Clinical impact of proximal fixation augmentation using the Najuta thoracic fenestrated stent graft during endovascular treatment for distal aortic arch aneurysm.

OBJECTIVE: Prevention of late type Ia endoleaks is the main concern in thoracic endovascular aortic aneurysm repair (TEVAR) for thoracic aortic aneurysm. Since 2017, we have performed zone 0 TEVAR with proximal fixation augmentation using a Najuta thoracic fenestrated stent graft in addition to zone 2 TEVAR for distal arch aneurysms. We report the early and midterm outcomes of TEVAR performed using this strategy. METHODS: This single-center retrospective study enrolled 386 cases of TEVAR for thoracic aortic disease between January 2013 and December 2020. Patients with thoracic aortic aneurysm treated by TEVAR landing at zone 2 was referred to as the standard group, whereas those treated by TEVAR landing at zone 0 using a Najuta fenestrated stent graft in addition to zone 2 TEVAR was referred to as the augmentation group. We retrospectively compared the clinical outcomes between the two groups. The primary end point was secondary intervention for postoperative type Ia endoleaks. Secondary end points were technical success, aneurysm-related death, and major adverse events (MAEs), including stroke, paraplegia, endoleaks, and secondary interventions. RESULTS: We performed TEVAR in 41 and 30 cases in the standard and augmentation groups, respectively. The mean aneurysm sizes in the standard and augmentation groups were 54.5 and 57.3 mm (P = .23), and the proximal neck lengths were 16.8 and 17.4 mm (P = .65), respectively. The anatomical characteristics seemed to be similar in both groups. The technical success rate in both groups was 100%. Three cases in the standard group had MAEs, including two stroke and one brachial artery pseudoaneurysm; whereas two cases had MAEs in the augmentation group, including one stroke and one paraplegia. There was no 30-day mortality or retrograde type A dissection in both groups. The mean observation periods in the standard and augmentation groups were 46 months (range, 1-123 months) and 35 months (range, 1-73 months), respectively. At 36 and 60 months after the procedure, the freedom from aneurysm-related death was 97.6% and 97.6% in the standard group, 100.0% and 100.0% in the augmentation group (P = .39); and the freedom from reintervention for type Ia endoleaks was 79.2% and 65.2% in the standard group, 100.0% and 100.0% in the augmentation group (P = .0087). A statistically significant decrease in reinterventions for type Ia endoleaks was observed in the augmentation group. CONCLUSIONS: Proximal fixation augmentation using the Najuta fenestrated stent graft during TEVAR for distal arch aneurysm is effective in preventing the postoperative late type Ia endoleaks.

Characterization of tumoricidal activities mediated by a novel immune cell regimen composing interferon-producing killer dendritic cells and tumor-specific cytotoxic T lymphocytes.

BACKGROUND: Although immune cell therapy has long been used for treating solid cancer, its efficacy remains limited. Interferon (IFN)-producing killer dendritic cells (IKDCs) exhibit cytotoxicity and present antigens to relevant cells; thus, they can selectively induce tumor-associated antigen (TAA)-specific CD8 T cells and may be useful in cancer treatment. Various protocols have been used to amplify human IKDCs from peripheral sources, but the complexity of the process has prevented their widespread clinical application. Additionally, the induction of TAA-specific CD8 T cells through the adoptive transfer of IKDCs to immunocompromised patients with cancer may be insufficient. Therefore, we developed a method for generating an immune cell-based regimen, Phyduxon-T, comprising a human IKDC counterpart (Phyduxon) and expanded TAA-specific CD8 T cells. METHODS: Peripheral blood mononuclear cells from ovarian cancer patients were cultured with human interleukin (hIL)-15, hIL-12, and hIL-18 to generate Phyduxon-T. Then, its phenotype, cytotoxicity, and antigen-presenting function were evaluated through flow cytometry using specific monoclonal antibodies. RESULTS: Phyduxon exhibited the characteristics of both natural killer and dendritic cells. This regimen also exhibited cytotoxicity against primary ovarian cancer cells and presented TAAs, thereby inducing TAA-specific CD8 T cells, as evidenced by the expression of 4-1BB and IFN-γ. Notably, the Phyduxon-T manufacturing protocol effectively expanded IFN-γ-producing 4-1BB+ TAA-specific CD8 T cells from peripheral sources; these cells exhibited cytotoxic activities against ovarian cancer cells. CONCLUSIONS: Phyduxon-T, which is a combination of natural killer cells, dendritic cells, and TAA-specific CD8 T cells, may enhance the efficacy of cancer immunotherapy.

