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Dysregulated oxidative stress plays a major role in cancer pathogenesis and some types of cancer cells are particularly vulnerable to inhibiting cellular antioxidant capacity. Glutamate-cysteine ligase (GCL) is the first and rate-limiting step in the synthesis of the major cellular antioxidant glutathione (GSH). Developing a GCL inhibitor may be an attractive therapeutic strategy for certain cancer types that are particularly sensitive to oxidative stress. In this study, we reveal a cysteine-reactive covalent ligand EN25 that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, leading to inhibition of GCL activity, lowering of cellular GSH levels, and impaired cell viability in ARID1A-deficient cancer cells that are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells. Our studies uncover a novel potential ligandable site within GCLM that can be targeted to inhibit the GSH synthesis in cancer cells to target vulnerable cancer cell types.

Supplementary Table 2: Genes commonly up-regulated or down-regulated by T-3775440 treatment in NCI-H1417, NCI-H510A, and NCI-526 cells. Supplementary Table 3: Plasma concentration and pharmacokinetic properties of T-3775440 in mice treated with a single dose of T-3775440 (30 mg/kg). Supplementary Figure 1: T-3775440 inhibits SCLC cell proliferation in a concentration-dependent manner. Supplementary Figure 2: INSM1 is strongly expressed in a subset of lung cancer cell lines. Supplementary Figure 3: INSM1 expression in AML (TF-1a and HEL), colon cancer (RKO), and SCLC cell lines (NCI-H510A, NCI-H526, and NCI-H1417). Supplementary Figure 4: SPR sensorgrams of the interaction of LSD1 with INSM1 peptide or GFI1B peptide. Supplementary Figure 5: Immunoblot analysis of siRNA-transfected cells. Supplementary Figure 6: ASCL1 and NeuroD1 are highly expressed in SCLC cells. Supplementary Figure 7: Microarray analysis of T-3775440-treated SCLC cells. Supplementary Figure 8: The PD markers KRT19, UMODL1, and VIM are upregulated in siINSM1-transfected NCI-H1417 cells. Supplementary Figure 9: Body weight changes in mice treated with T-3775440 or the vehicle control. Supplementary Figure 10: Plasma concentration of T-3775440 following a single oral dose of 30 mg/kg. Supplementary Figure 11: GFI1B expression in clinical SCLC samples.

T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe the anticancer effects and mechanism of action of T-3775440 in small-cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo. T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as ASCL1. INSM1 silencing phenocopied the effects of T-3775440 on gene expression and cell proliferation, consistent with the likelihood T-3775440 mediated its effects in SCLC by inhibiting INSM1. T-3775440 also inhibited proliferation of an SCLC cell line that overexpressed GFI1B, rather than INSM1, by disrupting the interaction between LSD1 and GFI1B. Taken together, our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC. Cancer Res; 77(17); 4652–62. ©2017 AACR.

Supplementary Table S1: Genes up-regulated or down-regulated in H1417, H510A, or H526 cell line upon T-3775440 treatment.

Background Cervical ossification of the ligamentum flavum (OLF) is a rare condition; however, the coexistence of OLF and ossification of the posterior longitudinal ligament (OPLL) is extremely uncommon. These can exist simultaneously and cause thinning of the cervical spinal cord. Sufficient decompression, dural ossification, semispinalis dissection, and postoperative kyphosis were evaluated. We report the successful treatment of coexisting cervical OLF and OPLL. Case Description A 70-year-old man had been experiencing weakness in the left knee and clumsiness in the left hand for 6 months. Hemiparesis was considered; however, magnetic resonance imaging revealed a cervical spinal lesion. Hence a spine surgeon diagnosed the patient with severe stenosis with OLF at the C2–C3 levels and OPLL at the C2–C4 levels. The patient presented with spastic gait and left-hand motor weakness. Computed tomography scan revealed the disappearance of the black line, indicating dural ossification surrounding the OLF. OPLL was observed in 61.5% of the C2 spinal canal. The K-line was (−); however, the alternative K-line between the C1 and C7 level was (+). Posterior laminectomy at the C2–C3 levels and laminoplasty at the C4–C7 levels with muscle preservation resulted in sufficient decompression. The patient's symptoms improved, and cervical alignment was maintained 2 years after surgery. Conclusions An alternative K-line comprised successful treatment for coexisting cervical OLF and OPLL. Surgeons must evaluate the severity of adhesion, damage of the paraspinal muscles, and necessity of posterior corrective surgery along with the patient's comorbidities and possible postoperative complications.

