The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4.

Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach.

Low reoperation rate after fixation of displaced femoral neck fractures with the femoral neck system (FNS).

PURPOSE: Operative fixation of femoral neck fractures (FNFs) remains challenging. Complications are not infrequent, especially in displaced patterns. Numerous fixation techniques have been previously described in the literature; however, there remains a paucity of data regarding outcomes of these injuries treated with the femoral neck system (FNS). METHODS: Patients with a displaced FNF (OTA/AO 31B) treated with the FNS at a single level 1 academic trauma center between 1/1/2019 and 1/1/2023 were identified. Radiographs were reviewed to assess fracture displacement, location, and characteristics. Patient records were further reviewed to assess for complications, reoperations, and osseous union. RESULTS: Forty-three patients (65% male) with 44 FNFs were identified with a mean age of 35.0 years (range, 13-61 years). Two patients developed a deep infection requiring surgical debridement, four patients underwent a total hip arthroplasty, and one patient underwent a valgus intertrochanteric osteotomy for nonunion. There were three cases of femoral head AVN. Mean follow-up was 482.5 days among all patients, and 36 fractures had at least 6 months of follow-up or reached bony union. CONCLUSIONS: Here, we present a series of patients treated with the FNS for internal fixation and report a 18% reoperation rate. This is lower than the average rate that has been previously reported in similar patient populations in the literature treated with alternative methods of internal fixation. Thus, the FNS appears to be a safe and effective option for treatment of these injuries.

Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex.

The metabolism of glucose and glutamine, primary carbon sources utilized by mitochondria to generate energy and macromolecules for cell growth, is directly regulated by mTORC1. We show that glucose and glutamine, by supplying carbons to the TCA cycle to produce ATP, positively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTORC1 assembly and its lysosomal localization. We discovered that the ATP-dependent TTT-RUVBL1/2 complex was disassembled and repressed by energy depletion, resulting in its decreased interaction with mTOR. The TTT-RUVBL complex was necessary for the interaction between mTORC1 and Rag and formation of mTORC1 obligate dimers. In cancer tissues, TTT-RUVBL complex mRNAs were elevated and positively correlated with transcripts encoding proteins of anabolic metabolism and mitochondrial function-all mTORC1-regulated processes. Thus, the TTT-RUVBL1/2 complex responds to the cell's metabolic state, directly regulating the functional assembly of mTORC1 and indirectly controlling the nutrient signal from Rags to mTORC1.

ATM: Promoter of metabolic "cost" reduction and "savings" usage during hypoxia through mTORC1 regulation.

Cells must sense environmental conditions and adjust to maintain metabolic homeostasis and survive stress conditions; in this issue, Cam et al. (2010) show that the tumor suppressor kinase ATM is activated by hypoxia, phosphorylates and stabilizes HIF-1α, and inhibits mTORC1.

Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply.

The mTORC1-signaling pathway integrates environmental conditions into distinct signals for cell growth by balancing anabolic and catabolic processes. Accordingly, energetic stress inhibits mTORC1 signaling predominantly through AMPK-dependent activation of TSC1/2. Thus, TSC1/2-/- cells are hypersensitive to glucose deprivation, and this has been linked to increased p53 translation and activation of apoptosis. Herein, we show that mTORC1 inhibition during glucose deprivation prevented not only the execution of death, but also induction of energetic stress. mTORC1 inhibition during glucose deprivation decreased AMPK activation and allowed ATP to remain high, which was both necessary and sufficient for protection. This effect was not due to increased catabolic activities such as autophagy, but rather exclusively due to decreased anabolic processes, reducing energy consumption. Specifically, TSC1/2-/- cells become highly dependent on glutamate dehydrogenase-dependent glutamine metabolism via the TCA cycle for survival. Therefore, mTORC1 inhibition during energetic stress is primarily to balance metabolic demand with supply.

Does Postoperative Radiation Decrease Heterotopic Ossification After the Kocher-Langenbeck Approach for Acetabular Fracture?