Effect of body mass index on acute postoperative complications following Total Ankle Arthroplasty (TAA).

BACKGROUND: Total ankle arthroplasty (TAA) is an effective treatment for various ankle pathologies, but some concern remains for the high associated complication and failure rates relative to major joint arthroplasty of the hip and knee. Patient body mass index (BMI) is a modifiable and potentially important preoperative variable when evaluating postoperative complications. The purpose of this study is to evaluate the effect of BMI, age and sex on the acute postoperative complication rate after TAA. METHODS: We retrospectively reviewed adult patients who underwent TAA between 2006 and 2021 from the NSQIP database. Using overweight patients as the reference BMI group, we utilized log-binomial models to estimate risk ratios on outcomes while adjusting for sex and age to investigate whether there were significant adjusted differences in complication rates among the BMI groups. RESULTS: We found that, relative to overweight patients, there were no statistically significant differences in the risk of acute complications for underweight (BMI < 18.5) (P = .118), healthy weight (18.5≤BMI < 25) (P = .544), obese (30≤BMI < 40) (P = .930), or morbidly obese (BMI < 40) (P = .602) patients who underwent TAA. There were also no statistically significant differences in the risk of acute complications based on age category (P = .482,.824) or sex (P = .440) for TAA. Additionally, there were no significant differences between the BMI groups for either major complications (P = .980) or minor complications (P = .168). CONCLUSION: Ultimately, we found that BMI, age, and sex did not lead to statistically significant differences in the risk of complications within 30 days postoperatively for TAA, even when stratified by major vs minor complications. LEVEL OF EVIDENCE: Level III.

A comparison of thoracoabdominal aortic aneurysms open repair in patients with or without "shaggy aorta".

OBJECTIVE: In the field of thoracoabdominal aortic aneurysm (TAAA) open surgical repair (OSR), some preoperative characteristics are established risk factors for adverse outcomes, whereas others are supposed to be relevant, but their role still need to be defined; among them, the presence of "shaggy aorta" (SA), an extensive and irregular atheroma within the aorta. The aim of this study is to report the results of a single-center large cohort of patients treated with OSR for TAAA with SA, comparing the outcomes with patients affected by TAAA without SA, and analyzing the impact of the scores for SA on the outcomes. METHODS: All consecutive patients receiving OSR for TAAA between 2012 and 2021 were retrospectively analyzed. Clinical data from patients with degenerative TAAA were included and analyzed for preoperative characteristics and postoperative outcomes; patients with ruptured TAAA, and patients with aortic dissection were excluded from the analysis. Patients with degenerative aortic aneurysm, thrombus measurement in non-aneurysmal aortic segments (≤40 mm), atheroma thickness ≥5 mm, and finger-like thrombus projection were included in the SA group, whereas the others were included in the non-shaggy aorta group (NSA group). The SA group and NSA group were compared using a propensity-matched comparison. Preoperative computed tomography scans of patients in the SA group were also stratified according to SA grading scores. RESULTS: A total of 58 patients with SA were identified (male, n = 43 [74.1%], mean age 70.1 ± 7.8 years) among 497 patients with TAAA treated with open surgical repair. After propensity matching, there were 57 patients in the SA group and 57 in the NSA group with correction of all differences in baseline characteristics. Patients in the SA group presented significantly higher in-hospital mortality (SA group, 14.0% vs NSA group, 3.5%; P = .047), postoperative acute renal failure (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease [RIFLE], 3-5) (SA group, 21.1% vs NSA group, 5.3%; P = .013), and postoperative embolization (SA group, 28.1% vs NSA group, 8.8%; P = .008). Spinal cord ischemia and stroke rate were not significantly influenced by the presence of SA. In the SA group, 16 patients (27.6%) with end-organ embolization were compared with 42 patients (72.4%) without a documented embolization considering the grade of aortic "shagginess" and no significant difference was identified (P = .546). CONCLUSIONS: Despite a better knowledge of the SA disease, new classifications, and intraoperative adjuncts, TAAA patients with SA treated with OSR have worse postoperative outcomes if compared with patients without SA. The presence of SA is a risk factor itself, whereas the grade of "shagginess" seems not to impact on postoperative outcomes.

