Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine.

Gut microbiota influence anti-tumor immunity, often by producing immune-modulating metabolites. However, microbes consume a variety of metabolites that may also impact host immune responses. We show that tumors grow unchecked in the omenta of microbe-replete mice due to immunosuppressive Tregs. By contrast, omental tumors in germ-free, neomycin-treated mice or mice colonized with altered Schaedler's flora (ASF) are spontaneously eliminated by CD8+ T cells. These mice lack Proteobacteria capable of arginine catabolism, causing increases in serum arginine that activate the mammalian target of the rapamycin (mTOR) pathway in Tregs to reduce their suppressive capacity. Transfer of the Proteobacteria, Escherichia coli (E. coli), but not a mutant unable to catabolize arginine, to ASF mice reduces arginine levels, restores Treg suppression, and prevents tumor clearance. Supplementary arginine similarly decreases Treg suppressive capacity, increases CD8+ T cell effectiveness, and reduces tumor burden. Thus, microbial consumption of arginine alters anti-tumor immunity, offering potential therapeutic strategies for tumors in visceral adipose tissue.

Activation of regulatory dendritic cells by Mertk coincides with a temporal wave of apoptosis in neonatal lungs.

Multiple mechanisms restrain inflammation in neonates, most likely to prevent tissue damage caused by overly robust immune responses against newly encountered pathogens. Here, we identify a population of pulmonary dendritic cells (DCs) that express intermediate levels of CD103 (CD103int) and appear in the lungs and lung-draining lymph nodes of mice between birth and 2 weeks of age. CD103int DCs express XCR1 and CD205 and require expression of the transcription factor BATF3 for development, suggesting that they belong to the cDC1 lineage. In addition, CD103int DCs express CCR7 constitutively and spontaneously migrate to the lung-draining lymph node, where they promote stromal cell maturation and lymph node expansion. CD103int DCs mature independently of microbial exposure and TRIF- or MyD88-dependent signaling and are transcriptionally related to efferocytic and tolerogenic DCs as well as mature, regulatory DCs. Correlating with this, CD103int DCs show limited ability to stimulate proliferation and IFN-γ production by CD8+ T cells. Moreover, CD103int DCs acquire apoptotic cells efficiently, in a process that is dependent on the expression of the TAM receptor, Mertk, which drives their homeostatic maturation. The appearance of CD103int DCs coincides with a temporal wave of apoptosis in developing lungs and explains, in part, dampened pulmonary immunity in neonatal mice. Together, these data suggest a mechanism by which DCs sense apoptotic cells at sites of noninflammatory tissue remodeling, such as tumors or the developing lungs, and limit local T cell responses.

Reversed windshield-wiper effect leads to failure of cement-augmented pedicle screw: Biomechanical mechanism analysis by finite element experiment.

The failure mode of cement-augmented pedicle screw (CAPS) was different from common pedicle screw. No biomechanical study of this failure mode named as "reversed windshield-wiper effect" was reported. To investigate the mechanisms underlying this failure mode, a series of finite element models of CAPS and PS were modified on L4 osseous model. Nine models were created according to the cement volume at 0.5 mL interval (range: 1-5 mL). Pullout load and cranio-caudal loads were applied on the screws. Stress and instantaneous rotation center (IRC) of the vertebra were observed. Under cranio-caudal load, the stress concentrated on the screw tip and pedicle region. The maximal stress (MS) at the screw tip region was +2.143 MPa higher than pedicle region. With cement volume increasing, the maximal stress (MS) at the screw tip region decreased dramatically, while MS at pedicle region was not obviously affected. As dose increased to 1.5 mL, the MS at pedicle region became higher than screw tip region and the maximal stress difference was observed at 3.5 mL. IRC of the vertebra located at the facet joint region in PS model. While IRC in CAPS models shifted anteriorly closer to the vertebral body with the increasing of cement volume. Under axial pull-out load, the maximal stress (MS) of cancellous bone in CAPS models was 29.53-50.04% lower than that 2.228 MPa in PS model. MS in the screw-bone interface did not change significantly with cement volume increasing. Therefore, the possible mechanism is that anterior shift of IRC and the negative difference value of MS between screw tip and pedicle region due to cement augmentation, leading to the screw rotate around the cement-screw complex as the fulcrum point.

Role of Posterior Longitudinal Ligament Complex in Spinal Deformity Secondary to Surgical Resection of the Intradural Tumor.

