Missing or erroneous information is a common problem in the analysis of pharmacokinetic (PK) data. This may present as missing or inaccurate dose level or dose time, drug concentrations below the ...analytical limit of quantification, missing sample times, or missing or incorrect covariate information. Several methods to handle problematic data have been evaluated, although no single, broad set of recommendations for commonly occurring errors has been published. In this tutorial, we review the existing literature and present the results of our simulation studies that evaluated common methods to handle known data errors to bridge the remaining gaps and expand on the existing knowledge. This tutorial is intended for any scientist analyzing a PK data set with missing or apparently erroneous data. The approaches described herein may also be useful for the analysis of nonclinical PK data.
The discovery of Rous sarcoma virus (RSV) led to the identification of cellular Src (c-Src), a non-receptor tyrosine kinase, which has since been implicated in the development of numerous human ...cancers. c-Src has been found to be highly activated in colon cancers, particularly in those metastatic to the liver. Studies of the mechanism of c-Src regulation have suggested that c-Src kinase activity is downregulated by phosphorylation of a critical carboxy-terminal tyrosine (Tyr 530 in human c-Src, equivalent to Tyr 527 in chicken Src) and have implied the existence of activating mutations in this C-terminal regulatory region. We report here the identification of a truncating mutation in SRC at codon 531 in 12% of cases of advanced human colon cancer tested and demonstrate that the mutation is activating, transforming, tumorigenic and promotes metastasis. These results provide, for the first time, genetic evidence that activating SRC mutations may have a role in the malignant progression of human colon cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one‐third of patients respond to treatment, ...and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL0) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies. This suggests CL0 may predict outcomes from ICI therapy, and cachectic signalling may link elevated CL0 and poor response. Our aim was to determine if mouse models of cancer cachexia will be useful for studying these phenomena and their underlying mechanisms.
Methods
We evaluated pembrolizumab CL in the C26 and Lewis lung carcinoma mouse models of cancer cachexia. A single treatment of vehicle or pembrolizumab, at a dose of 2 or 10 mg/kg, was administered intravenously by tail vein injection. Pembrolizumab was quantified by an ELISA in serial plasma samples, and FcRn gene (Fcgrt) expression was assessed in liver using real‐time quantitative reverse transcription PCR. Non‐compartmental and mixed‐effects pharmacokinetics analyses were performed.
Results
We observed higher pembrolizumab CL0 and decreased Fcgrt expression in whole liver tissue from tumour‐bearing vs. tumour‐free mice. In multivariate analysis, presence of tumour, total murine IgG, muscle weight and Fcgrt expression were significant covariates on CL, and total murine IgG was a significant covariate on V1 and Q.
Conclusions
These data demonstrate increases in catabolic clearance of monoclonal antibodies observed in humans can be replicated in cachectic mice, in which Fcgrt expression is also reduced. Notably, FcRn activity is essential for proper antigen presentation and antitumour immunity, which may permit the study of cachexia's impact on FcRn‐mediated clearance and efficacy of ICI therapies.
This paper provides an overview of the well-established and empirically supported behavioral interventions for the treatment of migraine. The considerable evidence base addressing behavioral ...interventions amassed since 1969 has conclusively established the efficacy of therapies featuring combinations of relaxation, biofeedback, and stress management training, and demonstrated they are capable of yielding benefits on par with pharmacological therapies for migraine. Behavioral interventions also are well suited for delivery across a variety of different contexts (e.g., group vs. individual, standard clinic vs. limited therapist contact, face-to-face vs. technology-assisted). Despite the amply established efficacy and effectiveness of these self-management interventions for the treatment of migraine, the availability and implementation of these approaches remain limited for many headache sufferers. We anticipate the technological advances in delivery platforms will provide better access to behavioral self-management strategies for migraine.