Tissue and plasma proteomic profiling indicates AHSG as a potential biomarker for ascending thoracic aortic aneurysms.

BACKGROUND: Thoracic Aortic Aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threatening vascular disorder due to the risk of aortic dissection and rupture. There is an urgent need to identify blood-borne biomarkers for the early detection of TAA. The goal of the present study was to identify potential protein biomarkers associated with TAAs, using proteomic analysis of aortic tissue and plasma samples. METHODS: Extracted proteins from 14 aneurysmal and 12 non-aneurysmal thoracic aortic tissue specimens as well as plasma samples from six TAA patients collected pre-and postoperatively and six healthy controls (HC), were analyzed by liquid chromatography-tandem mass spectrometry. Proteomic data were further processed and following filtering criteria, one protein was selected for verification and validation in a larger cohort of patients and controls using a targeted quantitative proteomic approach and enzyme-linked immunosorbent assay, respectively. RESULTS: A total of 1593 and 363 differentially expressed proteins were identified in tissue and plasma samples, respectively. Pathway enrichment analysis on the differentially expressed proteins revealed a number of dysregulated molecular pathways that might be implicated in aneurysm pathology including complement and coagulation cascades, focal adhesion, and extracellular matrix receptor interaction pathways. Alpha-2-HS glycoprotein (AHSG) was selected for further verification in 36 TAA and 21 HC plasma samples using targeted quantitative proteomic approach. The results showed a significantly decreased concentration of AHSG (p = 0.0002) in the preoperative plasma samples compared with HC samples. Further analyses using a larger validation dataset revealed that AHSG protein levels were significantly lower (p = 0.03) compared with HC. Logistic regression analysis on the validation dataset revealed males, advanced age, hypertension and hyperlipidaemia as significant risk factors for TAA. CONCLUSION: AHSG concentrations distinguish plasma samples derived from TAA patients and controls. The findings of this study suggest that AHSG may be a potential biomarker for TAA that could lead to better diagnostic capabilities.

Auxin Involvement in Ceratopteris Gametophyte Meristem Regeneration.

Growth and development of the Ceratopteris hermaphroditic gametophytes are dependent on cell proliferation in the marginal meristem, which when destroyed will regenerate at a new location on the body margin. We established a laser ablation method to destroy a single initial cell in the meristem. Ablation caused the cessation of cell proliferation accompanied by the disappearance of the expression of an auxin synthesis gene (CrTAA2) and a cell proliferation marker gene (CrWOXB). New meristem regeneration occurred within a predictable distance from the original two days post-ablation, signified by cell proliferation and the expression of CrTAA2. Treatment with the naturally occurring auxin indole-3-acetic acid (IAA), synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D), or the transport inhibitor naphthylphthalamic acid (NPA) altered positioning of the original marginal meristem toward the apex of the gametophyte. IAA altered positioning of the regenerated meristem after damaging the original meristem. A model of auxin involvement in the positioning of the marginal meristem in Ceratopteris is presented to encompass these results.

Hepatoprotective Effects of Biochanin A on Thioacetamide-Induced Liver Cirrhosis in Experimental Rats.

The protective effect of biochanin A (BCA) on the histopathology, immunohistochemistry, and biochemistry of thioacetamide (TAA)-induced liver cirrhosis in vivo was investigated. There was a significant reduction in liver weight and hepatocyte propagation, with much lower cell injury in rat groups treated with BCA (25 mg/kg and 50 mg/kg) following a TAA induction. These groups had significantly lower levels of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA). The liver homogenates showed increased antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as decreased malondialdehyde (MDA) levels. The serum biomarkers associated with liver function, namely alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transaminase (GGT), returned to normal levels, comparable to those observed in both the normal control group and the reference control group. Taken together, the normal microanatomy of hepatocytes, the inhibition of PCNA and α-SMA, improved antioxidant enzymes (SOD, CAT, and GPx), and condensed MDA with repairs of liver biomarkers validated BCA's hepatoprotective effect.

Ankle Arthroplasty-Does Preoperative Fixed Equinus Affect Patient-Reported Outcomes.

