Experimental realization of on-chip topological nanoelectromechanical metamaterials.

Guiding waves through a stable physical channel is essential for reliable information transport. However, energy transport in high-frequency mechanical systems, such as in signal-processing applications1, is particularly sensitive to defects and sharp turns because of back-scattering and losses2. Topological phenomena in condensed matter systems have shown immunity to defects and unidirectional energy propagation3. Topological mechanical metamaterials translate these properties into classical systems for efficient phononic energy transport. Acoustic and mechanical topological metamaterials have so far been realized only in large-scale systems, such as arrays of pendulums4, gyroscopic lattices5,6, structured plates7,8 and arrays of rods, cans and other structures acting as acoustic scatterers9-12. To fulfil their potential in device applications, mechanical topological systems need to be scaled to the on-chip level for high-frequency transport13-15. Here we report the experimental realization of topological nanoelectromechanical metamaterials, consisting of two-dimensional arrays of free-standing silicon nitride nanomembranes that operate at high frequencies (10-20 megahertz). We experimentally demonstrate the presence of edge states, and characterize their localization and Dirac-cone-like frequency dispersion. Our topological waveguides are also robust to waveguide distortions and pseudospin-dependent transport. The on-chip integrated acoustic components realized here could be used in unidirectional waveguides and compact delay lines for high-frequency signal-processing applications.

Tumour-infiltrating bystander CD8+ T cells activated by IL-15 contribute to tumour control in non-small cell lung cancer.

BACKGROUND: Tumour-unrelated, virus-specific bystander CD8+ T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet. METHODS: We studied the characteristics of bystander CD8+ TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy. RESULTS: We show that bystander CD8+ TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8+ TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8+ TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8+ TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment. CONCLUSION: Thus, the study demonstrates that bystander CD8+ TILs can be repurposed by IL-15 for tumour immunotherapy.

Comparative Analyses of mTOR/Akt and Muscle Atrophy-Related Signaling in Aged Respiratory and Gastrocnemius Muscles.

Sarcopenia is the degenerative loss of skeletal muscle mass and function associated with aging and occurs in the absence of any underlying disease or condition. A comparison of the age-related molecular signaling signatures of different muscles has not previously been reported. In this study, we compared the age-related molecular signaling signatures of the intercostal muscles, the diaphragm, and the gastrocnemii using 6-month and 20-month-old rats. The phosphorylation of Akt, ribosomal S6, and Forkhead box protein O1 (FoxO1) in diaphragms significantly increased with age, but remained unchanged in the intercostal and gastrocnemius muscles. In addition, ubiquitin-proteasome degradation, characterized by the levels of MuRF1 and Atrogin-1, did not change with age in all rat muscles. Interestingly, an increase in LC3BII and p62 levels marked substantial blockage of autophagy in aged gastrocnemii but not in aged respiratory muscles. These changes in LC3BII and p62 levels were also associated with a decrease in markers of mitochondrial quality control. Therefore, our results suggest that the age-related signaling events in respiratory muscles differ from those in the gastrocnemii, most likely to preserve the vital functions played by the respiratory muscles.

Analysis of the Molecular Signaling Signatures of Muscle Protein Wasting Between the Intercostal Muscles and the Gastrocnemius Muscles in db/db Mice.

Type 2 diabetes (T2D) patients suffer from dyspnea, which contributes to disease-related morbidity. Although T2D has been reported to induce a catabolic state in skeletal muscle, whether T2D induces muscle wasting in respiratory muscles has not yet been investigated. In this study, we examine the difference in the molecular signaling signature of muscle wasting between the intercostal and gastrocnemius muscles using db/db mice, a well-known diabetic mouse model. Akt phosphorylation was significantly decreased in both the intercostal and gastrocnemius muscles of db/db mice and was accompanied by a decrease in mTORC1 activity. In addition, FoxO phosphorylation was suppressed, and ubiquitin-proteasome degradation, characterized by the level of Atrogin-1 and MuRF1, was subsequently enhanced in both muscle types of db/db mice. An increase in LC3BII levels and a decrease in p62 levels marked the occurrence of substantial autophagy in the gastrocnemius muscle but not in the intercostal muscles of db/db mice. Therefore, we suggest that the signaling events of muscle wasting in the intercostal muscles of db/db mice are different from those in the gastrocnemius muscle of db/db mice.

