Exploiting human immune repertoire transgenic mice for protective monoclonal antibodies against antimicrobial resistant Acinetobacter baumannii.

The use of monoclonal antibodies for the control of drug resistant nosocomial bacteria may alleviate a reliance on broad spectrum antimicrobials for treatment of infection. We identify monoclonal antibodies that may prevent infection caused by carbapenem resistant Acinetobacter baumannii. We use human immune repertoire mice (Kymouse platform mice) as a surrogate for human B cell interrogation to establish an unbiased strategy to probe the antibody-accessible target landscape of clinically relevant A.

Rejuvenation of extensively passaged human chondrocytes to engineer functional articular cartilage.

Human articular chondrocytes (hACs) are scarce and lose their chondrogenic potential during monolayer passaging, impeding their therapeutic use. This study investigated (a) the translatability of conservative chondrogenic passaging and aggregate rejuvenation on restoring chondrogenic properties of hACs passaged up to P9; and (b) the efficacy of a combined treatment of transforming growth factor-beta 1 (TGF-1) (T), chondroitinase-ABC (C), and lysyl oxidase-like 2 (L), collectively termed TCL, on engineering functional human neocartilage via the self-assembling process, as a function of passage number up to P11. Here, we show that aggregate rejuvenation enhanced glycosaminoglycan (GAG) content and type II collagen staining at all passages and yielded human neocartilage with chondrogenic phenotype present up to P7.

An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression.

The immunosuppressive tumor microenvironment constitutes a significant hurdle to immune checkpoint inhibitor responses. Both soluble factors and specialized immune cells, such as regulatory T cells (Treg), are key components of active intratumoral immunosuppression. Inducible costimulatory receptor (ICOS) can be highly expressed in the tumor microenvironment, especially on immunosuppressive Treg, suggesting that it represents a relevant target for preferential depletion of these cells.

Translating the application of transforming growth factor-β1, chondroitinase-ABC, and lysyl oxidase-like 2 for mechanically robust tissue-engineered human neocartilage.

Strategies to overcome the limited availability of human articular chondrocytes and their tendency to dedifferentiate during expansion are required to advance their clinical use and to engineer functional cartilage on par with native articular cartilage. This work sought to determine whether a biochemical factor (transforming growth factor-β1 [T]), a biophysical agent (chondroitinase-ABC [C]), and a collagen crosslinking enzyme (lysyl oxidase-like 2 [L]) are efficacious in forming three-dimensional human neocartilage from expanded human articular chondrocytes. Among the treatment regimens, the combination of the three stimuli (TCL treatment) led to the most robust glycosaminoglycan content, total collagen content, and type II collagen production.

Facet Joints of the Spine: Structure-Function Relationships, Problems and Treatments, and the Potential for Regeneration.

The zygapophysial joint, a diarthrodial joint commonly referred to as the facet joint, plays a pivotal role in back pain, a condition that has been a leading cause of global disability since 1990. Along with the intervertebral disc, the facet joint supports spinal motion and aids in spinal stability. Highly susceptible to early development of osteoarthritis, the facet is responsible for a significant amount of pain in the low-back, mid-back, and neck regions.

Characterization of facet joint cartilage properties in the human and interspecies comparisons.

Unlabelled: The facet joint, a synovial joint located on the posterior-lateral spine, is highly susceptible to degenerative changes and plays a significant role in back-related morbidities. Despite its significance, the facet is rarely studied and thus current treatment strategies are lacking. This study aimed to characterize, for the first time, the properties of human, pig, monkey, and rabbit lumbar facet cartilage providing much-needed design criteria for tissue engineering approaches.

Determining the influence of calcification on the failure properties of abdominal aortic aneurysm (AAA) tissue.

Varying degrees of calcification are present in most abdominal aortic aneurysms (AAAs). However, their impact on AAA failure properties and AAA rupture risk is unclear. The aim of this work is evaluate and compare the failure properties of partially calcified and predominantly fibrous AAA tissue and investigate the potential reasons for failure.

The biaxial biomechanical behavior of abdominal aortic aneurysm tissue.