Postoperative sagittal range of motion, in particular degree of dorsiflexion, is critical for satisfactory outcomes in total ankle arthroplasty (TAA). Although there is literature discussing techniques to treat a preoperative fixed equinus we are not aware of any papers presenting patient outcomes. We present patient-reported outcomes for our cohort of patients undergoing TAA with preoperative fixed equinus compared to plantigrade ankles. This is a single surgeon, cohort study of consecutive cases. Cases of primary TAA were identified from a local joint registry which prospectively records Foot and Ankle Outcome Scores (FAOS), Short Form-36 (SF-36), and patient satisfaction. Revision cases or those with inadequate data were excluded. Patients were classified as fixed equinus or neutral based on both preoperative weightbearing lateral radiographs and clinical records. Overall 259 cases were identified, 92 were excluded leaving 167 cases for analysis (mean follow-up 81.7 months), 147 were classified as neutral and 20 fixed equinus. The fixed equinus group were significantly younger (neutral 63.9 vs equinus 52.9, p < .001). Stiffness was the only FAOS domain that was detectibly different at baseline (neutral 36.6 vs equinus 25.6, p = .044). Final FAOS scores, change from baseline and patient satisfaction was the same in all domains for both groups. There was no difference in revision rates. With the numbers available we did not demonstrate a postoperative difference in outcomes for patients with preoperative fixed equinus.

Tumour-associated antigenic peptides are present in the HLA class I ligandome of cancer cell line derived extracellular vesicles.

The recent success of monoclonal antibody checkpoint inhibitor therapies that enhance the ability of CD8+ T cells to detect cancer-related antigenic peptides has refocused the need to fully understand the repertoire of peptides being presented to the immune system. Whilst the peptide ligandome presented by cell surface human leucocyte antigen class I (HLA-I) molecules on cancer cells has been studied extensively, the ligandome of extracellular vesicles (EVs) remains poorly defined. Here, we report the HLA-I ligandome of both the cell surface and EVs from eight breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-361, MDA-MB-415, MDA-MB-453, HCC 1806, HCC 1395, and HCC 1954), and additionally the melanoma cell line ESTDAB-056 and the multiple myeloma line RPMI 8226. Utilizing HLA-I immunoisolation and mass spectrometry, we detected a total of 6574 peptides from the cell surface and 2461 peptides from the EVs of the cell lines studied. Within the EV HLA-I ligandome, we identified 150 peptides derived from tumour associated antigenic proteins, of which 19 peptides have been shown to elicit T-cell responses in previous studies. Our data thus show the prevalence of clinically relevant tumour-associated antigenic peptides in the HLA-I ligandome presented on EV.

The Transcription Factors TaTDRL and TaMYB103 Synergistically Activate the Expression of TAA1a in Wheat, Which Positively Regulates the Development of Microspore in Arabidopsis.

Pollen fertility plays an important role in the application of heterosis in wheat (Triticum aestivum L.). However, the key genes and mechanisms underlying pollen abortion in K-type male sterility remain unclear. TAA1a is an essential gene for pollen development in wheat. Here, we explored the mechanism involved in its transcriptional regulation during pollen development, focusing on a 1315-bp promoter region. Several cis-acting elements were identified in the TAA1a promoter, including binding motifs for Arabidopsis thaliana AtAMS and AtMYB103 (CANNTG and CCAACC, respectively). Evolutionary analysis indicated that TaTDRL and TaMYB103 were the T. aestivum homologs of AtAMS and AtMYB103, respectively, and encoded nucleus-localized transcription factors containing 557 and 352 amino acids, respectively. TaTDRL and TaMYB103 were specifically expressed in wheat anthers, and their expression levels were highest in the early uninucleate stage; this expression pattern was consistent with that of TAA1a. Meanwhile, we found that TaTDRL and TaMYB03 directly interacted, as evidenced by yeast two-hybrid and bimolecular fluorescence complementation assays, while yeast one-hybrid and dual-luciferase assays revealed that both TaTDRL and TaMYB103 could bind the TAA1a promoter and synergistically increase its transcriptional activity. Furthermore, TaTDRL-EAR and TaMYB103-EAR transgenic Arabidopsis plants displayed abnormal microspore morphology, reduced pollen viability, and lowered seed setting rates. Additionally, the expression of AtMS2, a TAA1a homolog, was significantly lower in the two repressor lines than in the corresponding overexpression lines or WT plants. In summary, we identified a potential transcriptional regulatory mechanism associated with wheat pollen development.