Background For the surgical treatment of spinal malignant tumor, spinal reconstruction with bone graft and instrumentation is necessary after tumor resection, but postoperative complications, including grafted bone resorption, may arise. Case Description A 42-year-old Asian woman presented with neck pain, tumorous masses on the neck, and left arm pain. Magnetic resonance imaging and computed tomography of the cervical spine showed extensive malignant spinal tumor. Histological examination of tumor biopsy revealed grade I chondrosarcoma. Complete resection of the tumor was performed using an anterior-posterior approach, followed by anterior iliac bone grafting and posterior spinal instrumentation. No tumor recurrence was observed on magnetic resonance imaging at final follow-up after 10 years. However, grafted bone resorption was identified immediately after surgery due to stress shielding by robust spinal instrumentation. To inhibit resorption of grafted bone, the bisphosphonate minodronate was administered for 5 years from 3 years postoperatively, before being replaced by denosumab from 8 years postoperatively. After use of these antibone resorptive agents, grafted bone resorption stopped. Conclusions Anteriorly grafted bone resorption due to stress shielding may occur after reconstructive cervical spine surgery with robust posterior spinal instrumentation. Bisphosphonates and denosumab may be considered to inhibit grafted bone resorption.

Study design Retrospective and comparative study. Purpose We assessed surgical treatment outcomes in patients with thoracic myelopathy due to ossification of the ligamentum flavum (OLF), and OLF combined with ossification of the posterior longitudinal ligament (OPLL) or vertebral fracture (VF) at the same level. Overview of literature OLF and OPLL cause severe thoracic myelopathy. Osteoporotic VF commonly occurs at the thoracolumbar junction. There have been no investigations of thoracic myelopathy due to OLF and VF. Methods Forty patients were divided among three groups: the OLF group (n=23): myelopathy due to OLF, the OLF+OPLL group (n=12): myelopathy due to OLF and OPLL, and the OLF+VF group (n=5): myelopathy due to OLF and VF. We recorded OLF, OPLL, and VF sites and operative procedures. Each patient's neurological status, according to the Japanese Orthopaedic Association (JOA) score, and walking ability were evaluated pre- and postoperatively. Results Patients in the OLF+OPLL group were significantly younger than those in the other two groups. The preoperative JOA score was significantly lower in the OLF+VF than OLF group. The final JOA score was significantly lower in the OLF+VF than OLF and OLF+OPLL groups. The JOA score recovery rate was significantly lower in the OLF+VF than OLF group. Final walking ability was significantly worse in the OLF+OPLL and OLF+VF groups than in the OLF group and significantly worse in the OLF+VF than OLF+OPLL group. Conclusions Thoracic myelopathy due to OLF+VF occurs primarily in older females, who also exhibit worse preoperative and postoperative neurological status, and worse walking ability, than patients with thoracic myelopathy due to OLF or OLF+OPLL.

Study design A retrospective analysis of prospectively collected multicenter observational data. Objective The aim of this study was to compare the health-related quality of life (HR-QOL) of double-door laminoplasty (DDL) and selective laminoplasty (SL) in patients with degenerative cervical myelopathy (DCM) in two institutions, with a minimum follow-up of 5 years. Summary of background data No study has compared DDL and SL regarding postoperative HR-QOL with a follow-up of more than 5 years. Methods One-hundred ninety patients who underwent DDL (n = 77) or SL (n = 113) participated in this study. Short-form 36 (SF-36), Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), Neck Disability Index (NDI), and visual analog scale (VAS) values were compared between the groups. Results Thirty-seven DDL and 52 SL patients were evaluated. The mean follow-up period was 8 years and the follow-up rate was 46.8%. No significant differences were found regarding age and JOA score at baseline. At the follow-up, there were no significant differences in SF-36, JOACMEQ, and VAS score, while the NDI score for headache and sleeping were higher in the SL group. After dividing the SL group into short and long SL subgroups, the long SL subgroup showed a significantly lower score in bodily pain in SF-36, lower and bladder function in JOACMEQ, and pain intensity, personal care, headaches, and sleeping in NDI compared with the other groups. Conclusion No significant differences were found in SF-36, JOA score, and NDI, except for the NDI subscale of headache and sleeping. The subgroup analysis showed that the long SL group showed a decreased QOL compared with the short SL and DDL groups. Level of evidence 3.