OBJECTIVE: In most cases, complete resection of the intradural tumor is accompanied by long-term neurological complications. Postoperative spinal deformity is the most common complication after surgical resection of intradural tumors, and posterior longitudinal ligament complex (PLC) plays an important role in postoperative spinal deformity. In this study, we investigated the role of PLC in spinal deformity after the surgical treatment of intradural tumors. METHODS: We analyzed the data of 218 consecutive patients who underwent intradural tumor resection from 2000 to 2018 in this retrospective study. Before 2010, patients underwent laminoplasty without maintaining the integrity of PLC (laminoplasty group, n = 155). After 2010, patients performed single-port laminoplasty to maintain the integrity of PLC (laminoplasty retain posterior ligament complex group, n = 63). The score of quality of life, painful cortex, spinal cord movement, progressive kyphosis or scoliosis, perioperative morbidity, and neurological results were analyzed in the laminoplasty group and laminoplasty retain posterior ligament complex group. The distributed variable was shown as mean ± standard deviation and an independent t-test or one-way analysis of variance was calculated. RESULTS: There are 155 patients (71.1%) included in the laminoplasty group, and 63 patients (28.9%) in the laminoplasty retain posterior ligament complex group. The average age of patients was 42 ± 2.3 years, and the average modified McCormick score was 2. There were 158 (72.4%) patients with intramedullary tumors and 115 (52.7%) patients with extramedullary tumors. The length of hospital stays (8 days vs. 6 days; p = 0.023) and discharge to inpatient rehabilitation (48.4% vs. 26.9%; p = 0.012) were significantly lower in the laminoplasty retain posterior ligament complex group than the laminoplasty group. There was no significant difference in the risk of progressive deformity between the two groups at 18 months after surgery (relative risk 0.12; 95% confidence interval [CI] 0.43-1.25; p = 0.258) and at 20 months after surgery (relative risk 0.24; 95% CI 0.21-2.1). CONCLUSION: Laminoplasty retains posterior ligament complex showed no impact on the spinal deformities compared with laminoplasty, but significantly improved the postoperative spinal activity, alleviated pain symptoms, and reduced hospital recovery time.

Circulating Tregs Accumulate in Omental Tumors and Acquire Adipose-Resident Features.

Tumors that metastasize in the peritoneal cavity typically end up in the omental adipose tissue, a particularly immune-suppressive environment that includes specialized adipose-resident regulatory T cells (Treg). Tregs rapidly accumulate in the omentum after tumor implantation and potently suppress antitumor immunity. However, it is unclear whether these Tregs are recruited from the circulation or derived from preexisting adipose-resident Tregs by clonal expansion. Here we show that Tregs in tumor-bearing omenta predominantly have thymus-derived characteristics. Moreover, naïve tumor antigen-specific CD4+ T cells fail to differentiate into Tregs in tumor-bearing omenta. In fact, Tregs derived from the pretumor repertoire are sufficient to suppress antitumor immunity and promote tumor growth. However, tumor implantation in the omentum does not promote Treg clonal expansion, but instead leads to increased clonal diversity. Parabiosis experiments show that despite tissue-resident (noncirculating) characteristics of omental Tregs in naïve mice, tumor implantation promotes a rapid influx of circulating Tregs, many of which come from the spleen. Finally, we show that newly recruited Tregs rapidly acquire characteristics of adipose-resident Tregs in tumor-bearing omenta. These data demonstrate that most Tregs in omental tumors are recruited from the circulation and adapt to their environment by altering their homing, transcriptional, and metabolic properties.

Outcomes in Thoracolumbar and Lumbar Traumatic Fractures: Does Restoration of Unfused Segmental Mobility Correlated to Implant Removal Time?

