Wide Range Of Doses Research Articles

Variable Delta-9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics After Cannabis Smoking in Regular Users.

Despite its federally restricted status, cannabis is widely used medicinally and recreationally. The pharmacokinetics (PK) and central nervous system (CNS) effects of tetrahydrocannabinol (THC), the major psychoactive cannabinoid, are not well understood. The objective of this study was to develop a population PK model of inhaled THC, including sources of variability, and to conduct an exploratory analysis of potential exposure-response relationships. Regular adult cannabis users smoked a single cannabis cigarette containing 5.9% THC (Chemovar A) or 13.4% THC (Chemovar B) ad libitum. THC concentrations in whole blood were measured and used to develop a population PK model to identify potential factors contributing to interindividual variability in THC PK and to describe THC disposition. Relationships between model-predicted exposure and heart rate, change in composite driving score on a driving simulator, and perceived highness were evaluated. From the 102 participants, a total of 770 blood THC concentrations were obtained. A two-compartment structural model adequately fit the data. Chemovar and baseline THC (THC BL ) were found to be significant covariates for bioavailability, with Chemovar A having better THC absorption. The model predicted that heavy users-those with the highest THC BL -would have significantly higher absorption than those with lighter previous use. There was a statistically significant relationship between exposure and heart rate, and exposure and perceived highness. THC PK is highly variable and related to baseline THC concentrations and different chemovars. The developed population PK model showed that heavier users had higher THC bioavailability. To better understand the factors affecting THC PK and dose-response relationships, future studies should incorporate a wide range of doses, multiple routes of administration, and different formulations relevant to typical community use.

Does the halo count on temporal and axillary ultrasound predict time to relapse in giant cell arteritis?

To determine whether the halo count (HC) on temporal and axillary artery ultrasound (TAUS) predicts time to relapse in giant cell arteritis (GCA). We conducted a single-centre retrospective study of GCA patients. HC, the number of vessels with non-compressible halo on the TAUS at diagnosis, was determined by retrospective review of the ultrasound report and images. Relapse was defined as increase in GCA disease activity requiring treatment escalation. Cox proportional hazard regression was used to identify predictors of time to relapse. 72 patients with confirmed GCA were followed up for a median of 20.9 months. 37/72 (51.4%) relapsed during follow-up, at a median prednisolone dose of 9 mg (range 0-40mg). Large-vessel (axillary artery) involvement did not predict relapse. On univariable analysis, a higher HC was associated with shorter time to relapse (per-halo HR 1.15, CI 95% 1.02, 1.30; p= 0.028). However, statistical significance was lost when the 10 GCA patients with HC of 0 were excluded from analysis. In this real-world setting, relapse occurred at a wide range of glucocorticoid doses and was not predicted by axillary artery involvement. GCA patients with a higher HC at diagnosis were significantly more likely to relapse, but significance was lost on excluding those with HC of zero. HC is feasible in routine care and may be worth incorporating into future prognostic scores. Further research is required to determine whether confirmed GCA patients with negative TAUS represent a qualitatively different subphenotype within the GCA disease spectrum.

Geotechnical Characterization of Laponite as Transparent Clay Surrogate

Abstract The use of so-called “transparent soils” as proxy geotechnical materials has allowed for the nonintrusive observation of a variety of models representing different engineered systems. Laponite is one such soft clay surrogate that has seen increased usage in recent years. However, this material has yet to be subjected to a thorough characterization and quantification of its physical and mechanical properties. The study presented herein followed a systematic approach toward the characterization of Laponite RD colloids from a geotechnical perspective across a wide range of mixes and additive dosages. Rheology tests were conducted to study the variation in apparent viscosity with time and after remixing. These tests identified two sources/types of strength gain: a reversible thixotropic strength gain and an irreversible particle aggregation strength gain. Different mixtures tested in a one-dimensional consolidation oedometer showed that mixes with laponite colloid contents as high as 21 % could be achieved from mixes with an initial colloid content of 11 % by mass. Finally, results from vane shear tests showed that the undrained shear strength increased with: (1) increasing laponite colloid content, (2) decreasing additive dosage, (3) aging time, and (4) increasing temperature. The base geotechnical characteristics and mechanical properties of the clay surrogate as provided in this study are expected to facilitate proper interpretation of the behavior of this surrogate material in geotechnical physical models involving transparent clays.