Retrospective epidemiological study. To investigate the epidemiology of traumatic spinal cord injury (TSCI) in the fastest aging area in Japan. Hospitals in Akita Prefecture, Japan. Akita Prefecture has the highest ratio of people aged 65 or older in Japan (30.4% in 2012 and 34.6% in 2016). Patients with acute TSCI who required hospital treatment between 2012 and 2016 were included. The incidence of TSCI, cause, level, skeletal injury, and Frankel grade were investigated. The mean annual incidence of TSCI excluding Frankel E was 86 per million (range 86–104 per million) during the 5-year study period, with a mean age of 65.9 years (male, 75.1%) and patients in their 60s as the largest age group. Cervical injury was seen in 89.8%, and cervical TSCI without skeletal injury was seen in 65.5%. Frankel D was the most common neurological deficit (53.5%). The most common cause was falls on level surfaces (32.1%), followed by low falls (21.6%) and road traffic accidents (15.6%). Recent incidence and characteristics of TSCI in the fastest aging society in Japan are presented. The incidence of incomplete cervical TSCI and falls on level surfaces appear to be increasing.

Spinal instrumented arthrodesis improves health-related quality of life (HRQOL), although mobility is impaired. This study evaluates activities of daily livings after thoracolumbosacroiliac arthrodesis for adult spinal deformity and patient satisfaction. Fifty patients who underwent surgery filled self-administered questionnaires (1-year preoperative and postoperative conditions), and 36 patients (3 men and 33 women; mean age 71.4 years) participated in the study. Twenty-five activities, including weeding, snow shoveling, toilet activities, and sleeping postures, were examined. Spinal alignment with Scoliosis Research Society (SRS)—Schwab classification, HRQOL with SRS-22, complications, and patient satisfaction were evaluated. Pre- and postoperative conditions were statistically compared. Spinal alignment improved postoperatively. Comparison data revealed that strenuous activities, such as weeding and farm work, significantly deteriorated postoperatively in 42.1–87.5% patients. Other basic activities, excluding Western toilet usage, sleeping supine, laundry and kitchen chores, and changing jacket/pants, also significantly deteriorated in 21–88% patients. Only activities such as sleeping supine, standing upright, vacuuming, doing laundry, and reaching for objects placed at heights became possible with significant difference postoperatively among activities that could not be performed preoperatively. Light activities were continued, but strenuous activities were restricted. Nevertheless, the patient satisfaction rate was 70%. Six patients exhibited complications; however, none were dissatisfied with surgery outcomes. Instrumentation or proximal junctional failures were associated with at least one strenuous work activity. Thoracolumbosacroiliac arthrodesis does not always improve activities postoperatively. Therefore, surgical indication for patients who continue activities preoperatively should be carefully decided. Level 3. These slides can be retrieved under Electronic Supplementary Material.

Myeloid sarcoma occurs in 1% - 9% of patients with myelogenous leukemia. Spinal epidural myeloid sarcoma is particularly rare, and its treatment has not been established. A 27-year-old woman complained of pain on her left chest, back around the scapula, and neck. Magnetic resonance imaging (MRI) showed a thoracic epidural tumor. One week after her visit, she developed motor weakness of her lower extremities and dysuria, and she was diagnosed with acute myelogenous leukemia (AML) on peripheral blood analysis. The epidural tumor was strongly suspected to be myeloid sarcoma. The paralysis of the lower extremities and bladder dysfunction were not progressive, and chemotherapy and local radiation therapy to the spine were performed. Improvement of paralysis and complete reduction of tumor volume were achieved by the combination of local low-dose radiation therapy and chemotherapy.