Rupture of the abdominal aortic aneurysm (AAA) occurs when the local wall stress exceeds the local wall strength. Knowledge of AAA wall mechanics plays a fundamental role in the development and advancement of AAA rupture risk assessment tools. Therefore, the aim of this study is to evaluate the biaxial mechanical properties of AAA tissue.

The impact of long term freezing on the mechanical properties of porcine aortic tissue.

Background: Preservation of the native artery׳s functionality can be important in both clinical and experimental applications. Although, simple cryopreservation techniques offer an attractive solution to this problem, the extent to which freezing affects the tissue׳s properties is widely debated. Earlier assessments of the mechanical properties post-freezing have been limited by one or more of the following: small sample numbers, uncontrolled inter-specimen/animal variability, failure to account for the impact of potential errors in thickness measurements, short storage times and uniaxial test methods.

Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery.

If immunized with an antigen of interest, transgenic mice with large portions of unrearranged human immunoglobulin loci can produce fully human antigen-specific antibodies; several such antibodies are in clinical use. However, technical limitations inherent to conventional transgenic technology and sequence divergence between the human and mouse immunoglobulin constant regions limit the utility of these mice. Here, using repetitive cycles of genome engineering in embryonic stem cells, we have inserted the entire human immunoglobulin variable-gene repertoire (2.

The biaxial mechanical behaviour of abdominal aortic aneurysm intraluminal thrombus: classification of morphology and the determination of layer and region specific properties.

Intraluminal thrombus (ILT) is present in 75% of clinically-relevant abdominal aortic aneurysms (AAAs) yet, despite much research effort, its role in AAA biomechanics remains unclear. The aim of this work is to further evaluate the biomechanics of ILT and determine if different ILT morphologies have varying mechanical properties. Biaxial mechanical tests were performed on ILT samples harvested from 19 patients undergoing open surgical repair.

Comparison of methods used to measure the thickness of soft tissues and their influence on the evaluation of tensile stress.

Measuring the physical dimensions of soft tissue is difficult due to its deformable nature. Such measurements are used to evaluate the tissue's mechanical properties. Imprecise measurements of the tissue's thickness can alter the assessment of tensile stress which may have significant clinical relevance when used as a diagnostic tool.

An open trial of a comprehensive anger treatment program on an outpatient sample.

Background: This pilot study was designed to investigate the efficacy of a cognitive behavioral treatment for anger.

Method: Twelve (5 men and 7 women) outpatient adults completed 2-hour group sessions for 16 sessions. Participants were diagnosed with 29 Axis I and 34 Axis II disorders with high rates of comorbidity.

A placebo controlled, double-blind study of mecamylamine treatment for cocaine dependence in patients enrolled in an opiate replacement program.

A placebo controlled, double-blind trial of mecamylamine treatment of cocaine dependence was performed in methadone or LAAM maintained subjects who met DSM-IV criteria for cocaine dependence. After an eight-week placebo run-in screening period, 35 subjects were randomly assigned to receive either mecamylamine (6 mg/day) or placebo transdermal patches for a 16-week treatment period. Outcome measures included quantitative urine benzoylecognine (BE) levels, self-report of cocaine use, cocaine craving, global impression scores, mood, retention, and safety.

Sensitization to the psychosis-inducing effects of cocaine compared with measures of cocaine craving and cue reactivity.

A previous study has suggested that sensitization to the psychosis-inducing effects of cocaine may be a marker of vulnerability to relapse in cocaine addiction. In this report, cocaine-dependent subjects participating in a study on naturally occurring and cue-induced cocaine craving were interviewed about prior experience of cocaine-induced psychosis and the degree to which this effect had become more frequent or severe or had occurred at lower cumulative doses. Sensitization to cocaine-induced psychosis was negatively correlated with baseline measures of drug dependence severity and indices of cocaine craving over the preceding 24 hours but not with measures of cocaine cue reactivity.

Quantitative electroencephalographic studies of cue-induced cocaine craving.

Quantitative electroencephalographic (qEEG) profiles were studied in cocaine dependent patients in response to cocaine cue exposure. Using neurometric analytical methods, the spectral power of each primary bandwidth was computed and topographically mapped. Additional measures of cue-reactivity included cocaine craving, anxiety and related subjective ratings, and physiological measures of skin conductance, skin temperature, heart rate, and plasma cortisol and HVA levels.