Outcomes of Curative-Intent Surgery and Adjuvant Treatment for Pulmonary Large Cell Neuroendocrine Carcinoma.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is pathologically classified as non-small-cell lung cancer (NSCLC), but its clinical behavior is more aggressive than other types of NSCLC. Accordingly, the optimal treatment strategy for LCNEC, including the indication of adjuvant treatment, remains controversial. METHODS: A retrospective review of 139 patients who underwent curative-intent surgery for LCNEC was performed to investigate clinicopathologic features and survival outcomes and to evaluate whether adjuvant treatment affected survival outcomes. RESULTS: The mean patient age was 64 years (126 men, 90.6%). Operative procedures included 111 lobectomies (79.8%), 12 pneumonectomies (8.6%), and 2 sublobar resections. Pathologic stage was IA in 31 (22%), IB in 36 (26%), IIA in 34 (24%), IIB in 9 (6%), IIIA in 19 (14%), IIIB in 2 (1.4%), and IV in 4 patients (2.9%). Postoperatively, 50 patients (36%) received adjuvant treatment. The median follow-up duration was 33 months. The 5-year overall survival (OS) rate was 53%, and 5-year disease-free survival (DFS) rate was 39%. In patients with pathologic stage I, there was no significant difference in either OS or DFS according to the addition of adjuvant treatment. However, in patients with pathologic stage II or higher, patients who underwent adjuvant treatment showed significantly better OS (p = 0.023) and DFS (p = 0.038). CONCLUSIONS: Our findings showed that patients who underwent curative-intent surgery for LCNEC benefitted from the use of adjuvant treatment especially in pathologic stage II or higher.

CTLA4 overexpressing adipose tissue-derived mesenchymal stem cell therapy in a dog with steroid-refractory pemphigus foliaceus.

BACKGROUND: Canine pemphigus foliaceus is an autoimmune antibody-mediated skin disease characterized by acantholysis. The objective of this case report is to present the successful management of steroid refractory pemphigus foliaceus with cytotoxic T-lymphocyte antigen 4 (CTLA4)-overexpressing adipose tissue mesenchymal stem cells (ATMSCs). CASE PRESENTATION: A 10-year-old, 12.3-kg, castrated male Shih Tzu presented with severe pruritus and anorexia. The diagnosis of pemphigus foliaceus was made based on its history, physical examination, and histopathology results of a skin biopsy. Treatment with prednisolone and combination therapy of other immunosuppressive drugs had failed; therefore, immunosuppressive gene, CTLA4 overexpressing ATMSCs (CTLA4-ATMSCs) and/or naive ATMSCs administration was performed with the consent of the owner. ATMSCs were administered 21 times over a period of 20 months with intervals of 2 to 8 week. Prednisolone was gradually tapered concurrently and no relapse of the clinical signs was observed. After the termination of CTLA4-ATMSCs and/or naive ATMSCs treatment, the skin lesions had improved and could be managed with a low dose of prednisolone for 12 months. CONCLUSION: CTLA4-ATMSCs or naive ATMSCs transplantation may be beneficial as adjunctive therapy to initiate and maintain the remission of skin lesions caused by pemphigus foliaceus in veterinary medicine.

Proper compression landmark and depth for cardiopulmonary resuscitation in patients with pectus excavatum: a study using CT.