Experimental and Simulation Studies on Hematite Interaction with Na-Metasilicate Pentahydrate.

Iron ore is a fundamental pillar in construction globally, however, its process is highly polluting and deposits are becoming less concentrated, making reusing or reprocessing its sources a sustainable solution to the current industry. A rheological analysis was performed to understand the effect of sodium metasilicate on the flow curves of concentrated pulps. The study was carried out in an Anton Paar MCR 102 rheometer, showing that, in a wide range of dosages, the reagent can reduce the yield stress of the slurries, which would result in lower energy costs for transporting the pulps by pumping. To understand the behavior observed experimentally, computational simulation has been used by means of quantum calculations to represent the metasilicate molecule and the molecular dynamics to study the adsorption of metasilicate on the hematite surface. It has been possible to obtain that the adsorption is stable on the surface of hematite, where increasing the concentration of metasilicate increases its adsorption on the surface. The adsorption could be modeled by the Slips model where there is a delay in adsorption at low concentrations and then a saturated value is reached. It was found that metasilicate requires the presence of sodium ions to be adsorbed on the surface by means of a cation bridge-type interaction. It is also possible to identify that it is absorbed by means of hydrogen bridges, but to a lesser extent than the cation bridge. Finally, it is observed that the presence of metasilicate adsorbed on the surface modifies the net surface charge, increasing it and, thus, generating the effect of dispersion of hematite particles which experimentally is observed as a decrease in rheology.

Developing a mechanistic understanding of the nonlinear pharmacokinetics of letermovir and prospective drug interaction with everolimus using physiological-based pharmacokinetic modeling.

Letermovir is approved for use in cytomegalovirus-seropositive hematopoietic stem cell transplant recipients and is investigated in other transplant settings. Nonlinear pharmacokinetics (PKs) were observed in clinical studies after intravenous and oral dosing across a wide dose range, including the efficacious doses of 240 and 480 mg. A physiologically-based PK (PBPK) model for letermovir was built to develop a plausible explanation for the nonlinear PKs observed in clinical studies. In vitro studies suggested that letermovir elimination and distribution are mediated by saturable uridine glucuronosyltransferases (UGT)-metabolism and by saturable hepatic uptake via organic anion-transporting polypeptides (OATP) 1B. A sensitivity analysis of parameters describing the metabolism and distribution mechanisms indicated that the greater than dose-proportional increase in letermovir exposure is best described by a saturable OATP1B-mediated transport. This PBPK model was further used to evaluate the drug interaction potential between letermovir and everolimus, an immunosuppressant that may be co-administered with letermovir depending on regions. Because letermovir inhibits cytochrome P450 (CYP) 3A and everolimus is a known CYP3A substrate, an interaction when concomitantly administered is anticipated. The drug-drug interaction simulation confirmed that letermovir will likely increase everolimus are under the curve by 2.5-fold, consistent with the moderate increase in exposure observed with midazolam in the clinic. The output highlights the importance of drug monitoring, which is common clinical practice for everolimus to maintain safe and efficacious drug concentrations in the targeted patient population when concomitantly administered with letermovir.

