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Abstract Background Complement represents a crucial mediator of neuroinflammation and neurodegeneration after traumatic brain injury. The role of the terminal complement activation pathway, leading to generation of the membrane attack complex (MAC), has not been thoroughly investigated. CD59 is the major regulator of MAC formation and represents an essential protector from homologous cell injury after complement activation in the injured brain. Methods Mice deleted in the Cd59a gene (CD59a-/-) and wild-type littermates (n = 60) were subjected to focal closed head injury. Sham-operated (n = 60) and normal untreated mice (n = 14) served as negative controls. The posttraumatic neurological impairment was assessed for up to one week after trauma, using a standardized Neurological Severity Score (NSS). The extent of neuronal cell death was determined by serum levels of neuron-specific enolase (NSE) and by staining of brain tissue sections in TUNEL technique. The expression profiles of pro-apoptotic (Fas, FasL, Bax) and anti-apoptotic (Bcl-2) mediators were determined at the gene and protein level by real-time RT-PCR and Western blot, respectively. Results Clinically, the brain-injured CD59a-/- mice showed a significantly impaired neurological outcome within 7 days, as determined by a higher NSS, compared to wild-type controls. The NSE serum levels, an indirect marker of neuronal cell death, were significantly elevated in CD59a-/- mice at 4 h and 24 h after trauma, compared to wild-type littermates. At the tissue level, increased neuronal cell death and brain tissue destruction was detected by TUNEL histochemistry in CD59a-/- mice within 24 hours to 7 days after head trauma. The analysis of brain homogenates for potential mediators and regulators of cell death other than the complement MAC (Fas, FasL, Bax, Bcl-2) revealed no difference in gene expression and protein levels between CD59a-/- and wild-type mice. Conclusion These data emphasize an important role of CD59 in mediating protection from secondary neuronal cell death and further underscore the key role of the terminal complement pathway in the pathophysiology of traumatic brain injury. The exact mechanisms of complement MAC-induced secondary neuronal cell death after head injury require further investigation.

Abstract: The Notch signaling pathway has been shown to be upregulated in colorectal cancer (CRC) and important for the self-renewal of cancer stem cells. In this study, we evaluated the efficacy of PF-03084014, a γ-secretase inhibitor, in combination with irinotecan to identify the effects of treatment on tumor recurrence and the tumor-initiating population in our CRC preclinical explant model. The combination of PF-03084014 and irinotecan had the greatest effect at reducing tumor growth on four CRC tumors when compared with treatment with PF-03084014 or irinotecan alone. The combination significantly reduced tumor recurrence in two CRC explants (CRC001 and CRC036) after treatment was discontinued. Both of these tumors exhibited elevated baseline levels of Notch pathway activation as well as an increase in NOTCH1 gene copy number when compared with the two CRC explants (CRC026 and CRC027) where tumors reappeared quickly after termination of treatment. Isolation and injection of aldehyde dehydrogenase (ALDH+ and ALDH−) cells in an in vivo explant model demonstrated that the ALDH+ cell population were tumorigenic. Evaluation of the ALDH+ cells after 28 days of treatment showed that the combination reduced the ALDH+ population in the tumors that did not regrow. Furthermore, ALDH+ cells from CRC001 and CRC027 were injected in vivo and treated immediately for 28 days. Two months after treatment, tumors were evident in the combination treatment group for CRC027 but not for CRC036. These results indicate the combination of PF-03084014 and irinotecan may be effective in reducing tumor recurrence in CRC patients whose tumors exhibit elevated levels of the Notch pathway. [Copyright &y& Elsevier]

Background: Tibial tubercle fractures (TTFs) are uncommon injuries, comprising <3% of all proximal tibial fractures. These fractures occasionally occur in conjunction with a patellar tendon injury (PTI). We aimed to identify risk factors associated with combined TTF and PTI., Methods: A retrospective review was performed of patients presenting to a single, tertiary children's hospital with TTF between 2012 and 2023. Demographic data, operative details, radiographs, and injury patterns were analyzed. Radiographs were assessed for the epiphyseal union stage (EUS), Ogden classification, and fracture patterns. Multiple logistic regression models were used to assess the impact of body mass index, comminution, fracture fragment rotation, EUS, bilateral injury, and Ogden classification on injury type., Results: We identified 262 fractures in 252 patients (mean age, 13.9 ± 1.31 years). Of the patients, 6% were female and 48% were Black. Of the 262 fractures, 228 (87%) were isolated TTFs and 34 (13%) were TTFs with PTI. Multivariable analysis demonstrated fragment rotation on lateral radiographs (p < 0.0001) and Ogden Type-I classification (p < 0.0001) to be the most predictive risk factors for a combined injury. Rotation was associated with a substantial increase in the odds of a combined injury, with an odds ratio of 22.1 (95% confidence interval [CI], 6.1 to 80.1). Ogden Type-I fracture was another significant risk factor, with an odds ratio of 10.2 (95% CI, 3.4 to 30.4)., Conclusions: The Ogden classification and fragment rotation are the most useful features for distinguishing between isolated TTF and combined TTF with PTI. This is the first study to identify risk factors for TTF combined with PTI. Surgeons may use this information to aid in preoperative planning., Level of Evidence: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: No external funding was received for this work. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/I213)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)