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Science Translational Medicine May 2023This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP)...
This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent ( = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks ( = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8 and Ki67CD8 T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.
Topics: Humans; CD8-Positive T-Lymphocytes; Neoplasms; Fibroblasts
PubMed: 37163618
DOI: 10.1126/scitranslmed.abp9229 -
Physical Review Letters Jun 2020We present the development of a high-Q monolithic silica pendulum weighing 7 milligram. The measured Q value for the pendulum mode at 2.2 Hz was 2.0×10^{6}. To the...
We present the development of a high-Q monolithic silica pendulum weighing 7 milligram. The measured Q value for the pendulum mode at 2.2 Hz was 2.0×10^{6}. To the best of our knowledge this is the lowest dissipative milligram-scale mechanical oscillator to date. By employing this suspension system, the optomechanical displacement sensor for gravity measurements we recently reported in Matsumoto et al. [Phys. Rev. Lett. 122, 071101 (2019)PRLTAO0031-900710.1103/PhysRevLett.122.071101] can be improved to realize quantum-noise-limited sensing at several hundred hertz. In combination with the optical spring effect, the amount of intrinsic dissipation measured in the pendulum mode is enough to satisfy requirements for measurement-based quantum control of a massive pendulum confined in an optical potential. This paves the way for not only testing dark matter via quantum-limited force sensors, but also Newtonian interaction in quantum regimes, namely, between two milligram-scale oscillators in quantum states, as well as improving the sensitivity of gravitational-wave detectors.
PubMed: 32567925
DOI: 10.1103/PhysRevLett.124.221102 -
Science (New York, N.Y.) Nov 2011Ultralight (<10 milligrams per cubic centimeter) cellular materials are desirable for thermal insulation; battery electrodes; catalyst supports; and acoustic, vibration,...
Ultralight (<10 milligrams per cubic centimeter) cellular materials are desirable for thermal insulation; battery electrodes; catalyst supports; and acoustic, vibration, or shock energy damping. We present ultralight materials based on periodic hollow-tube microlattices. These materials are fabricated by starting with a template formed by self-propagating photopolymer waveguide prototyping, coating the template by electroless nickel plating, and subsequently etching away the template. The resulting metallic microlattices exhibit densities ρ ≥ 0.9 milligram per cubic centimeter, complete recovery after compression exceeding 50% strain, and energy absorption similar to elastomers. Young's modulus E scales with density as E ~ ρ(2), in contrast to the E ~ ρ(3) scaling observed for ultralight aerogels and carbon nanotube foams with stochastic architecture. We attribute these properties to structural hierarchy at the nanometer, micrometer, and millimeter scales.
PubMed: 22096194
DOI: 10.1126/science.1211649 -
Surgery, Gynecology & Obstetrics Feb 1992The most frequently used postoperative analgesia techniques are intramuscular injection (IM) and patient controlled analgesia (PCA). Recently, the use of epidural... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The most frequently used postoperative analgesia techniques are intramuscular injection (IM) and patient controlled analgesia (PCA). Recently, the use of epidural catheter injection (EPI) has been done with success. This study was done to prospectively compare these three techniques for postoperative analgesia after extensive operations upon the colon and rectum. Patients were randomized to one of three analgesia groups--IM, intramuscular morphine sulfate; PCA, patient controlled morphine sulfate, and EPI, epidural morphine sulfate. Data collected included age, time to first bowel movement, amount of narcotic, number achieving 75 per cent of preoperative forced vital capacity, postoperative pruritus, headache, nausea and vomiting, respiratory depression, atelectasis or pneumonitis. A visual analog pain scale was used to evaluate postoperative pain severity (0, no; 1, partial; 2, marked, and 3, total relief). Sixty-eight patients were eligible for study (IM, 19; PCA, 22; EPI, 23, and excluded, four). The EPI group required significantly less daily narcotic compared with either the IM or PCA groups (17.0 +/- 6.12 milligrams; 67.8 +/- 26.8 milligrams; 40.5 +/- 20.6 milligrams, respectively, less than 0.05 ANOVA) and total narcotic (81.3 +/- 31.3 milligrams; 355.4 +/- 147.7 milligrams; 215.3 +/- 105.4 milligrams, respectively, p less than 0.05 ANOVA). EPI achieves excellent pain control in more patients with a significantly lower dose of narcotics and significantly fewer pulmonary complications. Therefore, epidural analgesia is the optimal method of postoperative analgesia after extensive abdominal operations.
