CCT and Cullin1 Regulate the TORC1 Pathway to Promote Dendritic Arborization in Health and Disease.

The development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy in Drosophila Class IV (CIV) multi-dendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1) in vitro. Through targeted genetic manipulations, we confirm that an LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases the dendritic complexity in CIV neurons. Furthermore, both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus, we examine CIV dendritic development in disease conditions as well. The expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through the regulation of TORC1 in both health and disease.

Senescent and disease-associated microglia are modifiable features of aged brain white matter.

Brain white matter tracts undergo structural and functional changes linked to late-life cognitive decline, but the cellular and molecular contributions to their selective vulnerability are not well defined. In naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampus-adjacent white matter. Through gold-standard gene expression and immunolabeling combined with high-dimensional spatial mapping, we identified microglial cell fates in aged white matter characterized by aberrant morphology, microenvironment reorganization, and expression of senescence and DAM markers, including galectin 3 (GAL3/Lgals3), B-cell lymphoma 2 (Bcl2), and cyclin dependent kinase inhibitors, including Cdkn2a/p16ink4a. Pharmacogenetic or pharmacological targeting of p16ink4a or BCL2 reduced white matter GAL3+ DAM abundance and rejuvenated microglial fimbria organization. Our results demonstrate dynamic changes in microglial identity in aged white matter that can be reverted by senotherapeutic intervention to promote homeostatic maintenance in the aged brain.

Evaluating Outcomes of Stand-Alone Anterior Lumbar Interbody Fusion: A Systematic Review.

BACKGROUND: Stand-alone anterior lumbar interbody fusion (ALIF) is an effective surgical approach for selected spinal pathologies. It avoids the morbidity and complications associated with instrumented ALIF, such as plate fixation and the traditionally used posterior approach. Despite improved disc space visualization and clearance, the associated posterior instability and increased risk of nonfusion present major challenges to this approach. The integral cage design aims to address these challenges by providing the necessary stabilization through intracorporeal screws. However, there is limited and controversial data available for stand-alone ALIF and integral cage fixation. To our knowledge, this is the first systematic review to evaluate recent findings on outcomes of stand-alone ALIF devices to explore areas of controversy and identify directions for future research. METHODS: Two reviewers conducted independent, systematic literature searches for appropriate studies in 5 electronic databases as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were filtered by the use of specified selection criteria, particularly exclusion of studies with supplementary fixation to ALIF and studies published before the year 2000. A total of 17 studies met the criteria, and their data were comprehensively extracted and analyzed. RESULTS: The current literature is supportive of stand-alone ALIF due to acceptable clinical outcomes, promising fusion rates and disc height restoration. However, data and outcomes remain preliminary, and there are numerous areas of controversy. CONCLUSIONS: There is evidence for the efficacy and safety of stand-alone ALIF. However, the extent of improvement based on specific indications for surgery remains unclear. Further investigation utilizing more methodologically rigorous studies of long-term outcomes is necessary to address these issues.

Impact of Elderly Age on Complications and Clinical Outcomes Following Anterior Lumbar Interbody Fusion Surgery.

BACKGROUND: Anterior lumbar interbody fusion (ALIF) is a surgical technique used to treat patients with a variety of lumbar pathologies. Identification of risk factors leading to complication following ALIF surgery may allow surgeons to better judge candidacy and optimize care for high-risk patients. METHODS: A retrospective analysis was conducted on a prospectively collected database of 137 patients who all underwent ALIF surgery by a single primary spine surgeon. Patients were separated into age-based cohorts (≤49, 50-63, and ≥64 years of age). Chi-squared, Fisher exact test, and multivariate logistic regression models were used to identify independent risk factors. RESULTS: A total of 137 patients met the inclusion criteria. Patients were divided into age-based tertiles as follows: Group 1 (<49 years old, n = 45, 32.8%), Group 2 (50-63 years old, n = 46, 33.6%), and Group 3 (64 years old, n = 46, 33.6%). Univariate analysis revealed increasing age (relative to Group 1) to be an independent risk factor for postoperative hematoma and delayed subsidence at 6 weeks and 12 weeks postoperatively compared with immediately post operation (all P < 0.05). No significant differences were found among the groups in terms of clinical outcome. Multivariate analysis also demonstrated increased age to be independently associated with greater prevalence of delayed subsidence (odds ratio 9.174, P = 0.029). CONCLUSIONS: Increased age was not associated with adverse perioperative outcomes and complications of ALIF. However, there was an increased incidence of delayed subsidence in patients ≥64 years old.

