ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate.

Insufficient nutrients disrupt physiological homeostasis, resulting in diseases and even death. Considering the physiological and pathological consequences of this metabolic stress, the adaptive responses that cells utilize under this condition are of great interest. We show that under low-glucose conditions, cells initiate adaptation followed by apoptosis responses using PERK/Akt and MEK1/ERK2 signaling, respectively. For adaptation, cells engage the ER stress-induced unfolded protein response, which results in PERK/Akt activation and cell survival. Sustained and extreme energetic stress promotes a switch to isoform-specific MEK1/ERK2 signaling, induction of GCN2/eIF2α phosphorylation, and ATF4 expression, which overrides PERK/Akt-mediated adaptation and induces apoptosis through ATF4-dependent expression of pro-apoptotic factors including Bid and Trb3. ERK2 activation during metabolic stress contributes to changes in TCA cycle and amino acid metabolism, and cell death, which is suppressed by glutamate and α-ketoglutarate supplementation. Taken together, our results reveal promising targets to protect cells or tissues from metabolic stress.

Glycogen synthase kinase (GSK)-3 promotes p70 ribosomal protein S6 kinase (p70S6K) activity and cell proliferation.

The p70 ribosomal protein S6 kinase 1 (S6K1) plays a key role in cell growth and proliferation by regulating insulin sensitivity, metabolism, protein synthesis, and cell cycle. Thus, deregulation of S6K contributes to the progression of type 2 diabetes, obesity, aging, and cancer. Considering the biological and clinical importance of S6K1, a complete understanding of its regulation is critical. One of the key motifs in the activation of S6K1 is a turn motif, but its regulation is not well understood. Here we provide evidence for two mechanisms of modulating turn motif phosphorylation and S6K1 activity. First, mammalian target of rapamycin regulates turn motif phosphorylation by inhibiting its dephosphorylation. Second, we unexpectedly found that glycogen synthase kinase (GSK)-3 promotes turn motif phosphorylation. Our studies show that mammalian target of rapamycin and GSK-3 cooperate to control the activity of S6K1, an important regulator of cell proliferation and growth. Our unexpected results provide a clear rationale for the development and use of drugs targeting GSK-3 to treat diseases such as diabetes, cancer, and age-related diseases that are linked to improper regulation of S6K1.

Regulation of endothelial cell morphogenesis by the protein kinase D (PKD)/glycogen synthase kinase 3 (GSK3)ß pathway.

Vascular morphogenesis is a key process for development, reproduction, and pathogenesis. Thus understanding the mechanisms of this process is of pathophysiological importance. Despite the fact that collagen I is the most abundant and potent promorphogenic molecule known, the molecular mechanisms by which this protein regulates endothelial cell tube morphogenesis are still unclear. Here we provide strong evidence that collagen I induces tube morphogenesis by inhibiting glycogen synthase kinase 3ß (GSK3ß). Further mechanistic studies revealed that GSK3ß activity is regulated by protein kinase D (PKD). PKD inhibited GSK3ß activity, which was required for collagen I-induced endothelial tube morphogenesis. We also found that GSK3ß regulated trafficking of integrin α(2)ß(1) in a Rab11-dependent manner. Taken together, our studies highlight the important role of PKD in the regulation of collagen I-induced vascular morphogenesis and show that it is mediated by the modulation of GSK3ß activity and integrin α(2)ß(1) trafficking.

Sacroiliac Joint Fusion-A Shift Toward Variant Anatomy and Clinical Implications.

OBJECTIVE: To investigate impact of patient factors and sacroiliac joint (SIJ) anatomical structure on SIJ fusion outcomes. METHODS: This single-center, retrospective, observational study evaluated patients diagnosed with SIJ dysfunction refractory to conservative measures who had available preoperative imaging of the sacrum and underwent SIJ fusion surgery. The impact of patient sociodemographics on pain improvement was assessed by Mann-Whitney U test. Differences in patient sociodemographics and outcome information between anatomical subtypes were assessed with χ2 and Kruskal-Wallis tests. χ2 test was used to compare joint anatomy distribution between studies analyzing SIJ variations. RESULTS: We included 77 total joints that underwent instrumentation. There were significant differences between the anatomical subtypes with female sex having significantly higher rates of non-normal joint anatomy. Younger age was significantly more common in bipartite/dysmorphic anatomy (53.9 years) than normal anatomy (70 years) (P < 0.05). There was a trend toward better outcomes in bipartite/dysmorphic and accessory variants, while semicircular defect and crescent variants trended toward worse outcomes. Nonnormal anatomy was significantly more frequent in our population than previous reports on nonpathological SIJ. CONCLUSIONS: A pathological SIJ has a significantly higher prevalence of variant joint anatomy. There appears to be a trend toward differences in surgical outcomes based on SIJ anatomy. Future research with larger sample sizes is necessary to confirm these differences.

