The PARP inhibitor Rucaparib synergizes with radiation to attenuate atypical teratoid rhabdoid tumor growth.

Background: Atypical teratoid rhabdoid tumors (ATRT) are highly aggressive pediatric brain tumors. The available treatments rely on toxic chemotherapy and radiotherapy, which themselves can cause poor outcomes in young patients. Poly (ADP-ribose) polymerases (PARP), multifunctional enzymes which play an important role in DNA damage repair and genome stability have emerged as a new target in cancer therapy. An FDA-approved drug screen revealed that Rucaparib, a PARP inhibitor, is important for ATRT cell growth. This study aims to investigate the effect of Rucaparib treatment in ATRT. Methods: This study utilized cell viability, colony formation, flow cytometry, western blot, immunofluorescence, and immunohistochemistry assays to investigate Rucaparib's effectiveness in BT16 and MAF737 ATRT cell lines. In vivo, intracranial orthotopic xenograft model of ATRT was used. BT16 cell line was transduced with a luciferase-expressing vector and injected into the cerebellum of athymic nude mice. Animals were treated with Rucaparib by oral gavaging and irradiated with 2 Gy of radiation for 3 consecutive days. Tumor growth was monitored using In Vivo Imaging System. Results: Rucaparib treatment decreased ATRT cell growth, inhibited clonogenic potential of ATRT cells, induced cell cycle arrest and apoptosis, and led to DNA damage accumulation as shown by increased expression of γH2AX. In vivo, Rucaparib treatment decreased tumor growth, sensitized ATRT cells to radiation and significantly increased mice survival. Conclusion: We demonstrated that Rucaparib has potential to be a new therapeutic strategy for ATRT as seen by its ability to decrease ATRT tumor growth both in vitro and in vivo.

Is there a dose response for valgus unloader brace usage on knee pain, function, and muscle strength?

OBJECTIVE: To examine whether there was a dose response for valgus unloader brace wear on knee pain, function, and muscle strength in participants with medial compartment knee osteoarthritis. DESIGN: In this single-group study, participants with medial compartment knee osteoarthritis were followed for approximately 6 months. SETTING: Recruitment was conducted in the general community, and testing was performed at a university laboratory. PARTICIPANTS: A convenience sample of patients (N=32) who were prescribed a valgus unloader brace agreed to participate, met the inclusion criteria, and completed the baseline data collection. Twenty-four participants (20 men, 4 women) completed baseline and follow-up collections. INTERVENTION: Participants wore their valgus unloader brace as needed. MAIN OUTCOME MEASURES: Knee extensor, flexor, and plantar flexor strength was tested at baseline and follow-up. Participants filled out Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Medical Outcomes Study 36-Item Short-Form Health Survey questionnaires to assess pain and function. Self-selected walking velocity and stride length were objective measures of function. Brace usage (dose) and activity (step count) were recorded at least 4 days/week for the study duration. RESULTS: Positive relationships existed between brace wear usage and percent change in step count (r=.59, P=.006) and percent change in hamstrings strength (r=.37, P=.072). At follow-up, there was significant improvement in hamstrings strength (P=.013), and trends toward improvements in WOMAC pain (P=.059) and WOMAC function (P=.089). CONCLUSIONS: Our results indicate that greater brace use may positively affect physical activity level, but there was minimal effect of brace wear dosage on lower-limb muscle strength. Only knee flexion showed a positive relationship. Our finding of no decreased muscle strength indicates that increased brace use over a 6-month period does not result in muscle impairment.

Effect of a high intensity quadriceps fatigue protocol on knee joint mechanics and muscle activation during gait in young adults.

The purpose of this study was to determine the effect of impaired quadriceps function on knee joint biomechanics and neuromuscular function during gait. Surface electromyograms, three-dimensional motion and ground reaction forces were collected during gait before and after 20 healthy adults completed a high intensity quadriceps fatigue protocol. Pattern recognition techniques were utilized to examine changes in amplitude and temporal characteristics of all gait variables. The fatigue protocol resulted in decreased knee extensor torque generation and quadriceps median power frequencies for 18 of 20 participants (p < 0.05). The gait data from these 18 participants was analyzed. The knee external rotation angle increased (p < 0.05), the net external flexion and external rotation moments decreased (p < 0.05), and the net external adduction moment increased (p < 0.05). Post-fatigue changes in periarticular muscle activation patterns were consistent with the biomechanical changes, but were not significantly altered. Even for this low demand task of walking the knee motion and loading characteristics were altered following a high intensity fatigue protocol in a manner that may place the knee joint at greater risk for joint pathology and injury.