Topics: Adult; Aged; Aged, 80 and over; Analgesia, Epidural; Analgesia, Patient-Controlled; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Morphine; Pain Measurement; Pain, Postoperative; Postoperative Complications; Prospective Studies
PubMed: 1734572
DOI: No ID Found -
Expert Review of Neurotherapeutics Dec 2012Risperidone long-acting injection (RLAI) was the first second-generation antipsychotic available as a long-acting injection. Paliperidone (9-hydroxyrisperidone) is the... (Review)
Review
Risperidone long-acting injection (RLAI) was the first second-generation antipsychotic available as a long-acting injection. Paliperidone (9-hydroxyrisperidone) is the active metabolite of risperidone, introduced initially as an extended release oral (ORal Osmotic System, OROS®, Alza Corporation) formulation (Invega®, Janssen). Paliperidone long-acting injection (PLAI) has now been developed as a suspension of paliperidone palmitate nanocrystals in an aqueous formulation (Invega Sustenna®, Xeplion®), administered monthly by intramuscular injection (deltoid or gluteal). Doses of PLAI can be expressed either in milligram equivalents (mg eq) of paliperidone palmitate or in milligrams of the active fraction of paliperidone. The recommended initiation regimen of 150 mg eq (234 mg) on day 1 and 100 mg eq (156 mg) on day 8 (both administered in the deltoid) achieves therapeutic blood levels rapidly and without the necessity of oral supplementation. No refrigeration or reconstitution prior to administration is required. PLAI has been shown in to be effective in controlling the acute symptoms of schizophrenia as well as delaying time to relapse. Safety and tolerability are comparable to RLAI with no new safety signals. Thus, PLAI may represent the rational development of RLAI with greater ease of use.
Topics: Animals; Antipsychotic Agents; Humans; Isoxazoles; Paliperidone Palmitate; Palmitates; Schizophrenia
PubMed: 23237346
DOI: 10.1586/ern.12.137 -
Science Translational Medicine Nov 2022Hereditary antithrombin deficiency is caused by gene mutations and predisposes to recurrent venous thromboembolism that can be life-threatening. Therefore, lifelong...
Hereditary antithrombin deficiency is caused by gene mutations and predisposes to recurrent venous thromboembolism that can be life-threatening. Therefore, lifelong anticoagulation is required, which has side effects and may not be effective. In this study, peripheral blood mononuclear cells from a patient with severe antithrombin deficiency were reprogrammed into induced pluripotent stem cells (iPSCs). The mutation was corrected using CRISPR-Cas9 and Cre/LoxP genome editing. iPSCs were differentiated into hepatocytes, which were injected into the spleen of antithrombin knockout mice to restore the activity of antithrombin and reduce the thrombophilic state. Human iPSC-differentiated hepatocytes colonized mice and secreted antithrombin stably, normalizing antithrombin in plasma (activity: from 46.8 ± 5.7% to 88.6 ± 7.6%, < 0.0001; antigen: from 146.9 ± 19.5 nanograms per milliliter to 390.7 ± 16.1 nanograms per milliliter, < 0.0001). In venous thrombosis model, the rate of thrombosis in mice treated with edited hepatocytes, parental hepatocytes, and wild-type mice were 60, 90, and 70%, respectively. The thrombus weight was much lighter in mice treated with edited hepatocytes compared with parental hepatocytes (7.25 ± 2.00 milligrams versus 15.32 ± 2.87 milligrams, = 0.0025) and showed no notable difference compared with that in wild-type mice (10.41 ± 2.91 milligrams). The activity and concentration of antithrombin remained high for 3 weeks after injection. The liver and kidney function markers showed no obvious abnormality during the observation period. This study provides a proof of principle for correction of mutations in patient-derived iPSCs and potential therapeutic applications for hereditary thrombophilia.
Topics: Humans; Mice; Animals; Antithrombin III Deficiency; Gene Editing; Induced Pluripotent Stem Cells; Leukocytes, Mononuclear; Thrombophilia; Antithrombins; Anticoagulants; Mice, Knockout
PubMed: 36449603
DOI: 10.1126/scitranslmed.abq3202 -
Critical Reviews in Food Science and... 1996Food allergens are typically proteins that are resistant to digestion, acid, and heat treatments. However, some notable exceptions exist. The amount of these proteins... (Review)
Review
Food allergens are typically proteins that are resistant to digestion, acid, and heat treatments. However, some notable exceptions exist. The amount of these proteins needed to elicit an allergic response in previously sensitized individuals is quite low (milligram amounts). The allergenicity of specific proteins derived from known allergenic sources can be determined, whereas the potential allergenicity of proteins derived from sources of unknown allergenicity is much harder to assess.