Clinical outcomes for patients with lateral lumbar radiculopathy treated by percutaneous endoscopic transforaminal discectomy versus tubular microdiscectomy: A retrospective review.

BACKGROUND: Surgical management of lateral lumbar radiculopathy is evolving. TMD (Tubular microdiscectomy) and TELD (Transforaminal endoscopic lumbar discectomy) have emerged as viable MIS treatments. We aim to compare clinical outcomes of both techniques for the treatment of lateral lumbar radiculopathy in relation to pre-operative lumbar foraminal stenosis grade (LFS). METHODS: Retrospective observational cohort study of patients with back and leg pain from single level foraminal nerve root compression that underwent TMD or TELD. Data analyzed included pre- and post-operative VAS leg and back pain, MacNab clinical outcome scores, hospital length of stay, complication rates, and operative time. Outcomes were correlated with a pre-operative MRI grading system for LFS. RESULTS: 109 patients were enrolled (71 TELD and 38 TMD). Back and leg VAS pain scores improved in TELD and TMD (p < 0.0001). Patients with grade III stenosis showed significantly higher VAS scores (p < 0.01), and worse functional outcomes at latest follow-up compared with grade I/II LFS. Overall, there was no difference in outcome between procedure groups except that TMD VAS back pain scores were lower than TELD at last follow up (p < 0.05). Clinical outcome comparisons between procedures relating to LFS grade showed higher correlation of LFS to TELD (Spearman's rho (ρ)= 0.342 for TMD and 0.606 TELD). Regression analyses demonstrated correlation between higher-grade foraminal stenosis and poorer outcomes in TELD and TMD. CONCLUSIONS: Both TELD and TMD are viable for treating lateral lumbar radiculopathy. Higher-grade foraminal stenosis can be indicative of poorer outcomes regardless of procedure type, however, the severity of pre-operative LFS correlates with clinical outcomes in TELD more significantly than TMD.

Perspectives from a Residency Training Program Following the Implementation of a Wellness Initiative.

BACKGROUND AND OBJECTIVES: Programs that address overall wellbeing early in residency are necessary to prevent physician burnout and promote physician mental health to improve patient outcomes and ensure long and productive careers. A wellness initiative was implemented at our institution 3 years ago. We present feedback from participating residents across all levels of training. METHODS: A 17-question survey was administered to resident physicians in the department of neurosurgery at our institution. In addition to the resident survey results, we obtained personal perspective pieces from attendings and residents across all levels of training. RESULTS: A total of 8 resident physicians completed a 17-question survey. 100% of participants felt that health and wellness initiatives are "very important" for resident physicians, that the initiative has been "largely positive" for the department overall, and that is has positively impacted their personal life in addition to their professional life. The majority (75%) of respondents indicated that participation has not affected patient care responsibilities "at all." CONCLUSIONS: Participating resident perceptions of the wellness program are highly favorable. The survey results, combined with the perspectives across training levels, provide insight for other programs wishing to implement program of their own.

Casein kinase 1ε promotes cell proliferation by regulating mRNA translation.

Deregulation of translation initiation factors contributes to many pathogenic conditions, including cancer. Here, we report the definition of a novel regulatory pathway for translational initiation with possible therapeutic import in cancer. Specifically, we found that casein kinase 1ε (CK1ε) is highly expressed in breast tumors and plays a critical role in cancer cell proliferation by controlling mRNA translation. Eukaryotic translation initiation factor eIF4E, an essential component of the translation initiation complex eIF4F, is downregulated by binding the negative-acting factor 4E-BP1. We found that genetic or pharmacologic inhibition of CK1ε attenuated 4E-BP1 phosphorylation, thereby increasing 4E-BP1 binding to eIF4E and inhibiting mRNA translation. Mechanistic investigations showed that CK1ε interacted with and phosphorylated 4E-BP1 at two novel sites T41 and T50, which were essential for 4E-BP1 inactivation along with increased mRNA translation and cell proliferation. In summary, our work identified CK1ε as a pivotal regulator of mRNA translation and cell proliferation that acts by inhibiting 4E-BP1 function. As CK1ε is highly expressed in breast tumors, these findings offer an initial rationale to explore CK1ε blockade as a therapeutic strategy to treat cancers driven by deregulated mRNA translation.

Integrin trafficking and tumor progression.

Integrins are major mediators of cancer cell adhesion to extracellular matrix. Through this interaction, integrins play critical roles in cell migration, invasion, metastasis, and resistance to apoptosis during tumor progression. Recent studies highlight the importance of integrin trafficking, endocytosis and recycling, for the functions of integrins in cancer cells. Understanding the molecular mechanisms of integrin trafficking is pivotal for understanding tumor progression and for the development of anticancer drugs.