Background:Pediatric spinal infections are rare and often accompanied by abscesses. Delayed diagnosis commonly leads to a poor neurological prognosis, emphasizing the need for early diagnosis and treatment.Case Description:We report on two cases of spinal infection; one in a 5-year-old boy with a T8-11 epidural abscess and one in a 10-year-old boy with an L5-S1 epidural abscess. Both cases improved with conservative therapy.Conclusion:Early magnetic resonance imaging diagnosis and systemic treatment in collaboration with pediatricians are key factors in the successful management of children with spinal infections.

Background: Due to its rarity, surgical treatments for a complete fifth lumbar osteoporotic vertebral burst fracture (L5 OVBF) have yet to be well documented as compared to that for osteoporotic vertebral fractures of the thoracolumbar spine. The current case report discusses details of the surgical outcomes following posterior decompression and fusion for a complete L5 OVBF. Case Description: Three women, ranging in age from 69 years to 82 years, were surgically treated for a complete L5 OVBF. Two of these patients were being treated for rheumatoid arthritis. Surgery was performed using the L5 shortening osteotomy or vertebroplasty, with one- or two-level posterior lumbar interbody fusion, and posterior spinal fixation for the L2 or L3 to the pelvis. Although the spinal alignment parameters, which included lumbar lordosis (LL), pelvic incidence-lumbar lordosis, T1 pelvic angle, and sagittal vertical axis, were better as compared to that observed before the surgery, these worsened at the final follow-up due to clinical fractures that occurred at the adjacent vertebral body and proximal junctional kyphosis. Compared to preoperative Japanese Orthopaedic Association (JOA) scores, postoperative JOA scores were improved and maintained at the final follow-up. Conclusion: Posterior surgery of a complete L5 OVBF led to improvement of both the JOA score and spinal alignment after the surgery. Despite a worsening of the spinal alignment parameters, the JOA score was maintained at the final follow-up.

Background: The ideal surgery for spinal cord tumors is complete resection to prevent recurrence. However, it should be accomplished safely/effectively without risking increased morbidity. Here, we report a cervical meningioma that was totally resected, including the inner dura, through a laminoplasty performed with hydroxyapatite (HA) spacers. Case Description: A 61-year-old Asian male presented with a symptomatic intradural extramedullary C4-C6 cervical meningioma. At surgery, this required resection of the inner dural layer through an open-door laminoplasty. Preservation of the outer dural layer facilitated a watertight closure and the avoidance of a postoperative cerebrospinal fluid (CSF) fistula. Notably, the laminoplasty utilized HA spacers which were magnetic resonance (MR) compatible allowing for future follow-up studies to evaluate for tumor recurrence. At 5-year follow-up, the tumor had not recurred, the patient was asymptomatic, and alignment was maintained. Conclusion: Gross total resection of an intradural extramedullary C4-C6 cervical meningioma was performed with removal of just the inner dural layer. Preservation of the outer dural layer allowed for a watertight closure and the avoidance of a postoperative CSF leak. Further, laminoplasty using HA spacers allowed for successful tumor resection, adequate fusion/stabilization, while not interfering with future MR studies (e.g., HA MR compatible).

Objectives: The extent to which locomotive syndrome is associated with low back pain (LBP), health-related quality of life (HRQOL), and impairment of activities of daily living among elderly men and women remains poorly documented. This study evaluated associations between locomotive syndrome and both HRQOL and LBP as assessed using a questionnaire completed by elderly individuals, including some >80 years old. Methods: We conducted a survey assessing locomotive syndrome using the loco-check, HRQOL using the Short-Form 36 questionnaire (SF-36), and LBP using the Roland-Morris Disability Questionnaire (RDQ) among individuals >60 years old. SF-36 and RDQ scores were compared between 253 subjects with and without locomotive syndrome. Results: Fifty-seven men (48%) and 71 women (53%) were diagnosed with locomotive syndrome. Subjects of both sexes with locomotive syndrome scored significantly lower for eight items from SF-36. Physical and mental component summary scores were significantly worse in women with locomotive syndrome in their 60s and 70s. RDQ scores were significantly higher in participants with locomotive syndrome for men in their 60s and for both men and women in their 70s. Conclusions: Locomotive syndrome was associated with impaired HRQOL and worse LBP among men and women >60 years old. Differences in HRQOL and LBP between subjects with and without locomotive syndrome were significant for both men and women in their 60s and 70s, but not in their 80s. Locomotive syndrome should be prevented to maintain HRQOL, particularly for men and women in their 60s and 70s.

Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response., Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the role of PRMT7 in the cellular stress response.

Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.

Introduction. An arachnoid web (AW) is a relatively rare disease and shows clinical symptoms and radiological findings similar to those of an arachnoid cyst (AC) or spinal cord herniation (SCH). Since the operative procedures for an AW are generally different from those intrathecal disorders, correct preoperative differential diagnosis is important. The purposes of this study were to report the usefulness of magnetic resonance imaging (MRI) and computed tomography (CT) myelography for diagnosing AW and to show the histological findings and clinical results. Case Description. Two patients, a 79-year-old man and a 43-year-old woman, are presented. The primary diagnoses were AC with ossification of the ligamentum flavum and epidural hematoma, respectively, in previous hospitals. They were finally diagnosed by the characteristic MRI and CT myelogram finding called the “scalpel sign.” Histological findings showed epithelial cells and fibrous tissue derived from arachnoid tissues and microcalcifications. After surgery, the scalpel sign has vanished, and aggravation of their symptoms was prevented. Conclusion. An AW is refractory, but early detection by MRI and CT myelography and early treatment improve outcomes after surgery.

Background Safe excision of spinal cord tumors depends on sufficient visualization of the tumor and surrounding structures. In patients with spinal cord tumor adjacent to a stenotic spinal canal, extensive bony decompression proximal and distal to the tumor should be considered for safer excision of the tumor. Extensive wide laminectomy is one choice for such cases, but postoperative problems such as kyphotic deformity remain a concern. Case presentation A 76-year-old man and a 60-year-old woman presented with symptomatic intradural extramedullary spinal cord tumors in the cervical spine. Both patients showed a combination of spondylotic changes in the cervical spine and stenotic condition at the level of the tumor. Both tumors were successfully resected through open-door laminoplasty with hydroxyapatite (HA) spacers, with the tumor located on the side of the laminoplasty. Histological diagnosis was schwannoma for both tumors. HA spacers completely bonded to the host bone and did not interfere with postoperative magnetic resonance imaging (MRI) of the inside of the spinal canal. Cervical spine alignment was maintained at the final follow-up of 6 years in both cases. Conclusion Laminoplasty with HA spacers enabled successful tumor extirpation, reliable MRI follow-up after surgery, and maintenance of normal cervical spine alignment. Laminoplasty with HA spacers represents a good option for the treatment of cervical spinal cord tumor in patients combined with spinal stenosis.

Summary Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells. Furthermore, we found that SIRT3 KO cells upregulated the diversion of glutamine into de novo nucleotide synthesis through hyperactive mTORC1 signaling. Overexpression of SIRT3 suppressed mTORC1 and growth in vivo in a xenograft tumor model of breast cancer. Thus, we have uncovered a metabolic vulnerability of cells with SIRT3 loss by using an unbiased small-molecule screen., Graphical abstract SIRT3 is lost or downregulated in numerous pathologies. Loss of SIRT3 results in increased cell proliferation. Gonzalez Herrera et al. identify glutamine incorporation into nucleotides to be a driving force behind increased proliferation of cells lacking SIRT3.