OBJECTIVE: To determine by chest CT the proper compression landmark and depth for cardiopulmonary resuscitation in patients with pectus excavatum (PE). METHODS: The chest CT of 22 patients with PE (mean age=27 years; range 16-53 years, 10 male) from March 2002 to September 2011 were retrospectively evaluated as follows: length of sternum, external thickness/internal thickness (ET/IT) of the chest and the intrathoracic structures in the level of lower half (LH) of the sternum. In addition, Haller index (HI) and the degree of leftward displacement of the heart were measured. Finally, variables were also measured in an age/sex-matched control group (n=22) with no evidence of any chest wall deformity. RESULTS: The sternal length was not different and LH of the sternum was adequate to compress left ventricle (LV) in both groups. Patients had a significant higher HI and showed a greater leftward displacement of LV centre with a mean difference of 11 mm. PE patients showed a lesser ET/IT with a mean difference of approximately 20 mm than controls (mean ET/IT=174±18/70±10 mm vs 199±23/93±15 mm, p<0.001). CONCLUSIONS: The LH of the sternum is an appropriate chest compression landmark in PE patients to compress LV, although the centre of LV shows slightly leftward displacement. Since PE patients have sunken chest, a 3-4 cm may be the proper compression depth in the patients when considering the current compression guideline in normal subjects is 5-6 cm.

A rare presentation of catamenial hemoptysis as a solitary pulmonary nodule.

Thoracic endometriosis is a rare disorder characterized by the presence of functioning endometrial tissue within the pleura, lung parenchyma, or the airways. We report a case of catamenial hemoptysis with a rare presentation, that is, as a solitary pulmonary nodule with an internal cavity and surrounding ground glass opacity.

Feasibility of Home-Based Pulmonary Rehabilitation of Pediatric Patients with Chronic Respiratory Diseases.

BACKGROUND AND OBJECTIVE: Chronic respiratory diseases in children deteriorate their daily life due to dyspnea and reduced lung function. We aimed to evaluate the feasibility of home-based pulmonary rehabilitation in pediatric chronic respiratory diseases. METHODS: This prospective, single-arm, cohort study included children with chronic lung disease. They were instructed to perform home-based pulmonary rehabilitation 30 min/session, three sessions/week for three months. Pulmonary function test (PFT) using spirometry, respiratory muscle strength (RMT), cardiopulmonary exercise test (CPET), 6 min walk test (6MWT), dyspnea questionnaires, speech evaluation, and pediatric quality of life inventory (PedsQL) were assessed pre- and post-pulmonary rehabilitation. Compliance and satisfaction of the program were also evaluated. RESULTS: Twenty children (mean age: 11.2 ± 3.1 years) with chronic respiratory diseases without cardiopulmonary instability participated. The overall compliance was 71.1% with no related adverse events. After pulmonary rehabilitation, forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), RMT, 6MWT, dyspnea questionnaire, speech rate, and PedsQL (child) significantly improved (p < 0.05), particularly better in the FEV1 < 60% group than in the FEV1 ≥ 60% group and in the high-compliance group (compliance ≥ 50%) than in the low-compliance group (compliance < 50%). CONCLUSIONS: Home-based pulmonary rehabilitation for children with chronic lung disease was feasible with high compliance and effective in terms of objective functions, subjective dyspnea symptom, and quality of life.

Synovial sarcoma of primary bone origin arising from the cervical spine.

Synovial sarcoma of primary bone origin is very rare and has not been previously reported in the cervical vertebra. We report the first case of a synovial sarcoma of the cervical vertebra, presenting as an expansile osteolytic lesion in the posterior osseous elements of the C3 vertebra characteristically with prominent intratumoral vessels.

Facet Connectivity-Based Estimation Algorithm for Manufacturability of Supportless Parts Fabricated via LPBF.

Recent advances in additive manufacturing have provided more freedom in the design of metal parts; hence, the prototyping of fluid machines featuring extremely complex geometries has been investigated extensively. The fabrication of fluid machines via additive manufacturing requires significant attention to part stability; however, studies that predict regions with a high risk of collapse are few. Therefore, a novel algorithm that can detect collapse regions precisely is proposed herein. The algorithm reflects the support span over the faceted surface via propagation and invalidates overestimated collapse regions based on the overhang angle. A heat exchanger model with an extremely complex internal space is adopted to validate the algorithm. Three samples from the model are extracted and their prototypes are fabricated via laser powder bed fusion. The results yielded by the fabricated samples and algorithm with respect to the sample domain are compared. Regions of visible collapse identified on the surface of the fabricated samples are predicted precisely by the algorithm. Thus, the supporting span reflected by the algorithm provides an extremely precise prediction of collapse.