BACKGROUND: Controversy regarding heterotopic ossification (HO) prophylaxis exists after Kocher-Langenbeck for treatment of acetabular fracture. Prophylaxis options include antiinflammatory oral medications, single-dose radiation therapy, and débridement of gluteus minimus muscle. Prior literature has suggested single-dose radiation therapy as the best prophylaxis to prevent HO formation. However, recent reports have emerged of radiation-induced sarcoma after radiotherapy for HO prophylaxis, which has led many surgeons to reconsider the risks and benefits of single-dose radiation therapy. We set out to determine if radiotherapy, in addition to standard débridement of gluteus minimus muscle, affected postoperative HO formation after a Kocher-Langenbeck approach for acetabular fracture. QUESTIONS/PURPOSES: (1) After the Kocher-Langenbeck approach and gluteus minimus débridement, is single-dose radiotherapy associated with a decreased risk of HO? (2) Does addition of single-dose radiotherapy prolong length of stay after a Kocher-Langenbeck approach and gluteus minimus débridement as compared with patients without radiotherapy? METHODS: After institutional review board approval, all adult patients treated for acetabular fracture by a single surgeon with a Kocher-Langenbeck approach between August 2011 and October 2014 were identified (n = 60). Débridement of gluteus minimus muscle caudal to the superior gluteal bundle was standard in all patients. Radiotherapy was given with a single dose of 700 cGy within 72 hours of surgery from August 2011 until April 2013. Patients treated subsequently did not receive radiotherapy. Patients treated with indomethacin (n = 1) and with fewer than 10 weeks followup were excluded (n = 12) because several studies suggest that most HO that develops is visible by that point in time. Our study group totaled 46 patients with 24 in the radiotherapy and débridement group and 22 in the débridement group. Charts were reviewed to determine length of stay. Attending orthopaedic trauma surgeons who were blinded to the patient's treatment group graded all followup radiographs according to the Brooker system, and Classes III and IV HO were considered clinically important Fisher's exact test was used to analyze clinically significant differences HO between the two groups. Length of stay was compared using a t-test. RESULTS: Single-dose radiotherapy is associated with a decreased risk of clinically important (Brooker III-IV) HO after a Kocher-Langenbeck approach and gluteus minimus débridement (radiotherapy: one of 24 [4%], no radiotherapy: seven of 22 [32%], relative risk: 0.131 [95% confidence interval {CI}, 0.018-0.981], p = 0.020). Addition of single-dose radiotherapy did not result in increased length of stay (radiotherapy: 12 ± 7.0 days; no radiotherapy: 11 ± 7.2 days; mean difference: 1.0 [95% CI, -3.2 to 5.2] days, p = 0.635). CONCLUSIONS: Single-dose radiation in combination with gluteus minimus débridement decreases the risk of clinically important HO compared with gluteus minimus débridement alone after a Kocher-Langenbeck approach for acetabular fracture. No differences in length of stay were seen. Surgeons who chose not to use radiotherapy as a result of concern for future sarcoma may see higher rates of clinically significant HO after a Kocher-Langenbeck approach for acetabular fracture fixation. LEVEL OF EVIDENCE: Level III, therapeutic study.

Treatment of Infected Forearm Nonunions With Large Complete Segmental Defects Using Bulk Allograft and Intramedullary Fixation.

PURPOSE: The purpose of this study is to report the results of a series of infected forearm nonunions treated from 1998 to 2012 using a staged reconstruction technique. METHODS: At a median of 42 months follow-up, 7 patients who had an average segmental defect of 4.9 cm (range, 2.3-10.4 cm) were available for clinical and radiographic evaluation. Treatment consisted of serial debridement, implantation of an antibiotic cement spacer, and staged reconstruction using a bulk radius or ulna allograft with intramedullary fixation. RESULTS: All 7 patients ultimately achieved solid bone union, although 4 patients (57%) required additional surgery, consisting of autologous bone grafting and plating, to achieve healing at 1 of the allograft-host junction sites. No patient had recurrence of infection, and all reported substantial improvement with increased function and decreased pain. CONCLUSIONS: Our approach ultimately resulted in a 100% union rate without recurrence of infection, although many patients may require additional surgery to attain healing at both allograft-junction sites. Using bulk allograft provides the ability to span a large defect while reconstituting the forearm anatomy. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

TORgeting oncogene addiction for cancer therapy.