Hydroxyl radical dominated ibuprofen degradation by UV/percarbonate process: Response surface methodology optimization, toxicity, and cost evaluation

Ibuprofen (IBP) is a typical nonsteroidal anti-inflammatory drug with a wide range of applications, large dosages, and environmental durability. Therefore, ultraviolet-activated sodium percarbonate (UV/SPC) technology was developed for IBP degradation. The results showed that IBP could be efficiently removed using UV/SPC. The IBP degradation was enhanced with prolonged UV irradiation time, with the decreasing IBP concentration and the increasing SPC dosage. The UV/SPC degradation of IBP was highly adaptable to pH ranging from 4.05 to 8.03. The degradation rate of IBP reached 100% within 30 min. The optimal experimental conditions for IBP degradation were further optimized using response surface methodology. IBP degradation rate reached 97.3% under the optimal experimental conditions: 5 μM of IBP, 40 μM of SPC, 7.60 pH, and UV irradiation for 20 min. Humic acid, fulvic acid, inorganic anions, and natural water matrix inhibited the IBP degradation to varying degrees. Scavenging experiments of reactive oxygen species indicated that hydroxyl radical played a major role in the UV/SPC degradation of IBP, while carbonate radical played a minor role. Six IBP degradation intermediates were detected, and hydroxylation and decarboxylation were proposed as the primary degradation pathways. An acute toxicity test, based on the inhibition of luminescence in Vibrio fischeri, indicated that the toxicity of IBP during UV/SPC degradation decreased by 11%. An electrical energy per order value of 3.57 kWh m−3 indicated that the UV/SPC process was cost-effective in IBP decomposition. These results provide new insights into the degradation performance and mechanisms of the UV/SPC process, which can potentially be used for practical water treatment in the future.

Application of a Portable Colorimeter for Reading a Radiochromic Film for On-Site Dosimetry

Radiochromic films have widely been used for quality assurance (QA) in radiation therapy and have many advantageous features such as self-developing visible coloration, wide dose range and easiness to handle. These features have a good potential for application to other fields associated with high-dose radiation exposure, e.g., verification of various radiation sources used in industry and research, occupational radiation monitoring as a preparedness for radiological emergencies. One of the issues in such applications is the elaborate process of acquisition and analyses of the color image using a flatbed scanner and image processing software, which is desirably to be improved for achieving a practical on-site dosimetry. In the present study, a simple method for reading a radiochromic film by using a portable colorimeter (nix pro 2; abbreviated here “Nix”) was proposed and its feasibility for diagnostic X-rays was tested with a commercial radiochromic film (Gafchromic EBT-XD). It was found that the color intensities of red and green components of EBT-XD were successfully measured by Nix over a wide dose range up to 40 Gy. Though some angle dependence was observed, this error could be well averted by careful attention to the film direction in a reading process. According to these findings, it is expected that the proposed on-site dosimetry method of combining a radiochromic film and a portable colorimeter will be practically utilized in various occasions.

Neoadjuvant Therapy Regimens for Hilar Cholangiocarcinoma Before Liver Transplant.

Patients with unresectable hilar cholangiocarcinoma (hCCA) may be eligible for curative treatment through liver transplantation (LT). Neoadjuvant protocols often include radiotherapy (RT), however, there is no standard RT approach. The purpose of this study is to characterize practice patterns of RT use before transplantation for hCCA. A survey was administered to radiation oncologists practicing at LT centers identified through the U.S. Organ Procurement and Transplant Network and the International Cholangiocarcinoma Research Network. The survey consisted of 13 questions regarding RT details as well as approaches to systemic therapy. For cross-regimen comparison, the cumulative RT tumor dose was standardized using the EQD2 method. Twenty-three centers utilizing neoadjuvant therapy for hCCA were identified. Most respondents (96%) use both chemotherapy and RT as part of their protocol. Elective nodal volumes commonly included the portal vein lymph nodes (91%) and celiac artery lymph nodes (70%). After an initial 45 Gy plan, a wide range of sequential boost regimens was used. The median cumulative dose including boosts to the gross disease was 58 Gy (EQD2) with a wide range of 40 to 110 Gy. Five (22%) include brachytherapy as part of their treatment plan. The majority (96%) used concurrent chemotherapy with fluoropyrimidines. These results suggest significant variability of neoadjuvant RT use for hCCA before LT. A wide range of doses and fractionation schemes are utilized with cumulative doses ranging from 40 to 110 Gy (EQD2). A further study evaluating the efficacy and toxicity of these various approaches is warranted to better inform best practices.