Attenuation of Smooth Muscle Cell Phenotypic Switching by Angiotensin 1-7 Protects against Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) involves extracellular matrix (ECM) remodeling of the aortic wall, leading to reduced biomechanical support with risk of aortic dissection and rupture. Activation of the renin-angiotensin system, and resultant angiotensin (Ang) II synthesis, is critically involved in the onset and progression of TAA. The current study investigated the effects of angiotensin (Ang) 1-7 on a murine model of TAA. Male 8-10-week-old ApoEKO mice were infused with Ang II (1.44 mg/kg/day) and treated with Ang 1-7 (0.576 mg/kg/day). ApoEKO mice developed advanced TAA in response to four weeks of Ang II infusion. Echocardiographic and histological analyses demonstrated increased aortic dilatation, excessive structural remodelling, perivascular fibrosis, and inflammation in the thoracic aorta. Ang 1-7 infusion led to attenuation of pathological phenotypic alterations associated with Ang II-induced TAA. Smooth muscle cells (SMCs) isolated from adult murine thoracic aorta exhibited excessive mitochondrial fission, oxidative stress, and hyperproliferation in response to Ang II. Treatment with Ang 1-7 resulted in inhibition of mitochondrial fragmentation, ROS generation, and hyperproliferation. Gene expression profiling used for characterization of the contractile and synthetic phenotypes of thoracic aortic SMCs revealed preservation of the contractile phenotype with Ang 1-7 treatment. In conclusion, Ang 1-7 prevented Ang II-induced vascular remodeling and the development of TAA. Enhancing Ang 1-7 actions may provide a novel therapeutic strategy to prevent or delay the progression of TAA.

Recruiting Immunity for the Fight against Colorectal Cancer: Current Status and Challenges.

Cancer immunotherapies have changed the landscape of cancer management and improved the standard treatment protocols used in multiple tumors. This has led to significant improvements in progression-free survival and overall survival rates. In this review article, we provide an insight into the major immunotherapeutic methods that are currently under investigation for colorectal cancer (CRC) and their clinical implementations. We emphasize therapies that are based on monoclonal antibodies (mAbs) and adoptive cell therapy, their mechanisms of action, their advantages, and their potential in combination therapy. We also highlight the clinical trials that have demonstrated both the therapeutic efficacy and the toxicities associated with each method. In addition, we summarize emerging targets that are now being evaluated as potential interventions for CRC. Finally, we discuss current challenges and future direction for the cancer immunotherapy field.

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy.

An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as "concomitant immunity" suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

Quality Assessment of Modern Total Ankle Arthroplasty Clinical Outcomes Research.

Research demonstrating improved outcomes with third-generation ankle replacement implants has resulted in increasing utilization of total ankle arthroplasty over the past 3 decades. The purpose of this study was to examine the quality and trends of clinical outcomes research being published on third-generation total ankle arthroplasty implants. Two fellowship-trained foot and ankle surgeons reviewed all peer-reviewed, Medline-indexed English-language clinical outcomes studies evaluating total ankle arthroplasty published between 2006 and 2019. Articles were assessed for study design and indicators of study quality. A total of 694 published articles were reviewed and 231 met all inclusion criteria. The majority (78%) of studies were retrospective, most of which were case series (54%) or cohorts (32%). Ten percent (10%) of studies were funded by industry and 28% did not disclose funding sources. Thirty-eight percent (38%) of studies reported a conflict of interest and 6% did not disclose whether or not there were conflicts. The average patient follow-up time across studies was 72 months. We found that although the study of outcomes with third-generation total ankle arthroplasty prostheses is steadily increasing, most studies are Level IV, retrospective case series. Some studies have disclosed industry funding and/or a conflict of interest, and a considerable number did not disclose potential funding and/or financial conflicts. Future investigators should strive to design studies with the highest quality methodology possible.

Low-density vulnerable thrombus/plaque volume on preoperative computed tomography predicts for spinal cord ischemia after endovascular repair for thoracic aortic aneurysm.