Image-Guided Lateral Mass Osteotomy for En Bloc Resection of Cervical Ewing Sarcoma: A Technical Note.

BACKGROUND: En bloc resection of Ewing sarcoma in the cervical spine according to Enneking's principles is technically challenging owing to the proximity of important neurovascular structures, the complex local anatomy, and the biomechanical instability of radical resection. The rarity of Ewing sarcoma and variability of its presentation justifies ongoing exploration and compilation of the surgical nuances and subtleties of en bloc resection in the cervical spine. CASE DESCRIPTION: We present a 34-year-old male with Ewing sarcoma of the neck who underwent successful en bloc resection using a novel technique of splitting the laminae and osteomizing the lateral masses under imaging guidance. CONCLUSIONS: This novel and successful approach of en bloc resection in the cervical spine can add to the spinal surgeon's repertoire when dealing with complex cervical tumor masses.

Systematic review of cortical bone trajectory versus pedicle screw techniques for lumbosacral spine fusion.

Fusion of the lumbosacral spine is a common surgical procedure to address a range of spinal pathologies. Fixation in lumbar fusion has traditionally been performed using pedicle screw (PS) augmentation. However, an alternative method of screw insertion via cortical bone trajectory (CBT) has been advocated as a less invasive approach which improves initial fixation and reduces neurovascular injury. There is a paucity of robust clinical evidence to support these claims, particularly in comparison to traditional pedicle screws. This study aims to review the available evidence to assess the merits of the CBT approach. Six electronic databases were searched for original published studies which compared CBT with traditional PS and their findings reviewed. Nine comparative studies were identified through a comprehensive literature search. Studies were classified as retrospective cohort, prospective cohort or case control studies with medium quality as assessed by the GRADE criteria. The available literature is not cohesive regarding outcomes and complications of CBT versus PT procedures. Most studies found no difference in operative time, but reported less blood loss during CBT. Radiological outcomes show no difference in slippage at one year although CBT is associated with greater bone-density compared to PT. Results for post-operative pain are inconclusive.

Human SRMAtlas: A Resource of Targeted Assays to Quantify the Complete Human Proteome.

The ability to reliably and reproducibly measure any protein of the human proteome in any tissue or cell type would be transformative for understanding systems-level properties as well as specific pathways in physiology and disease. Here, we describe the generation and verification of a compendium of highly specific assays that enable quantification of 99.7% of the 20,277 annotated human proteins by the widely accessible, sensitive, and robust targeted mass spectrometric method selected reaction monitoring, SRM. This human SRMAtlas provides definitive coordinates that conclusively identify the respective peptide in biological samples. We report data on 166,174 proteotypic peptides providing multiple, independent assays to quantify any human protein and numerous spliced variants, non-synonymous mutations, and post-translational modifications. The data are freely accessible as a resource at http://www.srmatlas.org/, and we demonstrate its utility by examining the network response to inhibition of cholesterol synthesis in liver cells and to docetaxel in prostate cancer lines.

Illness perceptions and quality of life in Japanese and Dutch patients with non-small-cell lung cancer.

This study examined quality of life (QOL) and illness perceptions in Dutch and Japanese patients with non-small-cell lung cancer, thereby extending the body of knowledge on cultural differences and psychosocial aspects of this illness. 24 Dutch and 22 Japanese patients with non-small-cell lung cancer filled out questionnaires on three occasions: immediately before chemotherapy, 1 week later, and 8 weeks after the initial chemotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed QOL, and the Brief Illness Perception Questionnaire (B-IPQ) illness perceptions. Scores on several QOL measures indicated (a) major impact of first chemotherapy sessions, and (b) some tendency to returning to baseline measures at 8 weeks. Differences between Japanese and Dutch samples were found on five EORTC QLQ-C30 dimensions: global health status, emotional functioning, social functioning, constipation, and financial difficulties, with the Dutch patients reporting more favorable scores. Regarding illness perceptions, Japanese patients had higher means on perceived treatment control and personal control, expressing a higher sense of belief in the success of medical treatment than Dutch patients. In both Japanese and Dutch patients, impact of chemotherapy on QOL was evident. Some differences in illness perceptions and QOL between the two samples were observed, with implications for integral medical management. Both samples reported illness perceptions that reflect the major consequences of non-small-cell lung cancer. Incorporating symptom reports, illness perceptions, and QOL into medical management may have positive consequences for patients with non-small-cell lung cancer.