3D-Printed Auxetic Skin Scaffold for Decreasing Burn Wound Contractures at Joints.

For patients with severe burns that consist of contractures induced by fibrous scar tissue formation, a graft must adhere completely to the wound bed to enable wound healing and neovascularization. However, currently available grafts are insufficient for scar suppression owing to their nonuniform pressure distribution in the wound area. Therefore, considering the characteristics of human skin, which is omnidirectionally stretched via uniaxial stretching, we proposed an auxetic skin scaffold with a negative Poisson's ratio (NPR) for tight adherence to the skin scaffold on the wound bed site. Briefly, a skin scaffold with the NPR effect was fabricated by creating a fine pattern through 3D printing. Electrospun layers were also added to improve adhesion to the wound bed. Fabricated skin scaffolds displayed NPR characteristics (-0.5 to -0.1) based on pulling simulation and experiment. Finger bending motion tests verified the decreased marginal forces (<50%) and deformation (<60%) of the NPR scaffold. In addition, the filling of human dermal fibroblasts in most areas (>95%) of the scaffold comprising rarely dead cells and their spindle-shaped morphologies revealed the high cytocompatibility of the developed scaffold. Overall, the developed skin scaffold may help reduce wound strictures in the joints of patients with burns as it exerts less pressure on the wound margin.

Cost-effectiveness of physical activity interventions for prevention and management of cognitive decline and dementia-a systematic review.

BACKGROUND: Although increasing physical activity (PA) has been suggested to prevent and manage cognitive decline and dementia, its economic impact on healthcare systems and society is largely unknown. This study aimed to summarize evidence on the cost-effectiveness of PA interventions to prevent and manage cognitive decline and dementia. METHODS: Electronic databases, including PubMed/MEDLINE, Embase, and ScienceDirect, were searched from January 2000 to July 2023. The search strategy was driven by a combination of subject-heading terms related to physical activity, cognitive function, dementia, and cost-effectiveness. Selected studies were included in narrative synthesis, and extracted data were presented in narrative and tabular forms. The risk of bias in each study was assessed using the Consolidated Health Economic Evaluation Reporting Standards and Consensus on Health Economic Criteria list. RESULTS: Five of the 11 identified studies focused on individuals with existing dementia. Six of the 11 identified studies focused on individuals with no existing dementia, including 3 on those with mild cognitive impairment (MCI), and 3 on those with no existing MCI or dementia. PA interventions focused on individuals with no existing dementia were found to be cost-effective compared to the control group. Findings were mixed for PA interventions implemented in individuals with existing dementia. CONCLUSIONS: PA interventions implemented before or during the early stage of cognitive impairment may be cost-effective in reducing the burden of dementia. More research is needed to investigate the cost-effectiveness of PA interventions in managing dementia. Most existing studies used short-term outcomes in evaluating the cost-effectiveness of PA interventions in the prevention and management of dementia; future research should consider adding long-term outcomes to strengthen the study design.

Novel Strategy To Inhibit Transthyretin Amyloidosis via the Synergetic Effect of Chemoselective Acylation and Noncovalent Inhibitor Release.

Strategies for developing targeted covalent inhibitors (TCIs), which have the advantages of a prolonged duration of action and selectivity toward a drug target, have attracted great interest in drug discovery. Herein, we report chemoselective covalent inhibitors that specifically target lysine ε-amine groups that conjugate with an endogenous protein to prevent disease-causing protein misfolding and aggregation. These TCIs are unique because the benzoyl group is preferentially conjugated to Lys15 at the top of the T4 binding site within transthyretin (TTR) while simultaneously releasing a potent noncovalent TTR kinetic stabilizer. The potency of these covalent inhibitors is superior to tafamidis, the only FDA-approved drug for the treatment of hereditary TTR amyloidosis. In addition to investigations into the covalent modification of TTR via reverse-phase high-performance liquid chromatography, direct methods are performed to confirm and visualize the presumed covalent interaction via mass spectrometry and X-ray crystallography.