BACKGROUND In the MagnetisMM-3 (NCT04649359) study, elranatamab (ELRA) administered at a dose of 76 mg once-weekly (QW) with 2 step-up priming doses of 12 mg on day 1 and 32 mg on day 4 had a ...manageable safety profile, with 56.3% of patients developing cytokine release syndrome (CRS) and 98.8% of events occurring with the first 3 doses. Here, we report clinical factors associated with CRS and dosing recommendations for restarting treatment after dose interruptions in patients with relapsed or refractory multiple myeloma (RRMM) undergoing treatment with ELRA. METHODS Eligible patients received ELRA subcutaneously in step-up priming doses of 12 and 32 mg on days 1 and 4 of cycle 1, respectively, followed by 76 mg of ELRA QW. CRS events were graded according to the criteria of the American Society for Transplantation and Cellular Therapy and managed according to published guidelines. Multivariable analyses were performed to identify clinical factors associated with CRS. Baseline factors (extramedullary disease by BICR, prior antibody-drug conjugate, prior CAR-T, number of prior lines of therapy ≤5, >5, sex, and age continuous variable) were included in the model for CRS after the initial dose, and only post-baseline factors (time to previous CRS and time to initial tocilizumab use) were included in the model for CRS after the second dose. A previously described population pharmacokinetic (PK) model was used to simulate different interruption scenarios and determine how long it takes for ELRA exposure to drop below the threshold associated with CRS events (Hibma J, et al. Poster presented at PAGE 31 2023 abstract 10648). The data used to develop this model was collected from the following open-label elranatamab trials: MagnetisMM-1 (NCT03269136; phase 1), MagnetisMM-2 (NCT04798586; phase 1), MagnetisMM-3 (NCT04649359; phase 2), and MagnetisMM-9 (NCT05014412; phase 1/2). Of 183 patients who were treated in MagnetisMM-3 with the 2 step-up priming dosing, 106 patients (57.9%) experienced CRS, 43.7% grade 1, 13.7% grade 2, and 0.5% grade 3. Tocilizumab was used to manage CRS. Of the 130 CRS events, 37 (28.5%; 20 grade 1 and 17 grade ≥2) were treated with tocilizumab, and 93 (71.5%; 82 grade 1 and 11 grade ≥2) were not. After the initial elranatamab dose, 79/183 patients had CRS. The presence of extramedullary disease was predictive of a decreased risk of CRS after the initial dose. Of the 180 who received a second elranatamab dose, 35 had CRS afterwards. In a multivariable model also adjusting for CRS after the initial dose, prior tocilizumab use was predictive of a decreased risk of CRS after the second dose. After receiving doses of 76 mg of ELRA, 16 instances of dose delays lasting >6 to ≤12 weeks were observed. In most of these instances (11/16; 68.8%), patients did not repeat the 32-mg step-up dose. In 5 instances, patients restarted treatment with 32 mg of ELRA. No patients experienced CRS after retreatment. For the 4 instances of dose delays lasting >12 weeks after a 76-mg dose, patients repeated the 32-mg step-up dose in 2 instances, and patients received >32 mg ELRA after the interruption in the other 2 instances, with none experiencing CRS after retreatment. With dose delays of 6-12 weeks, ELRA exposure decreases below the C max after a 32-mg dose but not less than that for the 12-mg dose. With dose delays >12 weeks, ELRA exposure decreases below the C max after a 12-mg dose. To minimize the risk of CRS events after dose interruptions, clinical and PK data and modeling were used to develop recommendations for restarting therapy (Figure). CONCLUSIONS Extramedullary disease and use of tocilizumab were associated with a decreased risk of CRS. Based on clinical and PK data and modeling, it is recommended that patients receiving 76 mg ELRA who then experience dose delays lasting 6-12 or >12 weeks should restart treatment at doses of 32 or 12 mg, respectively.
Background
Migraine is a neurological disease involving recurrent attacks of moderate-to-severe and disabling head pain. Worsening of pain with routine physical activity during attacks is a principal ...migraine symptom; however, the frequency, individual consistency, and correlates of this symptom are unknown. Given the potential of this symptom to undermine participation in daily physical activity, an effective migraine prevention strategy, further research is warranted. This study is the first to prospectively evaluate (a) frequency and individual consistency of physical activity-related pain worsening during migraine attacks, and (b) potential correlates, including other migraine symptoms, anthropometric characteristics, psychological symptoms, and daily physical activity.
Methods
Participants were women (n = 132) aged 18–50 years with neurologist-confirmed migraine and overweight/obesity seeking weight loss treatment in the Women’s Health and Migraine trial. At baseline, participants used a smartphone diary to record migraine attack occurrence, severity, and symptoms for 28 days. Participants also completed questionnaires and 7 days of objective physical activity monitoring before and after diary completion, respectively. Patterning of the effect of physical activity on pain was summarized within-subject by calculating the proportion (%) of attacks in which physical activity worsened, improved, or had no effect on pain.
