy, ECOG PS 0 or 1, provision of a tumor sample for biomarker analysis, and either anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor, or SCLC. Pts received pembrolizumab 200 mg Q3W for 35 cycles or until PD, intolerable toxicity, or physician or pt decision. TMB was assessed in FFPE tumor samples using the FoundationOne CDx™ assay. TMB-high was defined as 10 Mut/Mb. Primary study endpoint was ORR (RECIST v1.1, central review); DOR, PFS, OS, and safety were secondary endpoints. The relationship between antitumor activity and TMB was an exploratory endpoint.
Results
Of the 1032 pts with ≥26 weeks of follow-up as of 06 Dec 2018, 755 (73.2%) had evaluable TMB; of these, 120 (15.9%) were TMB-high, with 15/120 (12.5%) known to be MSI-H. Baseline characteristics were generally similar for TMB-high and low. There was low correlation between TMB and PD-L1 expression (ρ = 0.19). ORR (95% CI) was 28.3% (20.5-37.3) for TMB-high (24.8% 16.9-34.1 non–MSI-H) and 6.5% (4.7-8.7) for TMB-low. Median DOR was not reached for TMB-high or low (range 2.2+ to 28.8+ and 4.1 to 30.6+, respectively). Median (95% CI) PFS for TMB-high and low was 2.1 mo (2.1-3.7) and 2.1 mo (2.1-2.3), respectively; 12-mo rates were 24.3% and 14.0%. Median (95% CI) OS for TMB-high and low was 11.1 mo (8.1-16.1) and 13.3 mo (11.5-14.8), respectively; 12-mo rates were 48.0% and 52.9%. The safety profile was consistent with that previously observed for pembrolizumab.
Conclusions
TMB-high was associated with higher ORR in pts with select advanced solid tumors treated with pembrolizumab monotherapy. The tail of the PFS curve favored TMB-high. These data suggest that TMB may be predictive of the efficacy of pembrolizumab monotherapy in pts with the tumor types included in KEYNOTE-158.
Clinical trial identification
NCT02628067, December 11, 2015.
Editorial acknowledgement
Melanie Leiby of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
A. Marabelle: Research grant / Funding (institution), principal investigator: Roche/Genentech, BMS, Merck (MSD), Pfizer, Lytix pharma, Eisai, AstraZeneca/MedImmune, Tesaro, Chugai ; Research grant / Funding (institution): MSD; Travel / Accommodation / Expenses: MSD, AstraZeneca, Roche/Genentech, BMS ; Research grant / Funding (institution), rincipal investigator, sponsor Unicancer; ACSE NIVOLUMAB/NCT03012581 : INCa, Ligue contre le Cancer & BMS; Research grant / Funding (institution), principal investigator, sponsor Leon Berard Cancer Center; ISIJX/NCT02977156: Transgene; Research grant / Funding (institution), principal investigator, sponsor Gustave Roussy; NIVIPIT/NCT02857569 : BMS; Research grant / Funding (institution), principal investigator, sponsor Gustave Roussy; PEMBIB/NCT02856425 : Boehringer Ingelheim; Research grant / Funding (institution): Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi ; Non-remunerated activity/ies, drug supply: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche ; Advisory / Consultancy: GSK, AstraZeneca; Advisory / Consultancy: Oncovir, Inc.; Advisory / Consultancy: Innate Pharma, Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE immunotherapeutics, Transgene, Gritstone, ; Speaker Bureau / Expert testimony: Roche/Genentech, BMS, Merck (MSD), Merck Serono, AstraZeneca/MedImmune, Amgen, Sanofi ; Advisory / Consultancy: Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daiichi Sankyo, Imaxio, Sanofi, BioNTech, Corvus, GLG, Deerfield, Guidepoint Global, Edimark, System Analytics, imCheck, Sotio, Bioncotech, Molecular Partners, Pillar Partners, Boehringer Inge; Shareholder / Stockholder / Stock options: Pegascy SAS (Gustave Roussy Spin Off for Drug Repositioning) ; Research grant / Funding (institution): Merus, BMS, Boehringer Ingelheim, Transgene, Fondation MSD Avenir; Officer / Board of Directors, supervisory board member: Gustave Roussy Foundation; Advisory / Consultancy, steering committee of the immuno-oncology task force: Unicancer; Research grant / Funding (institution), sub-investigator of clinical trials: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol; Licensing / Royalties, Patent Issued (not licensed yet) : “Humanized and Chimeric Monoclonal Antibodies to CD81”, Stanford Office of Technology Licensing, 3000 El Camino Real, Bldg. 5, Suite 300, Palo Alto, CA 94306-2100. U.S. Application Serial No. 62/351,054. M.G. Fakih: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Advisory / Consultancy: Array; Advisory / Consultancy: Bayer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Novartis; Research grant / Funding (institution): MSD. J. Lopez: Advisory / Consultancy: Genmab; Advisory / Consultancy: Novartis; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Basilea. M. Shah: Research grant / Funding (institution): MSD. R. Shapira-Frommer: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Medison; Advisory / Consultancy: Clovis Oncology. K. Nakagawa: Research grant / Funding (institution): MSD. H.C. Chung: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self): Foundation Medicine; Advisory / Consultancy, Research grant / Funding (institution): Taiho; Advisory / Consultancy: Celltrion; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Research grant / Funding (institution): GSK; Research grant / Funding (institution): BMS-ONO. H.L. Kindler: Research grant / Funding (institution): MSD. J.A. Lopez-Martin: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Celgene; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: PharmaMar; Advisory / Consultancy: Chobani. W. Miller: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GSK; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Methylene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Astellas. A. Italiano: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Epizyme; Advisory / Consultancy: ImmuneDesign; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): PharmaMar. S. Kao: Research grant / Funding (institution): MSD. S.A. Piha-Paul: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Aminex Therapeutics; Research grant / Funding (institution): BioMarin Pharmaceutical, Inc; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Cerulean Pharma Inc.; Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Flex Bio, Inc; Research grant / Funding (institution): Genmab A/S; Research grant / Funding (institution): GlaxoSmithKline; Resea
Synaptic contacts per unit area in the rat dentate gyrus reach adult numbers by the end of the first month after birth and remain constant thereafter. This experiment demonstrated that the rate at ...which synapses were replaced by sprouting after a lesion declined dramatically from 35 to 90 days of age. Thus, the juvenile period of the rat's life is marked by a considerable change in neuronal plasticity. This may be related to age-dependent effects in recovery from brain damage.
Current models to estimate daily energy expenditure (DEE) for free-living birds are limited to either those that use fixed thermoregulatory costs or those that more accurately estimate ...thermoregulatory costs, but require extensive and often logistically difficult measurements. Here, we propose a model based on basal metabolic rate (BMR), activity budgets, and site-specific energetic costs of thermoregulation that requires only simple measures of ambient temperature and wind speed to provide estimates of DEE. We use the model to calculate the DEE of Buffleheads (Bucephala albeola) wintering at six habitats that afford differing degrees of protection from exposure within Narragansett Bay, Rhode Island. Bufflehead activity budget data collected during the winters of 2001–2002 and 2002–2003, along with average temperatures and wind speeds at the sites, were used to calculate DEE that ranged from 46.9 to 52.4 kJ/hr and increased with increasing wind speed. The energetic cost of thermoregulation composed as much as 28% of total DEE and increased with wind speed. Our DEE values were 13.4% higher, and thermoregulatory costs were up to 2× higher than those calculated using an existing model that incorporates fixed thermoregulatory costs. We also saw an increase in feeding activity with increasing wind speed; sensitivity analysis of the effects of wind speed and feeding activity showed that a 1 m/sec increase in wind speed at our sites increased DEE by 2.5%, whereas a corresponding increase in feeding activity increased DEE by 4.5%. This suggests that in temperate winter habitats, increased feeding activity may have a greater impact on Bufflehead DEE than wind exposure. Site-specific model estimates of DEE could also provide additional insight into the relative contribution of environmental conditions and changes in waterfowl behavior to DEE.
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