Aggressive Lymphoma after CD19 CAR T-Cell Therapy.

The development of a fatal, clonal, autonomously proliferating CD4-CD8- chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. The PTCL had a clonal T-cell receptor rearrangement, which was already detectable in the apheresis product for CAR T-cell manufacturing and 7 months earlier for autologous transplantation. Somatic and mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autotransplant.

Identification of Catecholamine and Drug Target α-Adrenoceptor in Human Testis and Human Testicular Peritubular Cells.

Clonidine has been used in clinical medicine, e.g., to treat high blood pressure and other conditions.

A Picture is Worth 1000 Words: Teaching Science Communication with Graphical Abstract Assignments.

An important part of scientific training in undergraduate curriculum involves teaching students how to effectively communicate in science. Scientific writing and oral presentations are important parts of most science classes. The same cannot be said about a new and emerging aspect of many recent scientific articles: graphical abstracts.

The use of recovery animals in nonclinical safety assessment studies with monoclonal antibodies: further 3Rs opportunities remain.

Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies.

Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach.

To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs.

Gains in Scientific Identity, Scientific Self-Efficacy, and Career Intent Distinguish Upper-Level CUREs from Traditional Experiences in the Classroom.

Attrition from the science, technology, engineering, and math (STEM) pipeline limits the number of graduates needed to meet STEM workforce demand and impedes efforts to diversify the workforce. Identifying factors that underlie academic success and STEM persistence is an important component to increasing the number of STEM graduates. The current study utilizes the social influence process indicators of the Tripartite Integration Model of Social Influence to investigate effects of course-based undergraduate research experience (CURE) participation and to predict career intent in a diverse population.

Diagnostic and Therapeutic Utility of Positive Intravascular Catheter Tip Cultures.

This study evaluated the performance and clinical utility of performing intravascular catheter tip cultures (CTC). A retrospective chart review was conducted over a 2.5 year period on all patients who demonstrated growth of at least one organism on CTC.

Efficacy of Tourniquet Use in Total Knee Arthroplasty: A Retrospective Cohort Review.

Background: The use of a tourniquet has become widely accepted as standard practice during total knee arthroplasty (TKA). There are conflicting outcomes in using a tourniquet during TKA. This brings to question the role a tourniquet has in TKA.

Failure of Screw/Shell Interface in the Trident II Acetabular System in Total Hip Arthroplasty.

We report a case series of 2 patients with screw/shell interface failure in the Stryker Trident II Acetabular System. Both failures consisted of screw penetration through the Trident II acetabular shell. One failure was observed postoperatively after a revision from a cephalomedullary nail to a total hip arthroplasty while the other was observed intraoperatively during a primary total hip arthroplasty.

Clinical Significance of BD Bactec FX Blood Culture Incubation Beyond 96 Hours (4 Days).

Blood cultures (BC) for bacteria and yeast have traditionally been incubated for 5 days using modern instruments. Many organisms may grow sooner, and the need for the full 5-day incubation period has been questioned. This study evaluated the clinical significance of isolates recovered beyond 96 h.

Immunosuppression Profile of CFZ533 (Iscalimab), a Non-Depleting Anti-CD40 Antibody, and the Presence of Opportunistic Infections in a Rhesus Monkey Toxicology Study.

CFZ533 (iscalimab) is a nondepleting anti-CD40 antibody intended for inhibition of transplant organ rejection and treatment of autoimmune diseases. In a safety assessment in rhesus monkeys, CFZ533 was administered for 13 weeks up to 150 mg/kg/week subcutaneously. CFZ533 was shown previously to completely inhibit primary and secondary T-cell-dependent antibody responses.

Independent Study for the Detectx Combined Assay for the Detection of Aspergillus, Salmonella, and STEC (stx1 and/or 2) in Dried Cannabis Flower and Dried Hemp Flower: Level 3 Modification Study 012201.

Background: The PathogenDx family of assays uses microarray technology to simultaneously detect the presence of bacterial and fungal pathogens in food products, environmental surfaces, and cannabis products.

Objective: The Detectx Combined assay was validated for the detection of Aspergillus, (Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Aspergillus terreus), Salmonella, and a broad range of STEC (stx1 and/or 2) species. The validation consisted of two matrix studies in dried hemp flower and dried cannabis flower (>0.

Effect of a U:G mispair on the water around DNA.

DNA repair proteins are able to discriminate DNA lesions among an abundance of intact DNA with high selectivity. To investigate detectable characteristics of one specific lesion, we compare statistical results from molecular dynamics simulations of two different DNA in water, one with an intact C:G pair and one that contains a U:G mispair, and perform a comparative analysis of the water dynamics around the two. Our data show that in addition to the local DNA conformation, also the surrounding water shell exhibits significant differences that may help mispair discrimination.

PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion.

Diffuse alveolar hemorrhage (DAH) is one of the most serious clinical complications of systemic lupus erythematosus (SLE). The prevalence of DAH is reported to range from 1 to 5%, but while DAH is considered a rare complication there is a reported 50-80% mortality. There is at present no proven effective treatment for DAH and the therapeutics that have been tested have significant side effects.

Nonclinical Development of Biologics: Integrating Safety, Pharmacokinetics, and Pharmacodynamics to Create Smarter and More Flexible Nonclinical Safety Programs Optimizing Animal Use.

Safety assessment of biological drugs has its challenges due to the multiple new different modalities, for example, antibody-drug conjugates, bispecifics, nanobodies, fusion proteins and advanced therapy medicinal products (ATMPs), their different pharmacokinetic and pharmacodynamic properties, and their ability to trigger immunogenicity and toxicity. In the public and in the pharmaceutical industry, there is a strong and general desire to reduce the number of animals used in research and development of drugs and in particular reducing the use of nonhuman primates. Important discussions and activities are ongoing investigating the smarter designs of early research and dose range finding studies, reuse of animals, and replacing animal experiments with in vitro studies.

Nonclinical Studies that Support Viral Vector-Delivered Gene Therapies: An EFPIA Gene Therapy Working Group Perspective.

Nonclinical development strategies for gene therapies are unique from other modalities. The European Federation of Pharmaceutical Industries and Associates (EFPIA) Gene Therapy Working Group surveyed EFPIA member and nonmember pharmaceutical and biotechnology companies about their current practices for designing and implementing nonclinical toxicology studies to support the development of viral vector-delivered gene therapies. Compiled responses from 17 companies indicated that these studies had some variability in species selection, study-design elements, biodistribution, immunogenicity or genomic insertion assessments, safety pharmacology, and regulatory interactions.

Interstitial high-dose-rate brachytherapy in the primary treatment of inoperable glioblastoma multiforme.

Purpose: To report our results of image-guided interstitial (IRT) high-dose-rate (HDR) brachytherapy (BRT) in the primary treatment of patients with inoperable glioblastoma multiforme (GBM) in the pre-temozolomide period.

Material And Methods: Between 1994 and 2004, 17 patients were treated with HDR BRT for inoperable GBM. Of those, only 11 patients were treated with IRT BRT, and the remaining six patients received combined IRT BRT and external beam radiotherapy (EBRT).

Neural Correlates of Group Bias During Natural Viewing.

Individuals from different social groups interpret the world in different ways. This study explores the neural basis of these group differences using a paradigm that simulates natural viewing conditions. Our aim was to determine if group differences could be found in sensory regions involved in the perception of the world or were evident in higher-level regions that are important for the interpretation of sensory information.

Nonclinical Safety Assessment of CFZ533, a Fc-Silent Anti-CD40 Antibody, in Cynomolgus Monkeys.

CFZ533 is a pathway blocking, nondepleting anti-CD40 antibody that is in clinical development for inhibition of transplant organ rejection and therapy for autoimmune diseases. A 26-week GLP toxicity study in sexually mature Cynomolgus monkeys was conducted in order to support chronic application of CFZ533. CFZ533 was subcutaneously administered at doses up to 150 mg/kg/week and was safe and generally well tolerated.

Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody.

The CD40-CD154 costimulatory pathway is essential for T cell-dependent immune responses, development of humoral memory, and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions.

Determination of 14 aminoglycosides by LC-MS/MS using molecularly imprinted polymer solid phase extraction for clean-up.

An LC-MS/MS method for screening 14 aminoglycosides in foodstuffs of animal origin is presented. Its scope includes raw materials and processed ingredients but also finished products composed of milk, meat, fish, egg or fat. Aminoglycosides are extracted in an acidic aqueous solution, which is first recovered after centrifugation, then diluted with a basic buffer and finally purified by molecularly imprinted polymer-solid phase extraction (MIP-SPE).

Biotherapeutics in non-clinical development: Strengthening the interface between safety, pharmacokinetics-pharmacodynamics and manufacturing.

Biological drugs comprise a wide field of different modalities with respect to structure, pharmacokinetics and pharmacological function. Considerable non-clinical experience in the development of proteins (e.g.

NANOCI-Nanotechnology Based Cochlear Implant With Gapless Interface to Auditory Neurons.

: Cochlear implants (CI) restore functional hearing in the majority of deaf patients. Despite the tremendous success of these devices, some limitations remain. The bottleneck for optimal electrical stimulation with CI is caused by the anatomical gap between the electrode array and the auditory neurons in the inner ear.