Background: Amyotrophic lateral sclerosis (ALS) is an intractable progressive disease, with an incidence of 2.2– 2.3 per 100,000 individuals, which is not extremely low. ALS symptoms are accompanied by spinal myeloradicular motor deficit; its differential diagnosis is must because progressive paralysis needs emergency surgery. Case Description: A 64-year-old man with suspected ALS showing progressive paralysis with cervical myelopathy was diagnosed as normal after performing a nerve conduction study preoperatively. Postoperative diffuse fasciculation after posterior decompression allowed the diagnosis of ALS through needle electromyography (EMG). Thereafter, the patient’s condition slowly deteriorated and he died after 16 months. Conclusion: Surgery might aggravate ALS symptoms; however, surgery for progressive paralysis in patients with suspected ALS is required for distinguishing patients with non-ALS paralysis. Approximately 70% of cases have spinal-onset ALS lacking typical cranial nerve symptoms; thus, to prevent unnecessary surgery, surgeons should at least know the characteristic features of ALS and should be aware that early diagnosis requires needle EMG for definitive diagnosis of ALS.

T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe the anticancer effects and mechanism of action of T-3775440 in small-cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo. T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as ASCL1. INSM1 silencing phenocopied the effects of T-3775440 on gene expression and cell proliferation, consistent with the likelihood T-3775440 mediated its effects in SCLC by inhibiting INSM1. T-3775440 also inhibited proliferation of an SCLC cell line that overexpressed GFI1B, rather than INSM1, by disrupting the interaction between LSD1 and GFI1B. Taken together, our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC. Cancer Res; 77(17); 4652–62. ©2017 AACR.

This study compared spinal alignment, muscular strength, and quality of life (QOL) between women with postmenopausal osteoporosis and healthy volunteers. The results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness. Increased spinal kyphosis is common in patients with osteoporosis and negatively impacts quality of life (QOL). Muscular strength is also important for QOL in patients with osteoporosis. However, spinal kyphosis and muscle weakness also occur in healthy individuals with advancing age. The purposes of this study were thus to compare spinal alignment, muscular strength, and QOL between women with postmenopausal osteoporosis and healthy volunteers. Participants comprised 236 female patients with postmenopausal osteoporosis (mean age, 68.7 years) and 93 healthy volunteer women (mean age, 71.0 years). Body mass index (BMI), angles of spinal kyphosis, back extensor strength, grip strength, and QOL were compared between groups. BMI, back extensor strength, and grip strength were significantly higher in the volunteer group than in the osteoporosis group (p

Spinal deformities can affect quality of life (QOL) and risk of falling, but no studies have explored the relationships of spinal mobility and sagittal alignment of spine and the lower extremities simultaneously. Purpose of this study is to clarify the relationship of those postural parameters to QOL and risk of falling. The study evaluated 110 subjects (41 men, 69 women; mean age, 73 years). Upright and flexion and extension angles for thoracic kyphosis, lumbar lordosis, and spinal inclination were evaluated with SpinalMouse®. Total-body inclination and hip and knee flexion angles in upright position were measured from lateral photographs. Subjects were divided into Fallers (n=23, 21%) and Non-fallers (n=87, 79%) based on past history of falls. QOL was assessed using the Short Form 36 Health Survey (SF-36®). Age, total-body inclination, spinal inclination upright and in extension, thoracic kyphosis in flexion, lumbar lordosis upright and in extension, and knee flexion correlated significantly with the SF-36. Multiple regression analysis revealed total-body inclination and knee flexion to have the most significant relationships with the SF-36. SF-36, total-body inclination, spinal inclination in extension, thoracic kyphosis in flexion, lumbar lordosis upright and in extension, and hip and knee flexion angles differed significantly between Fallers and Non-fallers (P

Yuji Kasukawa, Naohisa Miyakoshi, Michio Hongo, Yoshinori Ishikawa, Daisuke Kudo, Masazumi Suzuki, Takashi Mizutani, Ryouta Kimura, Yuichi Ono, Yoichi Shimada Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan Abstract: Lumbar kyphosis and the decreased mobility of the lumbar spine increase the risk of falls and impair both the quality of life and the ability to perform activities of daily living. However, in the elderly Japanese population, little is known about the age-related changes and sex-related differences in muscle strength, including of the upper and lower extremities and back extensors. An adequate kyphotic or lordotic angle has also not been determined. In this study, we evaluated the age-related changes in muscle strength and spinal kyphosis in 252 males and 320 females ≥50years of age. Grip, back extensor, hip flexor, and knee extensor strength; thoracic and lumbar kyphosis; and spinal inclination in the neutral standing position were assessed, together with the range of motion of the thoracic and lumbar spine and spinal inclination. Grip strength, back extensor strength, and the strength of the hip flexors and knee extensors decreased significantly with aging, both in males (P