Results
Participants reported 5.5 ± 2.8 (mean ± standard deviation) migraine attacks over 28 days. The intraclass correlation (coefficient = 0.71) indicated high consistency in participants’ reports of activity-related pain worsening or not. On average, activity worsened pain in 34.8 ± 35.6% of attacks, had no effect on pain in 61.8 ± 34.6% of attacks and improved pain in 3.4 ± 12.7% of attacks. Few participants (9.8%) reported activity-related pain worsening in all attacks. A higher percentage of attacks where physical activity worsened pain demonstrated small-sized correlations with more severe nausea, photophobia, phonophobia, and allodynia (r = 0.18 – 0.22, p < 0.05). Pain worsening due to physical activity was not related to psychological symptoms or total daily physical activity.
Conclusions
There is large variability in the effect of physical activity on pain during migraine attacks that can be accounted for by individual differences. For a minority of participants, physical activity consistently contributed to pain worsening. More frequent physical activity-related pain worsening was related to greater severity of other migraine symptoms and pain sensitivity, which supports the validity of this diagnostic feature.
Study protocol
ClinicalTrials.govIdentifier: NCT01197196
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diagnosis of Borrelia‐associated uveitis in two horses Priest, Heather L.; Irby, Nita L.; Schlafer, Donald H. ...
Veterinary ophthalmology,
November 2012, 2012-Nov, 2012-11-00, 20121101, Letnik:
15, Številka:
6
Journal Article
Recenzirano
Borrelia burgdorferi, the etiologic agent of Lyme disease is a tick born spirochetal infection. Clinical signs of Lyme borreliosis are uncommon in horses, but when present they are often vague and ...nonspecific. In horses, Lyme borreliosis has been implicated in musculoskeletal, neurological, reproductive, and ocular disorders, including uveitis, but definitive diagnosis can be challenging as the causative agent is rarely isolated and serologic tests can be unreliable and do not confirm active disease. Here, we report two cases of equine uveitis associated with B. burgdorferi based on the identification of spirochetes within ocular fluids and confirmed with PCR testing. The two cases illustrate some of the challenges encountered in the recognition and diagnosis of equine Lyme borreliosis. Although only one of many possible causes of equine uveitis, Lyme disease should be considered a differential diagnosis, especially in endemic areas. Given the possibility for false negative results of serum tests during uveitis associated with B. burgdorferi and the failure of such tests to confirm active infection, a combination of cytologic assessment, antibody, and/or PCR testing of ocular fluids may be worthwhile if the clinical suspicion for Lyme uveitis is high.
Objectives: To evaluate the safety and immunogenicity of unconjugated Haemophilus influenzae type b (Hib) polysaccharide (PRP) vaccine and two PRP‐protein‐conjugated vaccines as a model for the ...comparison of protein‐conjugated versus plain polysaccharide vaccines in the elderly.
Design: Randomized, double‐blind, prospective study.
Setting: University‐based center for vaccine research and development.
Participants: A total of 125 adults, aged 64 to 92, who were judged to be in general good health and lacking any significant underlying medical conditions.
Intervention: Subjects were randomized to receive one of three vaccines: Group 1 (n=39), PRP; Group 2 (n=44), PRP conjugated to an outer‐membrane protein complex of Neisseria meningitidis (PRP‐OMP); and Group 3 (n=42), PRP conjugated to diphtheria toxoid (PRP‐D). Sera were obtained before immunization and 1 and 12 months later.
Measurements: Subjects maintained a diary of injection site and systemic reactions for 3 days after immunization. A radioantigen‐binding assay was used to measure total concentrations of serum anticapsular antibody, and an enzyme‐linked immunosorbent assay was used to measure immunoglobulin (Ig) G1 and IgG2 anticapsular antibody responses. Antibody functional activity was assessed using a complement‐mediated bactericidal assay.