Thermoluminescence investigations and kinetic analysis of highly sensitive LiCaAlF6: Eu,Y phosphor for dosimetric applications

The paper presents detailed thermoluminescence characterization and kinetic analysis of highly sensitive and dosimetric grade lithium calcium aluminum fluoride doped with europium and co-doped with yttrium (LiCaAlF6:Eu,Y). It is synthesized by melt processing technique. The thermoluminescence (TL) and optically stimulated luminescence (OSL) correlation was systematically studied. The study reveals that the OSL signal is attributed to the observed TL peaks in this material. Thus, same defects are responsible for TL and OSL in LiCaAlF6:Eu,Y. Further characterization involved measurement of TL emission spectrum, OSL emission spectrum, steady state photoluminescence (PL) spectra, phosphorescence, sensitivity, fading, dose response etc. The TL sensitivity of this phosphor was observed to be ∼5 times and ∼3 times to that of CaSO4:Dy and commercially available Al2O3:C respectively. PL, TL and OSL emission spectra suggest that Eu2+ ion acts as a luminescence center in this material. Minimum measureable dose for the phosphor in TL mode was found to be 0.3 μGy with negligible fading post 10 days of irradiation. The fading of TL signal in this material is similar to the one observed for OSL signal. The thermal stability and hygroscopic nature of LiCaAlF6:Eu, Y were studied using thermogravimetric and differential scanning calorimetry techniques. Owing to the attributes like high sensitivity, wide dynamic dose range it stands as a viable and excellent phosphor material for various radiological and dosimetric applications.

Abstract 846: Utilizing quantitative systems pharmacology (QSP) model to understand cytokine release syndrome (CRS) following administration of epcoritamab in DLBCL patients

Abstract Background: Epcoritamab is a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells (1). Epcoritamab’s pharmacokinetics (PK), pharmacodynamics, and safety profiles were investigated in GCT3013-01 escalation study across a wide range of doses. CRS is an adverse event of special interest for T cell engagers such as Epcoritamab. As such, step-up dosing (SUD) has been investigated in study GCT3013-01 escalation to minimize release of cytokines and mitigate severe CRS symptoms. Seventeen permutations of SUD were tested, with doses ranging from 0.004 to 60 mg. Based on observed CRS data, a SUD regimen of 0.16/0.8/48 mg was selected. The aim of the analysis was to develop a QSP model capable of predicting cytokine release which can be used to identify potential optimal SUD regimen. Method: Leveraging Epcoritamab preclinical and clinical data, we have developed a QSP platform that captures the observed tumor responses and allows for systemic predictions of biomarkers with the selected SUD regimen. A minimal physiologically based PK model was linked to submodels of T cell activation, proliferation, and cytotoxicity of target-bearing cells, to create an integrated QSP model of the DLBCL system. Epcoritamab-mediated cross-linking of target(s) and CD3 receptor to form trimer complexes drives cell trafficking and cytokine production as well as inducing death of target-bearing cells. The model described the PK, cellular effects, and observed cytokine profiles within the plasma, and simulated similar effects in lymph node(s), tumor, and other peripheral body tissue. Result: After SC administration of Epcoritamab, transient and modest elevation of selected cytokines was observed. Patients’ cytokine profiles were categorized into three different trends based on Cycle 1 data. By accounting for the interaction of receptors and ligands at the nano-scale level (time and physical size) we characterized the dose response and dynamics of T cells, B cells, IL6, and IL10 in patients enrolled in the study by using the QSP model. Conclusions: This analysis integrated underlying mechanisms to predict various systemic biomarkers dynamics including T cells, B cells, IL6 and IL10 following administration of Epcoritamab. The well-studied pathways and mechanisms allow implementation of the model in disease indications other than DLBCL.