BACKGROUND: Similar to open surgical repair, thoracic endovascular aortic repair (TEVAR) carries a risk of spinal cord ischemia (SCI). However, the generally lower incidence of SCI after TEVAR compared with that after open surgical repair, despite the inability to preserve the intercostal arteries, indicates different pathophysiologic mechanisms with the two procedures. We hypothesized that a microembolism from an aortic mural thrombus is the main cause of SCI. Thus, we evaluated the association between the density of a mural thrombus in the descending thoracic aorta and the development of SCI. METHODS: A retrospective review of a prospectively assembled database was performed for all patients who had undergone surgery at a single institution from October 2008 to December 2018. Patient demographics and procedure-related variables were collected. The volume and Hounsfield unit (HU) value of mural thrombi in the whole descending thoracic aorta were estimated on preoperative computed tomography using a three-dimensional workstation. Logistic regression analysis was performed to identify the risk factors for SCI development. RESULTS: Of the 367 patients who had undergone TEVAR during the study period, 155 were excluded because of previous arch surgery (n = 59), previous descending thoracic aortic surgery (n = 6), previous TEVAR (n = 6), unavailability of optimal preoperative computed tomography data (n = 17), double-barreled dissection (n = 40), and other reasons. The mean ± standard deviation age of the remaining 212 patients was 75.8 ± 6.4 years, and 42 (19.8%) were women. Of the 212 patients, 14 (6.6%) developed SCI after TEVAR. The low mean density of the mural thrombus, total thrombus volume, low-density (≥-100 HU but <30 HU) thrombus volume, intermediate-density (≥30 HU but <150 HU) thrombus volume, treatment length, urgent surgery, and baseline dialysis differed significantly between patients with and without SCI. Although subsequent multivariate analysis could not be performed owing to the small number of SCI events, vulnerable low-density thrombus/plaque was a stronger predictor among the aneurysm-related factors of SCI after TEVAR on univariate analysis. Well-known risk factors, such as distal coverage between T8 and L1, left subclavian artery coverage, previous abdominal aortic surgery, and prophylactic spinal drainage, did not show significant differences. CONCLUSIONS: The results from the present study have demonstrated that among aneurysm-related factors, a lower density mural thrombus/plaque in the descending thoracic aorta is a predictor of SCI development after TEVAR. These results suggest that microembolism is one of the important mechanisms of SCI after TEVAR, which might change the prophylactic strategy.

The production of auxin by dying cells.

In this review, I discuss the possibility that dying cells produce much of the auxin in vascular plants. The natural auxin, indole-3-acetic acid (IAA), is derived from tryptophan by a two-step pathway via indole pyruvic acid. The first enzymes in the pathway, tryptophan aminotransferases, have a low affinity for tryptophan and break it down only when tryptophan levels rise far above normal intracellular concentrations. Such increases occur when tryptophan is released from proteins by hydrolytic enzymes as cells autolyse and die. Many sites of auxin production are in and around dying cells: in differentiating tracheary elements; in root cap cells; in nutritive tissues that break down in developing flowers and seeds; in senescent leaves; and in wounds. Living cells also produce auxin, such as those transformed genetically by the crown gall pathogen. IAA may first have served as an exogenous indicator of the presence of nutrient-rich decomposing organic matter, stimulating the production of rhizoids in bryophytes. As cell death was internalized in bryophytes and in vascular plants, IAA may have taken on a new role as an endogenous hormone.

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion.

Cell surface biochemical changes, notably excessive increase in outer leaflet sphingomyelin (SM) content, are important in cancer initiation, growth, and immune evasion. Innumerable reports describe methods to initiate, promote, or enhance immunotherapy of clinically detected cancer, notwithstanding the challenges, if not impossibility, of identification of tumor-specific, or associated antigens, the lack of tumor cell surface membrane expression of major histocompatibility complex (MHC) class I alpha and ß2 microglobulin chains, and lack of expression or accessibility of Fas and other natural killer cell immune checkpoint molecules. Conversely, SM synthesis and hydrolysis are increasingly implicated in initiation of carcinogenesis and promotion of metastasis. Surface membrane SM readily forms inter- and intra- molecular hydrogen bond network, which excessive tightness would impair cell-cell contact inhibition, inter- and intra-cellular signals, metabolic pathways, and susceptibility to host immune cells and mediators. The present review aims at clarifying the tumor immune escape mechanisms, which face common immunotherapeutic approaches, and attracting attention to an entirely different, neglected, key aspect of tumorigenesis associated with biochemical changes in the cell surface that lead to failure of contact inhibition, an instrumental tumorigenesis mechanism. Additionally, the review aims to provide evidence for surface membrane SM levels and roles in cells resistance to death, failure to respond to growth suppressor signals, and immune escape, and to suggest possible novel approaches to cancer control and cure.