BACKGROUND: Posterior fixation without fusion can treat thoracolumbar and lumbar traumatic fractures effectively in certain cases. However, whether patients benefit from implant removal and the correlation between the range of motion (ROM) of the involved segments and the removal time have not been determined. METHODS: From 2018 to 2020, we retrospectively reviewed data of patients with AO spine type A or B thoracolumbar or lumbar traumatic fractures who underwent implant removal. A total of 17 patients (group A), 21 patients (group B), and 12 patients (group C) underwent implant removal after the index surgery within 12 months, between 12 and 24 months, and over 24 months, respectively. Clinical and radiological outcomes, including visual analog scale for back pain, patient satisfaction, Oswestry disability index, and EuroQol 5 dimensions questionnaire, for quality of life and segmental ROM were analyzed. RESULTS: The average follow-up time was 9.1 ± 5.7 months after implant removal. There were no significant differences in visual analog scale and patient satisfaction among the 3 groups at the same observation time point. Among the 3 groups, patients in group A gained the lowest Oswestry disability index and highest EuroQol 5 dimensions questionnaire scores after removal and at the final follow-up. The best ROM was obtained in group A followed by groups B and C (11.5° ± 6.2°, 5.5° ± 1.6°, and 2.4° ± 0.6°, respectively). CONCLUSIONS: Immobilization of the involved segments over 24 months may lead to loss of ROM. Regained segmental ROM is correlated negatively with implant removal time, and removal within 12 months promises a better ROM and quality of life.

Intraarticular bone grafting in atlantoaxial facet joints via a posterior approach: nonstructural or structural-a minimum 24-month follow-up.

OBJECTIVE: To investigate the necessity of nonstructural or structural intraarticular bone grafting in atlantoaxial facet joints via a posterior approach and the influence by the presence of basilar invagination (BI). METHODS: From November 2016 to October 2018, patients who underwent posterior atlantoaxial or occipitocervical arthrodesis surgery at one institute were retrospectively reviewed. Operation records, preoperative and postoperative clinical status, and radiological films were analyzed. RESULTS: Thirty-three patients (19 without BI, 14 with BI) underwent posterior facet joint release followed by intraarticular bone grafting were enrolled finally. Twenty-four nonstructural (15 without BI, 9 with BI) and 9 structural (4 without BI, 5 with BI) grafting were performed. The average follow-up was 32.15±6.73 months (24-47 months). Among them, 1 (3.03%) implant failure occurred, and 32 (96.97%) achieved satisfactory neurological outcomes, including 28 (84.85%) complete and 4 (12.12%) acceptable reductions with complete fusion within 6 months. For patients without BI, structural and nonstructural grafting showed no significant difference in terms of reduction maintenance (100% vs 73.33%, p = 0.530), while for those with BI, structural grafting significantly increased the postoperative height of the joint space (5.67±1.22 mm vs 3.43±1.78 mm, p = 0.002) and maintained it much better than nonstructural grafting (88.89% vs 20.00%, p = 0.023), contributing notably to BI correction. CONCLUSION: Intraarticular structural bone grafting in atlantoaxial facet joints has the advantage of maintaining anterior column height in the case of lateral mass collapse or when BI correction is needed; otherwise, nonstructural bone grafting is enough.

Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate.

TREX1 as a Novel Immunotherapeutic Target.

Mutations in the TREX1 3' → 5' exonuclease are associated with a spectrum of autoimmune disease phenotypes in humans and mice. Failure to degrade DNA activates the cGAS-STING DNA-sensing pathway signaling a type-I interferon (IFN) response that ultimately drives immune system activation. TREX1 and the cGAS-STING DNA-sensing pathway have also been implicated in the tumor microenvironment, where TREX1 is proposed to degrade tumor-derived DNA that would otherwise activate cGAS-STING. If tumor-derived DNA were not degraded, the cGAS-STING pathway would be activated to promote IFN-dependent antitumor immunity. Thus, we hypothesize TREX1 exonuclease inhibition as a novel immunotherapeutic strategy. We present data demonstrating antitumor immunity in the TREX1 D18N mouse model and discuss theory surrounding the best strategy for TREX1 inhibition. Potential complications of TREX1 inhibition as a therapeutic strategy are also discussed.

Biomechanical influence of the surgical approaches, implant length and density in stabilizing ankylosing spondylitis cervical spine fracture.

Ankylosing spondylitis cervical spine fractures (ASCFs) are particularly unstable and need special consideration when selecting appropriate internal fixation technology. However, there is a lack of related biomechanical studies. This study aimed to investigate the biomechanical influence of the pattern, length, and density of instrumentation for the treatment of ASCF. Posterior, anterior, and various combined fixation approaches were constructed using the finite element model (FEM) to mimic the surgical treatment of ASCFs at C5/6. The rate of motion change (RMC) at the fractured level and the internal stress distribution (ISD) were observed. The results showed that longer segments of fixation and combined fixation approaches provided better stability and lowered the maximal stress. The RMC decreased more significantly when the length increased from 1 to 3 levels (302% decrease under flexion, 134% decrease under extension) than from 3 to 5 levels (22% decrease under flexion, 23% decrease under extension). Longer fixation seems to be more stable with the anterior/posterior approach alone, but 3-level posterior fixation may be the most cost-effective option. It is recommended to perform surgery with combined approaches, which provide the best stability. Long skipped-screwing posterior fixation is an alternative technique for use in ASCF patients.

