Generalization of a Deep Learning Model for Continuous Glucose Monitoring-Based Hypoglycemia Prediction: Algorithm Development and Validation Study.

Background: Predicting hypoglycemia while maintaining a low false alarm rate is a challenge for the wide adoption of continuous glucose monitoring (CGM) devices in diabetes management. One small study suggested that a deep learning model based on the long short-term memory (LSTM) network had better performance in hypoglycemia prediction than traditional machine learning algorithms in European patients with type 1 diabetes. However, given that many well-recognized deep learning models perform poorly outside the training setting, it remains unclear whether the LSTM model could be generalized to different populations or patients with other diabetes subtypes. Objective: The aim of this study was to validate LSTM hypoglycemia prediction models in more diverse populations and across a wide spectrum of patients with different subtypes of diabetes. Methods: We assembled two large data sets of patients with type 1 and type 2 diabetes. The primary data set including CGM data from 192 Chinese patients with diabetes was used to develop the LSTM, support vector machine (SVM), and random forest (RF) models for hypoglycemia prediction with a prediction horizon of 30 minutes. Hypoglycemia was categorized into mild (glucose=54-70 mg/dL) and severe (glucose<54 mg/dL) levels. The validation data set of 427 patients of European-American ancestry in the United States was used to validate the models and examine their generalizations. The predictive performance of the models was evaluated according to the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Results: For the difficult-to-predict mild hypoglycemia events, the LSTM model consistently achieved AUC values greater than 97% in the primary data set, with a less than 3% AUC reduction in the validation data set, indicating that the model was robust and generalizable across populations. AUC values above 93% were also achieved when the LSTM model was applied to both type 1 and type 2 diabetes in the validation data set, further strengthening the generalizability of the model. Under different satisfactory levels of sensitivity for mild and severe hypoglycemia prediction, the LSTM model achieved higher specificity than the SVM and RF models, thereby reducing false alarms. Conclusions: Our results demonstrate that the LSTM model is robust for hypoglycemia prediction and is generalizable across populations or diabetes subtypes. Given its additional advantage of false-alarm reduction, the LSTM model is a strong candidate to be widely implemented in future CGM devices for hypoglycemia prediction.

Obstructive sleep apnea affects the psychological and behavioural development of children-a case-control study.

This study aims to investigate the effects of obstructive sleep apnea on paediatric psychological and behavioural abnormalities. A total of 1086 paediatric patients with obstructive sleep apnea and 728 sample snoring controls were enrolled in the study. Patients with obstructive sleep apnea underwent bilateral tonsillectomy plus adenoidectomy or adenoidectomy alone. Repeated Autism Behaviour Checklist, Spence Children's Anxiety Scale, and Children's Depression Inventory were performed to assess the autism symptoms, anxiety level and depressive symptoms before and after surgery. The score of Autism Behaviour Checklist in preschool children with obstructive sleep apnea was higher than that in control. In school children with obstructive sleep apnea, the score of Spence Children's Anxiety Scale was also higher. School children with obstructive sleep apnea with depressive symptoms were significantly higher than that in control. The scores of Autism Behaviour Checklist, Spence Children's Anxiety Scale, and Children's Depression Inventory in the obstructive sleep apnea group after surgery were significantly lower than that before surgery. Our study showed that the score of Spence Children's Anxiety Scale and Children's Depression Inventory had a close correlation with the illness course and hypoxia duration. The Spence Children's Anxiety Scale and Children's Depression Inventory scores are also closely associated with the Autism Behaviour Checklist score. These results suggest that obstructive sleep apnea may have a significant impact on autism symptoms, anxiety levels and depressive symptoms in children. We found that the longer the duration of the obstructive sleep apnea course and hypoxia, the greater the impact on anxiety level and depressive symptoms. The suspected autism symptoms, anxiety level and depressive symptoms in children with obstructive sleep apnea were also significantly correlated. Thus, early detection and timely treatment may often reverse the psychological and behavioural abnormalities caused by obstructive sleep apnea.

Technologies evolution in robot-assisted fracture reduction systems: a comprehensive review.