Long-term follow-up of Bologna-Oxford (BOX) total ankle arthroplasty.

PURPOSE: The purpose of this retrospective study was to evaluate the long-term results with a minimum of ten years follow-up of primary Bologna-Oxford (BOX) TAA. METHODS: Between December 2004 and December 2009, 80 patients (82 ankles) underwent a primary BOX TAA performed by a single senior surgeon, expert in foot and ankle surgery. Pain and functional outcomes were analysed using Visual Analogue Scale (VAS) for pain, American Orthopaedic Foot & Ankle Society (AOFAS) scoring system, Foot Functional Index Disability and Pain (FFI-Disability, FFI-Pain) score for comparative analysis. RESULTS: A total of 52 patients (54 implants) in a cohort of 80 (82 implants) were examined at a minimum ten years follow-up. Twenty implants out of 54 underwent implant failure (37 %) and 34 patients were enrolled in the present study. The mean VAS for pain decreased significantly from 8.5 ± 1.2 to 2.9 ± 2.2 (p<0.01) and the mean AFOAS score changed from 28.6 ± 11.8 pre-operatively to 72.7 ± 16.9 (p<0.01) at last follow-up. Ninety-seven percent was satisfied with a mean FFI-Disability score that improved from 77.6 ± 19.3 to 26.7 ± 25.4 (p<0.01) and FFI-Pain score that decreased from 76.2 ± 14.2 to 31.4 ± 25.6 (p<0.01). We calculated post-operative alignment using alpha, beta and gamma angles with no difference at long-term follow-up. The survival rate of the implant was 66% at ten years of follow-up. CONCLUSIONS: Our data suggest that BOX TAA is an implant with a good patient satisfaction rate at long-term follow-up; therefore, it is a valid option to increase the quality of life in subjects with end-stage osteoarthritis; however, long-term survivorship is unsatisfactory when compared to modern knee and hip implant.

Patient-specific instrumentation (PSI) in total ankle arthroplasty: a systematic review.

BACKGROUND: Patient-specific instrument (PSI) may theoretically make total ankle arthroplasty (TAA) more accurate. Several studies have reported the outcomes of PSI TAA. The aim of this study is to systematically review the literature of PSI TAA. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were systematically reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines for PSI TAA. The quality of the included studies was evaluated according to Methodological Index for Non-Randomized Studies (MINORS). RESULT: Nine articles were ultimately included in the systematic review. The implant position and function outcome of TAA was similar between PSI and SI. Prediction accuracy of implant size remained great difference. PSI can shorten the operative time and fluoroscopy time. The quality of current studies on PSI TAA is insufficient to produce high-level evidence. CONCLUSION: PSI can get similar implant position and clinical outcome in TAA compared to SI, but current evidence is not strong enough to evaluate PSI TAA.

Vitamin B Mitigates Thoracic Aortic Dilation in Marfan Syndrome Mice by Restoring the Canonical TGF-ß Pathway.

Thoracic aortic aneurysm (TAA) formation is a multifactorial process that results in diverse clinical manifestations and drug responses. Identifying the critical factors and their functions in Marfan syndrome (MFS) pathogenesis is important for exploring personalized medicine for MFS. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms have been correlated with TAA severity in MFS patients. However, the detailed relationship between the folate-methionine cycle and MFS pathogenesis remains unclear. Fbn1C1039G/+ mice were reported to be a disease model of MFS. To study the role of the folate-methionine cycle in MFS, Fbn1C1039G/+ mice were treated orally with methionine or vitamin B mixture (VITB), including vitamins B6, B9, and B12, for 20 weeks. VITB reduced the heart rate and circumference of the ascending aorta in Fbn1C1039G/+ mice. Our data showed that the Mtr and Smad4 genes were suppressed in Fbn1C1039G/+ mice, while VITB treatment restored the expression of these genes to normal levels. Additionally, VITB restored canonical transforming-growth factor ß (TGF-ß) signaling and promoted Loxl1-mediated collagen maturation in aortic media. This study provides a potential method to attenuate the pathogenesis of MFS that may have a synergistic effect with drug treatments for MFS patients.