The PI3K-Akt-mTOR growth-regulating pathway is conserved from mammals to flies and hyperactivated in many cancers. Accordingly, rapamycin analogs, which are inhibitors of mTOR-Raptor signaling, have recently garnered much interest as potential therapeutic agents against cancer. However, due to the heterogeneity of tumors, prior knowledge of the genetic and biochemical background of cancer cells will be required for effective targeted therapy. Thus, the identification of biological markers against activated oncogenic pathways is needed. In the January issue of Nature Medicine, Thomas et al. identify the loss of VHL tumor suppressor gene as a potential determining factor in tumor sensitivity to rapamycin.

The Role of 3D Custom Implants in Upper Extremity Surgery.

SUMMARY: As the technology of three-dimensional (3D) printing becomes more refined and accessible, multiple applications of its use are becoming more commonplace in upper extremity surgery. 3D-printed models have been beneficial in preoperative planning of complex cases of acute trauma or malunions, contributing to spatial understanding or even contouring of implants. Custom guides can also be created to assist intraoperatively with precise placement of osteotomies or arthroplasty implants. Finally, custom 3D implants have been described for cases of bone loss in the upper extremity. This can be for relatively small gaps after malunion correction or extensive defects, typically for trauma or tumor. Articular defects can also be addressed with this technology, although special considerations should be given to the implant design and longevity in these situations. Because of the relatively recent nature of 3D implants, long-term data are lacking. However, they show great promise in an expanding range of challenging clinical indications.

Multidimensional Fluoroscopy to Assess Closed Reduction in Displaced Young Femoral Neck Fractures: A Report of 3 Cases.

CASE: The authors present 3 physiologically young patients with displaced femoral neck fractures who underwent initial closed reduction and provisional fixation. Multidimensional fluoroscopy was used to assess fracture reduction before definitive fixation, with 1 patient requiring an open approach because of inadequate fracture reduction after closed attempts. CONCLUSION: Displaced femoral neck fractures in young patients remain difficult injuries to treat. Reduction quality is a significant predictor of patient outcomes. Intraoperative multidimensional fluoroscopy provides treating surgeons with a tool to assess fracture reduction after closed reduction maneuvers and allows for intraoperative treatment adjustment as needed.

The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1.

The Vpr protein of HIV-1 functions as a vital accessory gene by regulating various cellular functions, including cell differentiation, apoptosis, nuclear factor of kappaB (NF-kappaB) suppression and cell-cycle arrest of the host cell. Several reports have indicated that Vpr complexes with the glucocorticoid receptor (GR), but it remains unclear whether the GR pathway is required for Vpr to function. Here, we report that Vpr uses the GR pathway as a recruitment vehicle for the NF-kappaB co-activating protein, poly(ADP-ribose) polymerase-1 (PARP-1). The GR interaction with Vpr is both necessary and sufficient to facilitate this interaction by potentiating the formation of a Vpr-GR-PARP-1 complex. The recruitment of PARP-1 by the Vpr-GR complex prevents its nuclear localization, which is necessary for Vpr to suppress NF-kappaB. The association of GR with PARP-1 is not observed with steroid (glucocorticoid) treatment, indicating that the GR association with PARP-1 is a gain of function that is solely attributed to HIV-1 Vpr. These data provide important insights into Vpr biology and its role in HIV pathogenesis.

HIV-mediated phosphatidylinositol 3-kinase/serine-threonine kinase activation in APCs leads to programmed death-1 ligand upregulation and suppression of HIV-specific CD8 T cells.