Absolute Bed Rest Duration of 3 Days for Osteoporotic Vertebral Fractures: A Retrospective Study.

STUDY DESIGN: Retrospective case-control study. PURPOSE: To reduce unnecessary absolute bed rest (ABR), this study sought to determine the optimal aimed length of ABR in older patients getting conservative treatment for osteoporotic vertebral fractures (OVFs). OVERVIEW OF LITERATURE: OVFs are quite common in elderly patients. ABR is a vital part of conservative treatment for OVFs, although the length of ABR may increase patient. No recommendations regarding how long ABR should last. METHODS: This study was conducted in 134 patients with OVFs initially treated conservatively. The patients were split into two groups: 3-day and 7-day ABR. From the time of injury to 1, 4, and 12 weeks after injury, compression rate (CR) and local kyphotic angle (LKA) were assessed and compared between the two groups. Any complications such as pneumonia, deep vein thrombosis, delirium, and urinary tract infection known to be related to ABR were examined based on the electronic medical record. RESULTS: Forty-four patients underwent ABR for 3 days and 90 underwent ABR for 7 days. There was no significant difference in CR and LKA between the two groups at the time of injury versus 1, 4, and 12 weeks after injury. The patients were divided into two groups: those who received a 3-day ABR and those who received a 7-day ABR. CR and LKA were measured and compared between the two groups from the time of damage to 1, 4, and 12 weeks after injury. The ABR-related complication rate was 43.4% in the 7-day ABR group and 22.7% in 3-day ABR group (p=0.02). The duration of hospital stay was significantly shorter in the 3-day ABR group (12.8 days) than in the 7-day group (16 days) (p=0.01). CONCLUSIONS: Considering radiological outcomes, prognosis, complications, patient convenience, and economic impact, a 3-day ABR period is appropriate for the conservative treatment of OVFs.

Hydrophilic guidewire usage under ultrasound guidance in facilitating catheter advancement during endovenous treatment of incompetent great saphenous veins.

PURPOSE: This study was performed To investigate the use of hydrophilic guidewires for facilitating catheter advancement during varicose vein treatment using radiofrequency ablation (RFA) or cyanoacrylate closure (CAC). METHODS: From March 2016 to April 2019, 463 limbs of 285 with incompetent great saphenous veins were subjected to RFA (321 limbs of 197 patients) or CAC (142 limbs of 88 patients). Procedure records were reviewed for the use of a hydrophilic guidewire, reason for the guidewire usage, and diameter of the guidewire. RESULTS: A hydrophilic guidewire was used to facilitate catheter advancement to treat 92 of 463 limbs (19.9%). For RFA, a guidewire was used to treat 53 of 321 limbs (16.5%). Among them, 15 limbs (28.3%) had vasospasm, and 38 limbs (71.7%) had venous tortuosity. For CAC, guidewire was used for 39 of 142 limbs (27.5%). Among them, 10 limbs (25.6%) had vasospasm, 23 limbs (59.0%) had venous tortuosity, and 6 limbs (15.4%) had repeated engagement of a J-tip guidewire into the varicose tributaries. In CAC, the frequency of hydrophilic guidewire usage was higher than that in RFA (P = 0.006). All varicose vein treatment sessions were technically successful. CONCLUSION: Hydrophilic guidewire usage could facilitate catheter advancement when hindered by vasospasm, tortuosity of the saphenous vein, or repeated engagement into the varicose tributaries.

Detection of Lateral Hinge Fractures After Medial Closing Wedge Distal Femoral Osteotomy: Computed Tomography Versus Plain Radiography.