Are pediatrics taking the prescribed tablet dosage form? Practices of off-label tablet modification in pediatric wards: A prospective observational study

Tablet manipulation (modification) is a practice where the licensed tablet product is customized into reduced fractions of doses or changed into dispersions using solvents because of suitable dose for paediatrics and neonates are frequently unavailable. As a result, unlicensed dosage form frequently used after manipulation, outside what is approved by drug regulatory authorities. ObjectiveTo assess the practice of off-label tablet manipulation in pediatric and neonatal wards at selected public hospitals in Ethiopia. MethodsA prospective, direct observational approach was used to investigate the frequency, nature and appropriateness of tablet manipulations in neonatal and pediatrics patients of two public hospitals of Ethiopia from April 12, to June 30, 2021. ResultsDuring the study period a total of 303 tablet manipulations were observed. Two hundred nine (69%) of tablets were dispensed to pediatric patients to be taken after split into lower strengths. The remaining nighty four (31%) tablets were manipulated into dispersion using 0.9% normal saline as a main solvent. Interestingly, 48 (15.8%) of tablet manipulations into dispersions involved practically insoluble drugs whose manipulation may probably affect their bioavailability. In 12.5% (12/94) dispersion manipulations, large undissolved fractions were observed during administration through naso-gastric tubes. The most commonly manipulated tablets were drugs for central nervous system (n = 135, 44.6%) followed by cardiovascular drugs (n = 85, 28%). Conclusionsand recommendations: The study revealed the off-label use of tablets for pediatrics age groups is very common in Ethiopia. Evidence-based guidelines for tablet manipulations should be practiced to improve the safety of paediatric drug use. As for policy implication, this study concurs with previous scientific recommendations that manufacturers introduce a wide range of dosage forms to reduce the need for manipulations.

Pharmacokinetic-pharmacodynamic model of urinary δ-aminolevulinic acid reduction after givosiran treatment in patients with acute hepatic porphyria.

Givosiran, an RNA interference-based therapeutic, is a recent addition to the limited treatment armamentarium for acute hepatic porphyria (AHP). As a small interfering RNA that is selectively taken up in the liver, both the mechanism and targeted delivery create a complex relationship between givosiran pharmacokinetics (PK) and the pharmacodynamic (PD) response. Using pooled data from phase I-III clinical trials of givosiran, we developed a semimechanistic PK/PD model to describe the relationship between predicted liver and RNA-induced silencing complex concentrations of givosiran and the associated reduction in synthesis of δ-aminolevulinic acid (ALA), a toxic heme intermediate that accumulates in patients with AHP, contributing to disease pathogenesis. Model development included quantification of variability and evaluation of covariate effects. The final model was used to assess the adequacy of the recommended givosiran dosing regimen across demographic and clinical subgroups. The population PK/PD model adequately described the time course of urinary ALA reduction with various dosing regimens of givosiran, the interindividual variability across a wide range of givosiran doses (0.035-5mg/kg), and the influence of patient characteristics. None of the covariates tested had a clinically relevant effect on PD response that would necessitate dose adjustment. For patients with AHP, including adults, adolescents, and patients with mild to moderate renal impairment or mild hepatic impairment, the 2.5-mg/kg once monthly dosing regimen of givosiran results in clinically meaningful ALA lowering, reducing the risk for AHP attacks.

Does Green Exfoliation of Graphene Produce More Biocompatible Structures?

Graphene has been studied thoroughly for its use in biomedical applications over the last decades. A crucial factor for a material to be used in such applications is its biocompatibility. Various factors affect the biocompatibility and toxicity of graphene structures, including lateral size, number of layers, surface functionalization, and way of production. In this work, we tested that the green production of few-layer bio-graphene (bG) enhances its biocompatibility compared to chemical-graphene (cG). When tested against three different cell lines in terms of MTT assays, both materials proved to be well-tolerated at a wide range of doses. However, high doses of cG induce long-term toxicity and have a tendency for apoptosis. Neither bG nor cG induced ROS generation or cell cycle modifications. Finally, both materials affect the expression of inflammatory proteins such as Nrf2, NF-kB and HO-1 but further research is required for a safe result. In conclusion, although there is little to choose between bG and cG, bG's sustainable way of production makes it a much more attractive and promising candidate for biomedical applications.