Purpose. Medial meniscal extrusion (MME) has attracted attention as an index of knee pain in conjunction with clinical symptoms that could be more useful than the diagnosis of knee osteoarthritis on X-ray. However, the size of MME that would cause knee pain has not been clarified. The aim of the present study was to investigate the cut-off value of MME for knee pain. Methods. A total of 318 knees were evaluated. The presence of current or past knee pain was confirmed by interview. Next, MME was measured using vertical sonographic images of the medial joint spaces during weightbearing. Results. Overall, 71 knees were painful (P-group), and 247 knees were not (N-group). MME was 5.9 ± 1.8 mm in the P-group and 2.9 ± 1.5 mm in the N-group (P<0.0001). Analysis of the receiver operating characteristic curve showed that the cut-off value of MME for knee pain was 4.3 mm, with sensitivity of 0.8451 and specificity of 0.8502. In addition, 64% of knees without pain cases at the time of examination whose MME exceeded this cut-off value had past knee pain. Conclusions. The sensitivity and specificity of MME for knee pain were very high with a cut-off value of 4.3 mm.

Malnutrition is one of the important risk factors for postoperative complications. Transferrin, prealbumin, and retinol-binding protein, so-called rapid turnover proteins (RTPs), may be the better indicators for early detection of nutritional deficits. However, few studies have described the impact of serum RTP levels on postoperative surgical site infection (SSI) in spine surgery. The purpose of this study was to investigate the relationship between preoperative serum RTPs and postoperative SSI. The data of 105 patients (64 male, 41 female; average age 64.4 years; age range 20–88 years) who underwent spine surgery in a single institution between 2014 and 2015 were retrospectively analyzed. Preoperative total lymphocyte count, serum albumin, transferrin, prealbumin, retinol-binding protein, pre-and postopeartive C-reactive protein (CRP), white blood cell count (WBC), and total lymphocyte count were evaluated. Postoperative CRP, WBC, and total lymphocyte count were repeated two or three times/week until hospital discharge. A broad spectrum penicillin or second generation cephalosporin was administered as a prophylactic antibiotic to each patient. When repeated CRP elevation or lymphopenia (no more than 10% or 1000/μL) after postoperative day 3 or 4 was observed, possible SSI was diagnosed. Variables between possible SSI group and non-SSI group were compared using Mann–Whitney U or Chi square test. All variables on univariate analysis were included in multiple logistic regression analysis to identify risk factors for possible postoperative SSI. Thirty-five patients were diagnosed with possible SSI. The mean operative time of possible SSI group was significantly longer (p = 0.036), preoperative total lymphocyte count and serum prealbumin level of possible SSI group were significantly lower (p = 0.002, p = 0.048, respectively) than that of non-SSI group. On univariate analysis, operative time (p = 0.012), preoperative total lymphocyte count (p = 0.041), serum albumin level (p = 0.038), and serum prealbumin level (p = 0.044) were significant contributors to possible SSI, and multiple logistic regression analysis revealed that operative time was the significant contributor to possible SSI (odds ratio 1.008, 95% confidence interval (CI) 1.001–1.015, p = 0.024). A low prealbumin level is a possible risk factor for early-stage SSI in spine surgery, though it was not statistically significant; operative time was the most important indicator of SSI on multivariate analysis.

Background Lower limb compensation for spinal sagittal malalignment and its impact on quality of life (QOL) and low back pain (LBP) have not been well studied. Objective To clarify postural compensation and the impact of spinal and lower limb sagittal alignment and muscle strength on QOL and LBP in persons > 50 years old. Methods In this cross-sectional study, 122 rural community-dwelling, healthy adults (56 males, 66 females; average age 71.1 years; age range, 52-88 years) underwent assessments of QOL (36-Item Short-Form Health Survey; SF-36), LBP (Roland-Morris Disability Questionnaire; RDQ), thoracic kyphosis (TK), lumbar lordosis (LL), sacral inclination (SI), grip strength, lower limb strength, and back extensor strength (BES). On univariate and multivariate analyses, variables that correlated with QOL and the RDQ were identified. Results LL was moderately correlated with SI and weakly correlated with the knee flexion angle (KFA). LL, KFA, C7-L5D, and BES were correlated with SF-36 subscales and the RDQ. KFA contributed to the physical component summary of the SF-36. Female sex and BES contributed to the RDQ. Conclusions Knee flexion compensated for lumbar kyphosis, but affected physical QOL scores negatively; BES was the most reliable contributor to QOL and the RDQ.