BACKGROUND: Limited evidence exists in the literature regarding the detection rates of lateral hinge fracture (LHF) on computed tomography (CT) after medial closing wedge distal femoral osteotomy (MCDFO). Moreover, the effect of LHF on bone healing after MCDFO remains unclear. HYPOTHESIS: The detection rates of LHF after MCDFO would be higher on CT than on plain radiography. The incidence of problematic bone healing would be higher in the knees with LHF than in those without LHF. STUDY DESIGN: Cohort study (diagnosis), Level of evidence, 3. METHODS: Patients who underwent MCDFO between May 2009 and July 2019 were retrospectively evaluated. The presence of LHF was evaluated using immediate postoperative plain radiography and CT. The detection rates of LHF on plain radiography and CT were compared. The incidence of problematic bone healing (nonunion, delayed union, and loss of correction) was also compared between the knees with LHF and those without LHF. RESULTS: A total of 55 knees of 43 patients (mean age, 37.7 ± 16.7 years) were included in the study. Although 33 LHFs were detected on CT, only 19 LHFs were detected on plain radiography. The detection rate of LHF was significantly higher on CT than on plain radiography (60% vs 34.5%; P = .008). At 1-year follow-up, 10 cases of problematic bone healing (1 nonunion, 4 delayed unions, and 5 losses of correction) were identified. The incidence of problematic bone healing was significantly higher in the knees with LHF than in those without LHF as shown on plain radiography (36.8% vs 8.3%; P = .001) and CT (30.3% vs 0%; P = .004). CONCLUSION: LHF can be detected better on CT than on plain radiography and has a negative effect on bone healing after MCDFO. For patients with LHF detected on either plain radiography or CT, careful rehabilitation with close follow-up is recommended.

Deterioration of mitochondrial function in the human intercostal muscles differs among individuals with sarcopenia, obesity, and sarcopenic obesity.

BACKGROUND & AIMS: Sarcopenic obesity (SO) increases the risk of mortality more than sarcopenia or obesity alone. Sarcopenia weakens the peripheral and respiratory muscles, leading to respiratory complications. It also induces mitochondrial dysfunction in the peripheral muscle; however, whether mitochondrial dysfunction in respiratory muscles differs among individuals with obesity, sarcopenia, and SO remains unknown. We evaluated the deterioration of respiratory muscle strength and mitochondrial function among normal, sarcopenia, obesity, and SO subjects. METHODS: Twenty-five patients who underwent lung resections were enrolled between April 2017 and January 2021, and their intercostal muscles were harvested. Based on their L3 muscle index and visceral fat area, the patients were divided into four groups (normal, obesity, sarcopenia, and SO). The clinical data, mRNA expression, and protein expressions associated with mitochondrial biogenesis/fusion/fission in the intercostal muscles were compared among the four groups. RESULTS: The respiratory muscle strength was evaluated using peak expiratory flow rate (PEFR). The PEFR values of the four groups were not significantly different. The levels of pAkt/Akt and mTOR (a marker of protein synthesis) were not significantly different among the four groups; however, those in the SO group were substantially lower than those in the sarcopenia or obesity groups. The levels of Atrogen-1 and MuRF1 (a marker of protein degradation) were not significantly different among the four groups; however, those in the SO group were substantially higher than those in the sarcopenia or obesity groups. Expression of PGC1-α (a marker of mitochondrial biogenesis) in the SO group was significantly lower than that in the normal group. MFN1 and MFN2 (marker of mitochondrial fusion) levels were significantly lower in the SO group than those in the normal group. DRP1 (a marker of mitochondrial fission) level in the SO group was substantially lower than that in the normal group. The expression of TNF-α (a pro-inflammatory cytokine) in the SO group was substantially lower than that in the normal group. CONCLUSION: Our results suggest that the deterioration of protein synthesis and degradation of mitochondrial function in the respiratory muscles was most prominent in the SO before the weakening of the respiratory muscles. The deterioration mechanism may differentially regulate obesity, sarcopenia, and SO.

Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells.

