Targeting pheochromocytoma/paraganglioma with polyamine inhibitors.

BACKGROUND: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting. METHODS: Metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts. RESULTS: Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts. CONCLUSIONS: This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

Effect of Simultaneous Combined Treadmill Training and Magnetic Stimulation on Spasticity and Gait Impairments after Cervical Spinal Cord Injury.

Cervical spinal cord injury (CSCI) can induce lifelong disabilities, including spasticity and gait impairments. The objective of this pre-clinical study was to evaluate the therapeutic effects of simultaneous and combined early locomotor treadmill training (Tm) and injury site magnetic stimulation (TMSsc) on spasticity and gait impairments in a rat model of C6/7 moderate contusion SCI. The Tm training was initiated at post-injury (PI) day 8, whereas TMS treatment was added to Tm 14 days PI, and then the combined therapy (TMSTm) was continued for six weeks. Untreated CSCI animals revealed significant and enduring hindlimb spasticity (measured as velocity-dependent ankle torques and time-locked triceps surae electromyography), significant alterations in limb coordination, and significant reductions in forelimb grip strength. The TMSTm showed significantly lower spasticity, significantly more normal limb coordination (quantitated using three-dimensional (3D) kinematics and Catwalk gait analyses), and significantly greater forelimb grip strength compared with the CSCI untreated controls. In addition, three-dimensional gradient echo and diffusion tensor magnetic resonance imaging showed that TMSTm treated animals had smaller cavity volumes and better preservation of the white matter. In addition, compared with the CSCI untreated animals, the lumbar spinal cord (SC) of the treatment group revealed significant up-regulation of dopamine beta-hydroxylase, glutamic acid decarboxylase, gamma-aminobutyric acid receptor B, and brain-derived neurotrophic factor. The treatment-induced up-regulation of these molecules may have enhanced the activity-induced adaptive plasticity in the SC and contributed to normalization of pre- and post-synaptic reflex regulatory processes. In addition, the TMSTm therapy may have decreased injury-induced progressive maladaptive segmental and descending plasticity. Our data are the first to suggest that an early simultaneous combination of Tm and injury-site TMSsc application can be an effective therapy for CSCI-induced spasticity and gait impairments. These pre-clinical data demonstrated the feasibility and efficacy of a novel therapeutic strategy for SCI-induced spasticity and gait impairments.

Injury risk of interphalangeal and metacarpophalangeal joints under impact loading.

Injuries to the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hand are particularly disabling. However, current standards for hand protection from blunt impact are not based on quantitative measures of the likelihood of damage to the tissues. The aim of this study was to evaluate the probability of injury of the MCP and PIP joints of the human hand due to blunt impact. Impact testing was conducted on 21 fresh-frozen cadaveric hands. Unconstrained motion at every joint was allowed. All hands were imaged with computed tomography and dissected post-impact to quantify injury. An injury-risk curve was developed for each joint using a Weibull distribution with dorsal impact force as the predictive variable. The injury risks for PIP joints were similar, as were those for MCP joints. The risk of injury of the MCP joints from a given applied force was significantly greater than that of the PIP joints (p = 0.0006). The axial forces with a 50% injury risk for the MCP and PIP joints were 3.0 and 4.2 kN, respectively. This is the first study to have investigated the injury tolerance of the MCP and PIP joints. The proposed injury curves can be used for assessing the likelihood of tissue damage, for designing targeted protective solutions such as gloves, and for developing more biofidelic standards for assessing these solutions.

A review of impact testing methods for headgear in sports: Considerations for improved prevention of head injury through research and standards.

Standards for sports headgear were introduced as far back as the 1960s and many have remained substantially unchanged to present day. Since this time, headgear has virtually eliminated catastrophic head injuries such as skull fractures and changed the landscape of head injuries in sports. Mild traumatic brain injury (mTBI) is now a prevalent concern and the effectiveness of headgear in mitigating mTBI is inconclusive for most sports. Given that most current headgear standards are confined to attenuating linear head mechanics and recent brain injury studies have underscored the importance of angular mechanics in the genesis of mTBI, new or expanded standards are needed to foster headgear development and assess headgear performance that addresses all types of sport-related head and brain injuries. The aim of this review is to provide a basis for developing new sports headgear impact tests for standards by summarizing and critiquing: 1) impact testing procedures currently codified in published headgear standards for sports and 2) new or proposed headgear impact test procedures in published literature and/or relevant conferences. Research areas identified as needing further knowledge to support standards test development include defining sports-specific head impact conditions, establishing injury and age appropriate headgear assessment criteria, and the development of headgear specific head and neck surrogates for at-risk populations.

An in vitro model of impaction during hip arthroplasty.

Impaction is required to properly seat press-fit implants and ensure initial implant stability and long term bone ingrowth, however excessive impaction or press-fit presents a high fracture risk in the acetabulum and femur. Current in-vitro impaction testing methods do not replicate the compliance of the soft tissues surrounding the hip, a factor that may be important in fracture and force prediction. This study presents the measurement of compliance of the soft tissues supporting the hip during impaction in operative conditions, and replicates these in vitro. Hip replacements were carried out on 4 full body cadavers while impact force traces and acetabular/femoral displacement were measured. Compliance was then simulated computationally using a Voigt model. These data were subsequently used to inform the design of a representative in-vitro drop rig. Effective masses of 19.7 kg and 12.7 kg, spring stiffnesses of 8.0 kN/m and 4.1 kN/m and dashpot coefficients of 595 N s/m and 322 N s/m were calculated for the acetabular and femoral soft tissues respectively. A good agreement between cadaveric and in-vitro peak displacement and rise time during impact is found. Such an in-vitro setup is of use during laboratory testing, simulation or even surgical training.