Design, Synthesis, and Study of the Anxiolytic Activity of New Pyrrolo[1,2-<i>a</i>]pyrazine-Containing TSPO Ligands

A new group of 1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamides, in which substituents at the amide nitrogen atom are alkyl, benzyl or alkoxyphenylalkyl groups, amino acid residues or their derivatives, has been obtained in this work. The synthesized compounds have high theoretical affinities for the 18 kDa translocator protein (TSPO) and a favorable profile of ADMET characteristics, which makes them promising for drug development. Anxiolytic activity was detected for eight compounds at doses of 0.1–5.0 mg/kg when administered intraperitoneally under conditions of emotional stress in the open field test in Balb/c mice and in the elevated plus maze test in ICR mice. N-Benzhydryl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide was selected as a lead compound for further development as a potential anxiolytic agent, which showed the presence of anti-anxiety activity in a wide range of doses in both tests used.

New perspectives on randomized controlled trials with omega-3 fatty acid supplements and cognition: A scoping review.

Long chain polyunsaturated omega-3 fatty acids (n-3 FA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are known to be important components in a healthy diet and contribute to healthy functioning of the heart and the brain, among other organs. Although there are epidemiological studies on the strong relationship between fish or n-3 FA consumption and lower risk of cognitive decline, results from randomized controlled trials (RCTs) are less consistent. Here, we performed a scoping review on RCTs with n-3 FA supplementation where cognition was evaluated. Seventy-eight RCTs published before April 2022 were included in this review. Among these RCTs, 43.6% reported a positive cognitive outcome after the consumption of n-3 FA compared to the placebo. However, there was a large diversity of populations studied (age ranges and health status), wide range of doses of EPA +DHA supplemented (79mg/day - 5200mg/day) and a multitude of tests evaluating cognition, mainly diagnostic tests, that were used to assess cognitive scores and overall cognitive status. RCTs were thereafter categorized into non-cognitively impaired middle-aged adults (n=24), non-cognitively impaired older adults (n=24), adults with subjective memory complaints (n=14), adults with mild cognitive impairments (MCI, n=9) and people with diagnosed dementia or other cognitive changes (n=7). Among these categories, 66.7% of RCTs conducted with MCI adults reported a positive cognitive outcome when supplemented with n-3 FA vs. the placebo. Therefore, this scoping review provides rationale and questions to a) strengthen the design of future RCTs with n-3 FA for cognitive outcomes, and b) generate more informative data to support clinicians in their practice in assessing cognition before and after a nutritional intervention.

Silicone Elastomeric-Based Materials of Soft Pneumatic Actuator for Lower-Limb Rehabilitation: Finite Element Modelling and Prototype Experimental Validation

This study describes the basic design, material selection, fabrication, and evaluation of soft pneumatic actuators (SPA) for lower-limb rehabilitation compression therapy. SPAs can be a promising technology in proactive pressure delivery, with a wide range of dosages for treating venous-related diseases. However, the most effective design and material selection of SPAs for dynamic pressure delivery have not been fully explored. Therefore, a SPA chamber with two elastomeric layers was developed for this study, with single-side inflation. The 3D deformation profiles of the SPA chamber using three different elastomeric rubbers were analyzed using the finite element method (FEM). The best SPA-compliant behavior was displayed by food-grade silicone A10 Shore with a maximum deformation value of 25.34 mm. Next, the SPA chamber was fabricated using A10 Shore silicone and experimentally validated. During the simulation in FEM, the air pressure was applied on the inner wall of the chamber (i.e., the affected area). This is to ensure the applied pressure was evenly distributed in the inner wall while the outer wall of the chamber remained undeformed for all compression levels. During the inflation process, pressure will be applied to the SPA chamber, causing exerted pressure on the skin which is then measured for comparison. The simulation and experimental results show an excellent agreement of pressure transmission on the skin for the pressure range of 0–120 mmHg, as depicted in the Bland–Altman plots. The findings exhibited promising results in the development of the SPA chamber using low-cost and biocompatible food-grade silicone.