Chronic stress has a negative impact on many fertility-related functions; thus, the recent decline in female fertility seems to be at least partially associated with increased stress. The secretion of glucocorticoids is a typical endocrine response to chronic stress and indirectly reduces uterine receptivity through the hypothalamus-pituitary-gonadal (HPG) axis. However, in addition to its well-known canonical role, the direct effects of chronic stress-induced glucocorticoids on various uterine functions and their underlying molecular mechanisms are complex and have not yet been revealed. Recent studies have found that resident stem cell deficiency is responsible for the limited regenerative potential of the endometrium (the innermost lining of the uterine cavity) during each menstrual cycle, which subsequently increases infertility rates. In this context, we hypothesized that stress-induced glucocorticoids directly damage endometrial stem cells and consequently negatively affect endometrial reconstruction, which is important for uterine receptivity. In addition to its well-known canonical roles, we identified for the first time that cortisol, the most abundant and potent glucocorticoid in humans, directly suppresses the multiple beneficial functions (self-renewal, transdifferentiation, and migratory potential) of human endometrial stem cells through its functional receptor, glucocorticoid receptor (GR). Glucocorticoids inhibit well-known survival signals, such as the PI3K/Akt and FAK/ERK1/2 pathways. More importantly, we also found that immobilization of stress-induced glucocorticoids suppresses the various beneficial functions of tissue resident stem cells in vivo. To the best of our knowledge, this is the first study to investigate the direct effects of glucocorticoids on the regenerative capacity of endometrial stem cells, and the findings will facilitate the development of more promising therapeutic approaches to increase female fertility.

Prognostic significance of radiodensity-based skeletal muscle quantification using preoperative CT in resected non-small cell lung cancer.

BACKGROUND: Sarcopenia is associated with poor prognosis in lung cancer. Skeletal muscle area can be quantified based on radiodensity of CT scan. The purpose of this study was to evaluate the prognostic significance of radiodensity-based detailed skeletal muscle quantification on outcomes after surgery of non-small cell lung cancer (NSCLC). METHODS: Single cross-sectional area of the skeletal muscle (-29 to 150 HU) at the 3rd lumbar vertebra (L3) level retrospectively measured on preoperative CT for NSCLC patients (n=272), who underwent surgical resection during 2011 to 2016. The diagnosis of sarcopenia was made when a L3 muscle index (L3MI; L3 muscle area/height2) of less than 55 cm2/m2 for men and less than 39 cm2/m2 for women. Skeletal muscle was subsequently classified based on radiodensity level as low attenuation muscle (-29 to <30 HU) and high attenuation muscle (30 to 150 HU). Using a maximal-chi-squared test, low attenuation muscle accounted less than 24.5% of the total muscle, which was considered healthy muscle. Data on clinical characteristics (demographic information, TNM stage, histology) and prognosis (disease-free survival; DFS, and overall survival; OS) were collected. RESULTS: Sarcopenia was found 22.4% in preoperative CT (32.9% for men and 6.5% for women). The prevalence of patients with healthy muscle was 15.4% (21.3% for men and 6.5% for women). There was no significant difference between the 3-year DFS rate (77.0% vs. 67.0%, P=0.142) or 3-year OS rate (84.8% vs. 87.9%, P=0.576) between patients with and without sarcopenia. However, patients with healthy muscle tend to show longer 3-year DFS rate (79.4% vs. 67.2%, P=0.094) and 3-year OS rate (92.6% vs. 86.1%, P=0.176). In the multivariable analysis, healthy muscle was one of the independent prognosticators for a 3-year DFS rate (HR, 0.50, P=0.035), along with R1 resection (HR, 5.90, P<0.001), pathologic T stage (HR, 2.69, P<0.001), and pathologic N stage (HR, 2.43, P<0.001). CONCLUSIONS: The proportion of low attenuation muscle was associated with DFS in resected lung cancer patients. Further investigation is needed to establish whether radiodensity-based detailed skeletal muscle quantification could be early biomarker to predict prognosis in NSCLC.