Specialized immune responses in the peritoneal cavity and omentum.

The peritoneal cavity is a fluid filled space that holds most of the abdominal organs, including the omentum, a visceral adipose tissue that contains milky spots or clusters of leukocytes that are organized similar to those in conventional lymphoid tissues. A unique assortment of leukocytes patrol the peritoneal cavity and migrate in and out of the milky spots, where they encounter Ags or pathogens from the peritoneal fluid and respond accordingly. The principal role of leukocytes in the peritoneal cavity is to preserve tissue homeostasis and secure tissue repair. However, when peritoneal homeostasis is disturbed by inflammation, infection, obesity, or tumor metastasis, specialized fibroblastic stromal cells and mesothelial cells in the omentum regulate the recruitment of peritoneal leukocytes and steer their activation in unique ways. In this review, the types of cells that reside in the peritoneal cavity, the role of the omentum in their maintenance and activation, and how these processes function in response to pathogens and malignancy will be discussed.

Transplantation of neural stem cells preconditioned with high­mobility group box 1 facilitates functional recovery after spinal cord injury in rats.

Spinal cord injury (SCI) is a devastating disorder that often results in temporary and/or permanent functional impairment below the injured level. To date, few satisfactory therapeutic strategies are available to treat SCI. Hence, exploring novel strategies for SCI is an essential public health concern. Cell transplantation therapy, which is associated with neuroprotection, immunomodulation, axon regeneration, neuronal relay formation and myelin regeneration, provides a promising therapeutic strategy for SCI. The neuronal stem cell (NSC) preconditioning method is an emerging approach, which facilitates NSC survival and neuronal differentiation after implantation. The aim of the present study was to develop a feasible candidate for cell­based therapy following SCI in rats and to investigate the role of high mobility group box­1 (HMGB1) in NSC activation. The results of the present study showed that transplantation of NSCs, preconditioned with 1 ng/ml HMGB1, facilitated functional improvement of injured spinal cords, as indicated by Basso, Beattie and Bresnahan mean scores, mechanical hypersensitivity and cold stimulation. Meanwhile, the histological examination of hematoxylin and eosin staining indicated that engraftment of HMGB1­preconditioned NSCs resulted in decreased atrophy of the injured spinal cord. Meanwhile, the transplantation of HMGB1­preconditioned NSCs resulted in an increased number of functional Nissl bodies in neurons, as detected by Nissl staining, and an increase in the number of ßIII­tubulin+ cells in the epicenter of injured spinal cords in rats with SCI. In addition, the results also demonstrated that 1 ng/ml HMGB1 promoted the differentiation of NSCs into neurons, and that the ERK signaling pathway played an important role in this process. In conclusion, the present data indicated that the preconditioning strategy with 1 ng/ml HMGB1 may present a feasible candidate for cell­based therapy following SCI in rats, which may enlarge the scope of HMGB1 in NSC activation.

Single-dose intranasal administration of AdCOVID elicits systemic and mucosal immunity against SARS-CoV-2 in mice.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective preventive vaccination to reduce burden and spread of severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) in humans. Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry before viral spread to the lung. Although SARS-CoV-2 vaccine development is rapidly progressing, the current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity. Here, we show that AdCOVID, an intranasal adenovirus type 5 (Ad5)-vectored vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, elicits a strong and focused immune response against RBD through the induction of mucosal IgA, serum neutralizing antibodies and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. Therefore, AdCOVID, which promotes concomitant systemic and local mucosal immunity, represents a promising COVID-19 vaccine candidate.

Comparison of unilateral and bilateral polymethylmethacrylate-augmented cannulated pedicle screw fixation for the management of lumbar spondylolisthesis with osteoporosis.