The use of three-dimensional technologies in the development of oral solid dosage forms

Aim. To analyze the scientific literature data on the use of three-dimensional technologies in pharmacy, in particular in the technology of oral solid dosage forms, the advantages and disadvantages of 3D printing, and current research on the development of drugs using 3D printing. Materials and methods. To achieve this goal, bibliosemantic and analytical methods were used. Results and discussion. Personalized medicine is currently a major area of development in the healthcare sector. Its goal is to adapt treatment to a specific person, taking into account the peculiarities of the physiology, drug reactions, and the genetic profile. There are technologies that contribute to the paradigm shift from the traditional “one-size-fits-all”approach to personalized medicine, the main one being three-dimensional (3D) printing. 3D printing involves the creation of a three-dimensional object using various computer programs. 3D printing can be used to create a wide range of dosage forms that differ in shape, release profile, and drug combination. The main 3D printing technology platforms under study in the pharmaceutical sector include inkjet printing, binder inkjet printing, fused filament manufacturing, selective laser sintering, stereolithography, and injection microsyringing. Conclusions. The article discusses various 3D printing technologies and the prospects for their application in research on the development of new medicines, in particular oral solid dosage forms, and highlights their advantages and disadvantages.

Higher doses of tisagenlecleucel are associated with improved outcomes: a report from the pediatric real-world CAR consortium.

Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved forthis indication. Currently, patients receive a single dose of tisagenlecleucel across a wide doserange of 0.2 to 5.0× 106 and 0.1 to 2.5× 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7× 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300× 106 (n= 48 [27%]), 1.301 to 1.700× 106 (n= 46 [26%]), 1.701 to 2.400×106 (n= 43 [24%]), and 2.401 to 5.100× 106 (n= 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P= .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard totargeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.

Dynamics of temperature and body weight in irradiated mice: the dose-effect and time-effect relationships

In an experiment on outbred male ICR CD-1 mice irradiated at a wide range of doses of gamma irradiation 60Co from 7.4 to 9.4 Gy with a 30-day survival rate from 100 to 5%, the dose-effect and time-effect relationships in relation to animals’ temperature and body mass index during acute radiation sickness were studied. The latent phase of acute radiation sickness is already related to a decrease in body temperature, which is determined using a remote infrared thermometer, in presence of body weight loss. A maximum dose-dependent fall in body temperature was observed in the critical phase of acute radiation sickness, when animals die in large numbers. In the recovery phase, body temperature returned to normal with subsequent body weight gain. Body temperature of irradiated mice is considered as an important criterion for their asthenia and can be used both in theoretical and applied studies.

Sequence dependent UV damage of complete pools of oligonucleotides

Understanding the sequence-dependent DNA damage formation requires probing a complete pool of sequences over a wide dose range of the damage-causing exposure. We used high throughput sequencing to simultaneously obtain the dose dependence and quantum yields for oligonucleotide damages for all possible 4096 DNA sequences with hexamer length. We exposed the DNA to ultraviolet radiation at 266 nm and doses of up to 500 absorbed photons per base. At the dimer level, our results confirm existing literature values of photodamage, whereas we now quantified the susceptibility of sequence motifs to UV irradiation up to previously inaccessible polymer lengths. This revealed the protective effect of the sequence context in preventing the formation of UV-lesions. For example, the rate to form dipyrimidine lesions is strongly reduced by nearby guanine bases. Our results provide a complete picture of the sensitivity of oligonucleotides to UV irradiation and allow us to predict their abundance in high-UV environments.