Recent evidence demonstrates that HIV-1 infection leads to the attenuation of cellular immune responses, which has been correlated with the increased expression of programmed death (PD)-1 on virus-specific CD8(+) T cells. PD-1 is induced upon T cell activation, and its prolonged expression facilitates CD8(+) T cell inhibitory signals when bound to its B7 family ligands, PD-ligand (L)1/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1/PD-L interaction by Abs may help to counter the development of immune exhaustion driven by HIV viral persistence. To better understand the regulation of the PD-1 pathway during HIV infection, we examined the ability of the virus to induce PD-L expression on macrophages and dendritic cells. We found a direct relationship between the infection of APCs and the expression of PD-L1 in which virus-mediated upregulation induced a state of nonresponsiveness in uninfected HIV-specific T cells. Furthermore, this exhaustion phenotype was revitalized by the blockade of PD-L1, after which T cells regained their capacity for proliferation and the secretion of proinflammatory cytokines IFN-γ, IL-2, and IL-12 upon restimulation. In addition, we identify a critical role for the PI3K/serine-threonine kinase signaling pathway in PD-L1 upregulation of APCs by HIV, because inhibition of these intracellular signal transducer enzymes significantly reduced PD-L1 induction by infection. These data identify a novel mechanism by which HIV exploits the immunosuppressive PD-1 pathway and suggest a new role for virus-infected cells in the local corruption of immune responses required for viral suppression.

Total elbow arthroplasty: current options.

Total elbow arthroplasty (TEA) has changed considerably in the past three decades. Based on the good long-term results with TEA in patients with rheumatoid arthritis, the indications expanded to include management of acute traumatic and posttraumatic conditions in young, higher-demand patients. Today, unlinked, linked semiconstrained, and convertible devices are available. The high complication rate with earlier surgeries led to surgical advances such as new cementing technique and a focus on managing the triceps. Complications such as infection, aseptic loosening, polyethylene wear, periprosthetic fracture, triceps insufficiency, wound breakdown, and ulnar nerve injury will continue to spur the evolution of surgical technique and implant design. Refinement of surgical indications and improvement in implant fixation, polyethylene design, component implantation, and pathology-specific implants will determine the future success of TEA.

Distractor Application and Dry Arthroscopy to Improve Articular Visualization During Scapula Fracture Surgery Via a Posterior Approach.

SUMMARY: Intra-articular glenoid displacement is an indication for open reduction and internal fixation of scapular fractures. However, direct visualization of the glenoid is limited, and articular reductions are typically performed and assessed using extra-articular cortical reduction reads and fluoroscopic imaging. In this technique, we describe the application of a distractor for direct visualization of the glenoid articular surface. In this way, anatomic reduction of the glenoid articular surface can be assessed and achieved. In addition, we discuss the use of a portable, dry arthroscopy when needed. This technique has resulted in good-to-excellent articular reductions by adjusting extra-articular reads that seemed adequate before intra-articular visualization. This technique is safe, requires minimal extra set-up or instruments, and results in good-to-excellent articular reductions.

Open Reduction and Internal Fixation of Pediatric Scapula Fractures: A Report of 2 Cases.

CASE: Two pediatric patients with displaced, extra-articular scapula fractures who underwent surgery because of concerns for persistent deformity and decreased function with continued nonoperative management. CONCLUSION: We advocate careful consideration of all patient factors and treatment options when addressing pediatric scapula fractures. Specific fracture patterns with altered shoulder girdle mechanics may warrant surgical intervention to restore anatomic alignment and stability.

The Impact of Magnetic Resonance Imaging on the Diagnosis of High-Energy Ipsilateral Femoral Neck and Shaft Fractures.