BACKGROUND: Cannulated pedicle screw (CPS) augmented by polymethylmethacrylate (PMMA) can achieve satisfactory clinical efficacy in the treatment of lumbar spondylolisthesis with osteoporosis. However, accurate application of CPSs will help to avoid the difficulty of screw revision and reduce the incidence of PMMA-related complications. This study aimed to investigate the mid-term efficacy of CPS compared to unilateral and bilateral applications in this common lumbar degenerative disease. METHODS: May 2011 and May 2018, 50 patients with lumbar spondylolisthesis with osteoporosis who underwent posterior fixation and fusion using traditional pedicle screws or CPSs were included in the study. Patients were divided into two groups based on the application: the unilateral PMMA-augmented CPS group (UC, n = 29) and the bilateral PMMA-augmented CPS group (BC, n = 21). Operation time, blood loss, average hospitalization time, PMMA leakage, and other complications were recorded. The visual analog scale (VAS) and Oswestry disability index (ODI) scores were used to evaluate symptom recovery. Radiographic results were compared for intervertebral fusion and screw loosening. RESULTS: There were no significant differences in the baseline data of the two groups. The VAS and ODI scores improved significantly after surgery (P < 0.05), with no significant differences between the groups (P > 0.05). The operation time and blood loss in the UC group were significantly lower than those in the BC group (P < 0.05). However, the loss of intervertebral disk height and Taillard index did not differ significantly between the groups. The rates of PMMA leakage in the UC and BC groups were 7.0% and 11.9%, respectively (P < 0.05). Bony fusion was achieved in all groups without screw loosening at the last follow-up. Only one patient experienced superficial infection in both groups, while cerebrospinal fluid leakage was observed in two patients in the BC group. CONCLUSIONS: Unilateral application of PMMA-augmented CPS may provide adequate clinical safety and effectiveness in the surgical treatment of lumbar spondylolisthesis with osteoporosis.

Posterolateral fusion combined with posterior decompression shows superiority in the treatment of severe lumbar spinal stenosis without lumbar disc protrusion or prolapse: a retrospective cohort study.

BACKGROUND: Currently, discectomy and posterior decompression combined with lumbar circumferential fusion (CF) have been accepted as a major procedure for severe lumbar spinal stenosis (LSS). However, studies on severe LSS without protruded intervertebral disc to minimize study bias are lacking. We aimed to investigate the effectiveness of sole posterior decompression with lumbar posterolateral fusion (PLF) and the necessity of discectomy and CF in patients with severe LSS without lumbar disc protrusion or prolapse. METHODS: This retrospective cohort study included 153 severe LSS patients without lumbar disc protrusion or prolapse who were admitted in a tertiary spine center with at least a 2-year follow-up between January 2014 and August 2017. Patients were divided into the PLF (n = 77; those who underwent posterior decompression with PLF in 1-3 segments) or CF (n = 76; those who underwent posterior decompression and discectomy with CF in 1-3 segments) groups. Pedicle screw instrumentation was applied to avoid postoperative instability. Clinical outcomes were assessed by visual analog scale (VAS), Oswestry Disability Index (ODI), and Japanese Orthopedic Association Score (JOA, lumbar pain score). Duration of operation, blood loss, surgical cost, and postoperative complications were analyzed. Height of intervertebral space, lumbar lordosis, and bone union were confirmed by lumbar radiography or computed tomography. RESULTS: Both groups achieved significant improvement in JOA, ODI, and VAS compared with preoperative values (P < 0.001), but without significant difference between the two groups. Both groups achieved high fusion rate without difference and correction of lumbar lordosis and intervertebral space height (P < 0.001), especially in the CF group (P < 0.05). Duration of operation, blood loss, and operation cost were significantly higher in the CF group than in the PLF group (P < 0.001). Eight complications were found in both groups (1, PLF group; 7, CF group; P < 0.05). CONCLUSIONS: After posterior decompression, PLF successfully achieves bony fusion and symptom relief with lower complication rate, lesser surgical blood loss, shorter operative time, and lesser cost than CF. Thus, sole posterior decompression with PLF is an effective treatment for severe LSS without lumbar disc protrusion or prolapse.

Histone deacetylase inhibition promotes intratumoral CD8+ T-cell responses, sensitizing murine breast tumors to anti-PD1.