Results: Before vaccination, the geometric mean serum anticapsular antibody concentration was 0.8 μg/mL, but fewer than 10% of subjects had detectable bactericidal activity (titer>1:4). The magnitude, subclass distribution, and bactericidal activity of antibody responses to unconjugated PRP vaccine were similar to those observed in previous studies of younger adults immunized with PRP. The OMP conjugate, which is highly immunogenic after one dose in 2‐month old infants, did not elicit anticapsular antibody responses in the elderly greater than those elicited by PRP vaccine (P=.43). In contrast, the D conjugate, which is poorly immunogenic in 2‐month old infants, elicited higher anticapsular antibody responses than PRP vaccine in the elderly (P=.01) and higher levels than the OMP‐conjugate 1 year after vaccination (P<.006).
Conclusion: Elderly adults develop protective anticapsular antibody responses to unconjugated and conjugated PRP vaccine. The higher anticapsular antibody responses to the D conjugate but not to the OMP conjugate in the elderly, which is the reverse of that observed in immunized infants, implies fundamental differences in the immunological mechanisms by which the two age groups respond to PRP and by which the OMP and D conjugates elicit anticapsular antibody responses.
Whereas genetic paradigms are now defined for the development of human colon cancer, little is known regarding the mechanisms that regulate development of the metastatic phenotype. Recent reports ...have indirectly linked the expression and activation of c-Src to the process of human colon cancer metastasis. Whereas v-Src, a highly activated mutational derivative of c-Src, has been shown to induce metastasis, normal c-Src has not been tested for this property. We hypothesized that c-Src overexpression in the milieu of a poorly metastatic cancer cell might permit the development of a highly metastatic cell. Two poorly metastatic human colon cancer cell lines were stably transfected with expression vectors encoding normal human c-Src. Clones producing 4-10-fold more c-Src than controls were injected s.c. and intrasplenically into the nude mouse to assess primary tumor growth and liver metastatic potential. Whereas metastatic potential was unaffected, primary tumor growth in vivo was significantly enhanced by c-Src overexpression. No effects on rates of tumor cell proliferation were seen in vitro. Our findings suggest that normal c-Src may be necessary but is insufficient for the induction of the metastatic phenotype.
Objectives: To evaluate the safety and immunogenicity of unconjugated Haemophilus influenzae type b (Hib) polysaccharide (PRP) vaccine and two PRP-protein-conjugated vaccines as a model for the ...comparison of protein-conjugated versus plain polysaccharide vaccines in the elderly. Design: Randomized, double-blind, prospective study. Setting: University-based center for vaccine research and development. Participants: A total of 125 adults, aged 64 to 92, who were judged to be in general good health and lacking any significant underlying medical conditions. Intervention: Subjects were randomized to receive one of three vaccines: Group 1 (n=39), PRP; Group 2 (n=44), PRP conjugated to an outer-membrane protein complex of Neisseria meningitidis (PRP-OMP); and Group 3 (n=42), PRP conjugated to diphtheria toxoid (PRP-D). Sera were obtained before immunization and 1 and 12 months later. Measurements: Subjects maintained a diary of injection site and systemic reactions for 3 days after immunization. A radioantigen-binding assay was used to measure total concentrations of serum anticapsular antibody, and an enzyme-linked immunosorbent assay was used to measure immunoglobulin (Ig) G1 and IgG2 anticapsular antibody responses. Antibody functional activity was assessed using a complement-mediated bactericidal assay. Results: Before vaccination, the geometric mean serum anticapsular antibody concentration was 0.8 mu g-mL, but fewer than 10% of subjects had detectable bactericidal activity (titer>1:4). The magnitude, subclass distribution, and bactericidal activity of antibody responses to unconjugated PRP vaccine were similar to those observed in previous studies of younger adults immunized with PRP. The OMP conjugate, which is highly immunogenic after one dose in 2-month old infants, did not elicit anticapsular antibody responses in the elderly greater than those elicited by PRP vaccine (P=.43). In contrast, the D conjugate, which is poorly immunogenic in 2-month old infants, elicited higher anticapsular antibody responses than PRP vaccine in the elderly (P=.01) and higher levels than the OMP-conjugate 1 year after vaccination (P<.006). Conclusion: Elderly adults develop protective anticapsular antibody responses to unconjugated and conjugated PRP vaccine. The higher anticapsular antibody responses to the D conjugate but not to the OMP conjugate in the elderly, which is the reverse of that observed in immunized infants, implies fundamental differences in the immunological mechanisms by which the two age groups respond to PRP and by which the OMP and D conjugates elicit anticapsular antibody responses.
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