Background Symptomatic calcification of the ligamentum flavum (CLF) is common in the cervical spine but rare in the thoracic spine. Rapidly progressing CLF in the thoracic spine has not been reported in the literature. Case Description A 76-year-old Asian male experienced back pain after a fall and was diagnosed with osteoporotic vertebral fractures at T11 and L1. He was treated conservatively because of the lack of neurologic deficits. Nine months after the initial visit, he complained of progressive incomplete paraplegia. Magnetic resonance imaging and computed tomography of the thoracic spine showed CLF at T11-T12 severely compressing the spinal cord. This finding had not been seen on imaging studies at the initial visit. The patient underwent surgical resection of CLF and posterior instrumented spine fusion. Symptoms of muscle weakness recovered postoperatively. Conclusions In this case, sequential imaging studies with a 9-month interval showed evidence of rapidly progressing thoracic CLF. The preceding osteoporotic vertebral fracture may have triggered the development of CLF.

Background Venous air embolism (VAE) is a rare but, frequently, fatal complication that can occur during surgery. Several reported studies have shown visible bubbling of air at the surgical site as the first clinical indication of VAE-induced cardiovascular collapse during prone-position spine surgery. However, to the best of our knowledge, video imaging of this phenomenon has not been previously reported. Case Description A 41-year-old man had undergone cervical laminoplasty for ossification of the posterior longitudinal ligament and thoracic laminectomy for ossification of the posterior longitudinal ligament and ossification of the ligamentum flavum in the prone position. The entire surgery was recorded with video imaging. Before cardiac arrest due to the massive VAE, visible air bubbling had been observed at the operated site of the thoracic laminectomy, and this phenomenon had been incidentally recorded with the video. The patient recovered with cardiopulmonary resuscitation and intensive treatment against severe acute respiratory distress syndrome due to pulmonary damage. Conclusions The present case report offers the first video imaging evidence of intraoperative visible air bubbling as a sign of a massive VAE during prone-position spine surgery. To the best of our knowledge, this is also the first report of intraoperative VAE in a patient with extensive ossification of the spinal ligaments.

Introduction: C1 lateral mass screws and C2 pedicle screws are usually chosen to fix atlantoaxial (C1–C2) instability. However, there are a few situations in which these screws are difficult to use, such as in a case with a fracture line at the screw insertion point and bleeding from the fracture site. A new technique using a unilateral C1 posterior arch screw and a C2 laminar screw combined with a contralateral C1 lateral mass screws–C2 pedicle screws procedure for upper cervical fixation is reported. Case Report: A 24-year-old woman had an irreducible C1–C2 anterior dislocation with a type III odontoid fracture on the right side due to a traffic accident. The patient underwent open reduction and posterior C1–C2 fixation. On the left side, a C1 lateral mass screws and a C2 pedicle screws were placed. Because there was bleeding from the fracture site and a high-riding vertebral artery was seen on the right side, a C1 posterior arch screw and a C2 laminar screw were chosen. Eight months after the surgery, computed tomography scans showed healing of the odontoid fracture with anatomically correct alignment. Conclusions: Although there have been few comparable studies, fixation with unilateral C1 posterior arch screw–C2 laminar screw could be a beneficial choice for surgeries involving the upper cervical region in patients with fracture dislocation or arterial abnormalities.

Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective and cell active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells, is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 resulted in drastically reduced levels of arginine monomethylation of HSP70 family members and other stress-associated proteins. Structural and biochemical analysis revealed that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibited methylation of both constitutive and inducible forms of HSP70, and led to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.