Histone deacetylase (HDAC) inhibitors impair tumor cell proliferation and alter gene expression. However, the impact of these changes on anti-tumor immunity is poorly understood. Here, we showed that the class I HDAC inhibitor, entinostat (ENT), promoted the expression of immune-modulatory molecules, including MHCII, costimulatory ligands, and chemokines on murine breast tumor cells in vitro and in vivo. ENT also impaired tumor growth in vivo-an effect that was dependent on both CD8+ T cells and IFNγ. Moreover, ENT promoted intratumoral T-cell clonal expansion and enhanced their functional activity. Importantly, ENT sensitized normally unresponsive tumors to the effects of PD1 blockade, predominantly through increases in T-cell proliferation. Our findings suggest that class I HDAC inhibitors impair tumor growth by enhancing the proliferative and functional capacity of CD8+ T cells and by sensitizing tumor cells to T-cell recognition.

Imbalanced development of anterior and posterior thorax is a causative factor triggering scoliosis.

OBJECTIVE: Scoliosis is a common disease characterized by spinal curvature with variable severities. There is no generally accepted theory about the physical origin of the spinal deformation of scoliosis. The aim of this study was to explore a new hypothesis suggesting that the curvatures in scoliosis may be associated with the imbalance growth between thoracic vertebral column and sternum. METHODS: We undertook a comparative computed tomography (CT) based morphology study of thoracic vertebrae and sternum of patients with adolescent idiopathic scoliosis (AIS) and age-gender matched normal subjects. We further measured the ratios between the lengths of the sternum and thoracic vertebra of mice with deficiency of fibroblast growth factor receptor 3 (FGFR3), which exhibit scoliosis. Three-week-old C57BL/6J mice were used to generate bipedal and sternal growth plate injury model. Radiographs and histological images were obtained to observe the presence of sternal and spinal deformity. RESULTS: There was a significant correlation between the severities of scoliosis and the ratios of the sternum to thoracic vertebral lengths. We also found that FGFR3 deficient mice showed smaller ratio of the sternum to thoracic vertebra lengths than that of the wild-type mice, which were similar with that of the AIS patients. Surgery-induced injuries of sternal growth plates can accelerate and aggravate the scoliosis in bipedal mice and imbalanced development of anterior and posterior thoracic occurred before the appearance of scoliosis. CONCLUSIONS: Our findings suggest that the imbalanced growth between the thoracic vertebral column and the sternum is an important causative factor for the pathogenesis of scoliosis including AIS. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Imbalanced growth between the thoracic vertebral column and the sternum is associated with scoliosis. Surgical or rehabilitation intervention for scoliosis should focus on all components involved in the pathogenesis of curvature to obtain better outcome.

"Rule of Spence" and Dickman's Classification of Transverse Atlantal Ligament Injury Revisited: Discrepancy of Prediction on Atlantoaxial Stability Based on Clinical Outcome of Nonoperative Treatment for Atlas Fractures.

Detailed clinical information of 13 adult patients with acute atlantal fractures underwent nonoperative treatment was retrospectively studied. "Rule of Spence" was found inaccurate in predicting either integrity of transverse atlantal ligament (TAL) or atlantoaxial stability, whereas Dickman's classification of TAL injury was more superior to "rule of Spence" on both prediction. STUDY DESIGN: A retrospective study. OBJECTIVE: To evaluate the prediction accuracy of "Rule of Spence" and Dickman's classification of the transverse atlantal ligament (TAL) injury on clinical outcomes (mainly focused on atlantoaxial stability) of atlas fractures treated nonoperatively. SUMMARY OF BACKGROUND DATA: TAL is regarded as primary stabilizer of the atlantoaxial complex. Atlas fractures are categorized as unstable and stable according to TAL injury or not. "Rule of Spence" and Dickman's classification have been widely used to evaluate the integrity of TAL indirectly or directly. However, there is controversy about how to interpret and apply these image measures appropriately in treatment decision making, and comparing the two measures in same cohort has been lack. METHODS: From January 2013 to December 2015, 13 adult patients with atlas fractures, treated nonoperatively at acute posttraumatic phase and followed up for at least 2 years, were enrolled in the study. Lateral mass offset (LMO) and TAL injury were measured by radiography. Atlantoaxial stability, pain in occipital region, limitation of cervical motion, neurological dysfunction, and quality of daily life were evaluated as clinical outcomes. RESULTS: LMO less than 6.9 mm was inaccurate either to exclud TAL injury (4/8, 50% failed) or to predict clinical outcomes (2/8, 25% failed), whereas LMO greater than 6.9 mm was accurate to determine TAL injury (5/5, 100% succeeded) but not to predict atlantoaxial stability (4/5, 80% failed). Two cases with Dickman's classification type I injury (100%) failed to restore C1-2 stability and six of seven type II (85.7%) succeeded. Three patients were indicated for fusion surgery due to instability, and one due to traumatic arthritis. Overall clinical outcomes were satisfactory as pain and quality of life were considered. CONCLUSION: Dickman's classification of TAL injury is of higher superiority to "Rule of Spence" in term of the accuracy of predicting atlantoaxial stability of nonoperatively treated atlas fractures. LEVEL OF EVIDENCE: 4.