Topics: Allergens; Amino Acid Sequence; Chemical Phenomena; Chemistry, Physical; Dose-Response Relationship, Immunologic; Epitopes; Food; Food Handling; Food Hypersensitivity; Genetic Engineering; Humans; Proteins
PubMed: 8959380
DOI: 10.1080/10408399609527761 -
Endocrinology, Diabetes & Metabolism... 2016Estrogen is used to induce puberty in peripubertal girls with hypogonadism. Although both synthetic and natural forms are available, along with different routes of...
UNLABELLED
Estrogen is used to induce puberty in peripubertal girls with hypogonadism. Although both synthetic and natural forms are available, along with different routes of administration, in the UK oral ethinyl estradiol and the low-dose oral contraceptive pill are commonly used as hormone replacement therapy for practical reasons. We present five peripubertal girls (aged 12.5-14.9 years) with hypogonadism (two with primary hypogonadism due to Turner syndrome and three with central (secondary) hypogonadism as part of multiple pituitary hormone deficiency) who for a variety of reasons have received milligram doses of estradiol (E2) in error for between 6 weeks and 6 months, instead of the expected microgram doses of ethinyl estradiol. Although there are no direct comparisons in peripubertal girls between synthetic and natural estrogens, all girls had vaginal bleeding whilst receiving the milligram doses and have ended up with reduced final heights, below the 9th centile in 1 and below the 2nd centile in 4. Whilst reduction in final height may be part of the underlying condition (especially in Turner syndrome) the two girls with height predictions performed prior to receiving the estrogen overdose have not achieved their predicted height. Estrogen is one of the few drugs which is available in both milligram and microgram formulations. Clinicians need to be alert to the possibility of patients receiving the wrong formulation and dosage in error.
LEARNING POINTS
Girls with primary and secondary gonadal failure require assistance with pubertal induction.Although several different formulations and route of administration are available, for practical reasons, the majority of girls in the UK receive oral ethinyl estradiol.Estrogen preparations are available in both milligram and microgram formulations, with potential for receiving the wrong dose.Girls receiving milligram rather than microgram preparations all had vaginal bleeding and a short final height.
PubMed: 26843960
DOI: 10.1530/EDM-15-0096 -
Chemical Science May 2022The synthesis of secondary and tertiary amines through the reductive amination of carbonyl compounds is one of the most significant reactions in synthetic chemistry.... (Review)
Review
The synthesis of secondary and tertiary amines through the reductive amination of carbonyl compounds is one of the most significant reactions in synthetic chemistry. Asymmetric reductive amination for the formation of chiral amines, which are required for the synthesis of pharmaceuticals and other bioactive molecules, is often achieved through transition metal catalysis, but biocatalytic methods of chiral amine production have also been a focus of interest owing to their selectivity and sustainability. The discovery of asymmetric reductive amination by imine reductase (IRED) and reductive aminase (RedAm) enzymes has served as the starting point for a new industrial approach to the production of chiral amines, leading from laboratory-scale milligram transformations to ton-scale reactions that are now described in the public domain. In this perspective we trace the development of the IRED-catalyzed reductive amination reaction from its discovery to its industrial application on kg to ton scale. In addition to surveying examples of the synthetic chemistry that has been achieved with the enzymes, the contribution of structure and protein engineering to the understanding of IRED-catalyzed reductive amination is described, and the consequent benefits for activity, selectivity and stability in the design of process suitable catalysts.
PubMed: 35655886
DOI: 10.1039/d2sc00124a -
Current Protocols in Immunology May 2001The protocols in this unit describe methods for preparing bacterial plasmid DNA free from chromosomal DNA. The first is an alkaline lysis miniprep suitable for screening... (Review)
Review
The protocols in this unit describe methods for preparing bacterial plasmid DNA free from chromosomal DNA. The first is an alkaline lysis miniprep suitable for screening a moderate number of bacterial colonies by restriction endonuclease cleavage and agarose gel electrophoresis. The second is the first step to producing large amounts (milligrams) of plasmid DNA and is also based on alkaline lysis of the bacterial cells. The crude lysate generated in this protocol can be further purified by centrifugation using CsCl/ethidium bromide (CsCl/EtBr) equilibrium density gradients. Three support protocols provide information on how to grow overnight and larger cultures of bacteria, and how to monitor bacterial growth with a spectrophotometer. Other methods, some relying on commercially available ion-exchange columns, are discussed in the commentary.
Topics: Chromosomes, Bacterial; DNA, Bacterial; Escherichia coli; Plasmids
PubMed: 18432694
DOI: 10.1002/0471142735.im1003s27