Research Spotlight

Salash, J. R., R. H. Hossameldin, A. J. Almarza, J. C. Chou, J. P. McCain, L. G. Mercuri, L. M. Wolford and M. S. Detamore (2016). “Potential Indications for Tissue Engineering in Temporomandibular Joint Surgery.” J Oral Maxillofac Surg 74(4): 705-711.

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PURPOSE: Musculoskeletal tissue engineering has advanced to the stage where it has the capability to engineer temporomandibular joint (TMJ) anatomic components. Unfortunately, there is a paucity of literature identifying specific indications for the use of TMJ tissue engineering solutions. The objective of this study was to establish an initial set of indications and contraindications for the use of engineered tissues for replacement of TMJ anatomic components. FINDINGS: There was consensus among the authors that the management of patients requiring TMJ reconstruction as the result of 1) irreparable condylar trauma, 2) developmental or acquired TMJ pathology in skeletally immature patients, 3) hyperplasia, and 4) documented metal hypersensitivities could be indications for bioengineered condyle and ramus TMJ components. There was consensus that Wilkes stage III internal derangement might be an indication for use of a bioengineered TMJ disc or possibly even a disc-like bioengineered “fossa liner.” However, there was some controversy as to whether TMJ arthritic disease (e.g., osteoarthritis) and reconstruction after failed alloplastic devices should be indications. Further research is required to determine whether tissue-engineered TMJ components could be a viable option for such cases. Contraindications for the use of bioengineered TMJ components could include patients with TMJ disorders and multiple failed surgeries, parafunctional oral habits, persistent TMJ infection, TMJ rheumatoid arthritis, and ankylosis unless the underlying pathology can be resolved. CONCLUSIONS: Biomedical engineers must appreciate the specific indications that might warrant TMJ bioengineered structures, so that they avoid developing technologies in search of problems that might not exist for patients and clinicians. Instead, they should focus on identifying and understanding the problems that need resolution and then tailor technologies to address those specific situations. The aforementioned indications and contraindications are designed to serve as a guide to the next generation of tissue engineers in their strategic development of technologies to address specific clinical issues.

Raftopoulos, H., A. Laadem, P. J. Hesketh, J. Goldschmidt, N. Gabrail, C. Osborne, M. Ali, M. L. Sherman, D. Wang, J. A. Glaspy, M. Puccio-Pick, J. Zou and J. Crawford (2016). “Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies.” Support Care Cancer 24(4): 1517-1525.

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PURPOSE: Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer. METHODS: In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of >/=1 g/dL from baseline. RESULTS: Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of >/=1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of >/=1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon. CONCLUSIONS: Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA.

Nicholls, R. E., J. M. Sontag, H. Zhang, A. Staniszewski, S. Yan, C. Y. Kim, M. Yim, C. M. Woodruff, E. Arning, B. Wasek, D. Yin, T. Bottiglieri, E. Sontag, E. R. Kandel and O. Arancio (2016). “PP2A methylation controls sensitivity and resistance to beta-amyloid-induced cognitive and electrophysiological impairments.” Proc Natl Acad Sci U S A 113(12): 3347-3352.

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Elevated levels of the beta-amyloid peptide (Abeta) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer’s disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Abeta exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Abeta-induced impairments. Neither transgene affected Abeta production or the electrophysiological response to low concentrations of Abeta, suggesting that these manipulations selectively affect the pathological response to elevated Abeta levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Abeta levels in AD patients.

Dixon-Ibarra, A., S. Driver, K. Vanderbom and K. Humphries (2016). “Understanding physical activity in the group home setting: a qualitative inquiry.” Disabil Rehabil: Mar 23:1-10. [Epub ahead of print].

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PURPOSE: Persons with intellectual disabilities have low physical activity levels and high rates of chronic disease. One predictor limitedly explored is the home environment, which could influence the type and amount of physical activity in this population. The purpose of this study is to qualitatively explore physical activity in the group home setting and determine what key stakeholders want from a physical activity programme. METHOD: This study adopted a qualitative descriptive design, using semistructured focus groups. Twenty stakeholders (i.e., residents with intellectual disability, support staff and programme coordinators) participated in one of three focus groups, separated by stakeholder status. RESULTS: A number of factors emerged that would assist rehabilitation professionals in understanding physical activity within the group home setting. The following six meta-themes were identified: nature of residents’ physical activity, facilitators to physical activity, barriers to physical activity, personal factors, organizational factors and solutions to increase physical activity. CONCLUSIONS: Findings suggest that residents with intellectual disabilities have low physical activity and opportunities for participation. Key attributes of the group home setting were identified between barriers and facilitators to activity. Consideration for the development of physical activity programmes should focus on the unique needs of the group home setting as expressed by stakeholders. Implications for rehabilitation Physical activity can improve physical fitness, function, and community participation yet physical activity remains low among adults with intellectual disabilities. Understanding physical activity within the group home setting is essential to develop targeted interventions to increase activity within that environment. Key barriers for physical activity within the group home setting include; operational priorities, limited staff, staff turnover, busy schedules, and staff attitudes towards physical activity.

Coveler, A. L., A. H. Ko, D. V. Catenacci, D. Von Hoff, C. Becerra, N. C. Whiting, J. Yang and B. Wolpin (2016). “A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers.” Invest New Drugs Mar 18. [Epub ahead of print]

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Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.