A retrospective study. To evaluate the prediction accuracy of "Rule of Spence" and Dickman's classification of the transverse atlantal ligament (TAL) injury on clinical outcomes (mainly focused on atlantoaxial stability) of atlas fractures treated nonoperatively. TAL is regarded as primary stabilizer of the atlantoaxial complex. Atlas fractures are categorized as unstable and stable according to TAL injury or not. "Rule of Spence" and Dickman's classification have been widely used to evaluate the integrity of TAL indirectly or directly. However, there is controversy about how to interpret and apply these image measures appropriately in treatment decision making, and comparing the two measures in same cohort has been lack. From January 2013 to December 2015, 13 adult patients with atlas fractures, treated nonoperatively at acute posttraumatic phase and followed up for at least 2 years, were enrolled in the study. Lateral mass offset (LMO) and TAL injury were measured by radiography. Atlantoaxial stability, pain in occipital region, limitation of cervical motion, neurological dysfunction, and quality of daily life were evaluated as clinical outcomes. LMO less than 6.9 mm was inaccurate either to exclud TAL injury (4/8, 50% failed) or to predict clinical outcomes (2/8, 25% failed), whereas LMO greater than 6.9 mm was accurate to determine TAL injury (5/5, 100% succeeded) but not to predict atlantoaxial stability (4/5, 80% failed). Two cases with Dickman's classification type I injury (100%) failed to restore C1-2 stability and six of seven type II (85.7%) succeeded. Three patients were indicated for fusion surgery due to instability, and one due to traumatic arthritis. Overall clinical outcomes were satisfactory as pain and quality of life were considered. Dickman's classification of TAL injury is of higher superiority to "Rule of Spence" in term of the accuracy of predicting atlantoaxial stability of nonoperatively treated atlas fractures. Level of Evidence: 4.

The expression of MHC class II molecules on murine breast tumors delays T-cell exhaustion, expands the T-cell repertoire, and slows tumor growth.

The expression of MHC class II molecules (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we showed that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4+ and CD8+ T cells. In addition, MHCII-expressing tumors contained more TCR clonotypes expanded to a larger degree than control tumors. Functional CD8+ T cells in tumors depended on CD4+ T cells. However, both CD4+ and CD8+ T cells eventually became exhausted, even in MHCII-expressing tumors. Treatment with anti-CTLA4, but not anti-PD-1 or anti-TIM-3, promoted complete eradication of MHCII-expressing tumors. These results suggest tumor cell expression of MHCII facilitates the local activation of CD4+ T cells, indirectly helps the activation and expansion of CD8+ T cells, and, in combination with the appropriate checkpoint inhibitor, promotes tumor regression.

Human Serum Albumin-Delivered [Au(PEt3)]+ Is a Potent Inhibitor of T Cell Proliferation.

Using a modular library format in conjunction with cell viability (MTS) and flow cytometry assays, 90 cationic complexes [AuPL] n+ (P = phosphine ligand; L = thiourea derivative or chloride) were studied for their antiproliferative activity in CD8+ T lymphocyte cells. The activity of the compounds correlates with the steric bulk of the phosphine ligands. Thiourea serves as a leaving group that is readily replaced by cysteine thiol (NMR, ESI-MS). Taking advantage of selective thiourea ligand exchange, the fragments [Au(PEt3)]+ and [Au(JohnPhos)]+ (JohnPhos = 1,1'-biphenyl-2-yl)di-tert-butylphosphine) in compounds 1 and 2 were transferred to recombinant human serum albumin (rHSA). PEt3 promoted efficient modification of Cys34 in HSA (HSA-1), whereas use of bulky JohnPhos as a carrier ligand led to serum protein nonspecifically modified with multiple gold adducts (HSA-2) (Ellman's test, ESI-TOF MS). HSA-1, but not HSA-2, strongly inhibits T cell proliferation at nanomolar doses. The potential role of HSA as a delivery vehicle in gold-based autoimmune disease treatment is discussed.