OBJECTIVE: To evaluate the most common femoral shaft fracture morphology associated with an ipsilateral femoral neck fracture in high-energy blunt trauma using magnetic resonance imaging (MRI). DESIGN: Retrospective review. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: 219 consecutive patients sustaining 228 femoral shaft fractures from high-energy blunt trauma. MAIN OUTCOME MEASUREMENTS: Fracture patterns were analyzed using the OTA/AO classification system. In addition, location of the fracture was measured as the distance from the distal aspect of the lesser trochanter to the center of the femoral shaft fracture. RESULTS: An OTA/AO 31 type fracture was seen in 16.5% (20/121) of patients presenting with OTA/AO 32-A type fractures, 12% (6/50) of patients with OTA/AO 32-B type fractures, and 26.3% (15/57) of patients with OTA/AO 32-C type fractures. The fractures that occurred in the middle or distal third of the femur shaft constituted 95.1% (39/41). CONCLUSIONS: In this cohort, patients with middle and distal third OTA/AO 32-C type fractures had the highest association with an ipsilateral OTA/AO 31 type fracture. OTA/AO 32-A2 and 32-A3 type fractures had the highest association with femoral neck fractures seen only on MRI. The data presented suggest continued usage of the rapid sequence pelvic MRI for all patients with high-energy femoral shaft fractures in whom a femoral neck fracture was not seen on an x-ray or a computed tomography scan. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The injury characteristics of open pilon fractures predictive of complications.

OBJECTIVE: Determine predictive injury factors for wound complications in open pilon fractures (OTA/AO 43B and 43C). DESIGN: Retrospective Case Series. SETTING: Level I Trauma Center. PATIENTS/PARTICIPANTS: A total of 61 open pilon fractures in 60 patients were evaluated after meeting inclusion and exclusion criteria. INTERVENTION: The majority of injuries underwent a staged protocol with immediate antibiotics, debridement, irrigation and external fixation. Following soft tissue stabilization, internal fixation was performed and wound closure achieved in a coordinated fashion depending on the type of closure required. MAIN OUTCOME MEASUREMENTS: Early amputation rate, 90-day major (wound dehiscence or deep infection requiring operative intervention) and minor (superficial infection) wound complications. RESULTS: Four patients incurred early amputations, 11 had major wound complications and 5 had minor wound complications. An early amputation was more likely if they presented with an OTA Open Fracture Classification (OTA-OFC) Bone Loss Grade 3. A major wound complication was more likely if they presented with a fall from > 3 m, a multifragmentary articular surface, a segmental fibula fracture, or an OTA-OFC Contamination Grade 3. A multifragmentary articular surface was also predictive of developing any wound complication. CONCLUSIONS: Open pilon fractures are severe, limb-threatening injuries and are at risk for wound complications. Patients presenting with these injuries and a predictive factor should be counseled regarding the possibility of early limb loss or experiencing a wound complication that will require additional treatment. LEVEL OF EVIDENCE: Level III.

Is retrograde nailing superior to lateral locked plating for complete articular distal femur fractures?

INTRODUCTION: Nonunion rates for distal femur fractures treated with lateral locked plating (LLP) remains as high as 18-22% despite significant advances with implant design and construct modulation. However, whether treatment of distal femur fractures with rIMN has improved outcomes compared to LLP has not been well characterized. The purpose of this study was to compare outcomes of complete articular distal femur fractures (AO/OTA 33-C) treated with either LLP or rIMN. METHODS: 106 distal femur fractures in 106 patients between January 2014 and January 2018 were identified. Medical records were reviewed to collect patient age, gender, body mass index, sagittal and coronal plane alignment on immediate postoperative radiographs, time to union, incidence of nonunion, and incidence of secondary operative procedures for repair of a nonunion. RESULTS: Of 106 patients, 50 underwent rIMN and 56 underwent LLP. The mean age at the time of injury was 51 years (21 to 86 years) and there were 55 males. Average coronal alignment of 83.7° of anatomic lateral distal femoral angle (aLDFA) and sagittal alignment of <1° of apex anterior angulation in the rIMN group. In the LLP group there was an average of 87.9° of aLDFA and 1.9° of apex anterior angulation (p = .005 and p = .36). Average time to union in the rIMN group was 6 months and 6.6 months in the LLP group (p = .52). Incidence of nonunion in the rIMN group was 11.8% and 27.5% in the LLP group (p = .008). There were 8 secondary procedures for nonunion in the rIMN group and 18 in the LLP group (p = .43). CONCLUSIONS: Our results demonstrated a higher nonunion rate and coronal plane malalignment with LLP compared to rIMN. While prospective data is required, rIMN does appear to be an appropriate treatment for complete articular distal femur fractures with a potentially decreased rate of nonunion .