Background: Robot-assisted fracture reduction systems can potentially reduce the risk of infection and improve outcomes, leading to significant health and economic benefits. However, these systems are still in the laboratory stage and not yet ready for commercialization due to unresolved difficulties. While previous reviews have focused on individual technologies, system composition, and surgical stages, a comprehensive review is necessary to assist future scholars in selecting appropriate research directions for clinical use. Methods: A literature review using Google Scholar identified articles on robot-assisted fracture reduction systems. A comprehensive search yielded 17,800, 18,100, and 16,700 results for "fracture reduction," "computer-assisted orthopedic surgery," and "robot-assisted fracture reduction," respectively. Approximately 340 articles were selected, and 90 highly relevant articles were chosen for further reading after reviewing the abstracts. Results and Conclusion: Robot-assisted fracture reduction systems offer several benefits, including improved reduction accuracy, reduced physical work and radiation exposure, enhanced preoperative planning and intraoperative visualization, and shortened learning curve for skill acquisition. In the future, these systems will become integrated and practical, with automatic preoperative planning and high intraoperative safety.

Combination therapy of HIFα inhibitors and Treg depletion strengthen the anti-tumor immunity in mice.

Hypoxia-inducible factor 1 alpha (HIF1α), under hypoxic conditions, is known to play an oxygen sensor stabilizing role by exerting context- and cell-dependent stimulatory and inhibitory functions in immune cells. Nevertheless, how HIF1α regulates T cell differentiation and functions in tumor settings has not been elucidated. Herein, we demonstrated that T-cell-specific deletion of HIF1α improves the inflammatory potential and memory phenotype of CD8+ T cells. We validated that T cell-specific HIF1α ablation reduced the B16 melanomas development with the indication of ameliorated antitumor immune response with enhanced IFN-γ+ CD8+ T cells despite the increase in the Foxp3+ regulatory T-cell population. This was further verified by treating tumor-bearing mice with a HIF1α inhibitor. Results indicated that HIF1α inhibitor also recapitulates HIF1α ablation effects by declining tumor growth and enhancing the memory and inflammatory potential of CD8+ T cells. Furthermore, a combination of Treg inhibitor with HIF1α inhibitor can substantially reduce tumor size. Collectively, these findings highlight the notable roles of HIF1α in distinct CD8+ T-cell subsets. This study suggests the significant implications for enhancing the potential of T cell-based antitumor immunity by combining HIF1α and Tregs inhibitors.

Pparα knockout in mice increases the Th17 development by facilitating the IKKα/RORγt and IKKα/Foxp3 complexes.

The helper CD4+ T cell-type 17 (Th17) cells and regulatory CD4+ T cells (Tregs) are balanced through numerous molecular regulators, particularly metabolic factors, and their alteration causes immune dysregulation. Herein, we report that peroxisome proliferator of activated receptor-alpha (Pparα), a lipid metabolism regulator, suppresses Th17 differentiation. We demonstrated that Pparα ablation improves Th17 and pro-Th17 factor HIF-1α by enhancing the expression and nuclear localization of NFκB-activator IκB kinase-alpha (IKKα). Unexpectedly, we found that IKKα directly interacts with RORγt and enhances the expression of Il17a gene. Meanwhile, IKKα also interacts with Foxp3, leading to the post-translational regulation of Foxp3 by elevating its proteasomal degradation, and influencing Th17 development. Pparα deficiency leads to enhanced Th17 development in vivo and is associated with enhanced pathology in a murine experimental autoimmune encephalomyelitis (EAE) model. Overall, our data indicate that Pparα may serve as a potential therapeutic target for autoimmune and inflammatory diseases.

Preoperative Inflammation-Associated Blood Cell Markers in Patients with Non-Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Study.

Purpose: This study aimed to investigate the association between preoperative inflammation-associated blood cell markers and the prognosis of patients with non-metastatic clear cell renal cell carcinoma (ccRCC) who underwent nephrectomy. Patients and Methods: We retrospectively analyzed data from our single-center cohort of patients who underwent radical or partial nephrectomy for non-metastatic ccRCC. The optimal cutoff values for red blood cell distribution width (RDW), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR) were determined using X-tile software. We evaluated recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) using the Kaplann-Meier method. Cox proportional-hazards regression models were utilized to assess predictors of RFS, CSS, and OS. The predictive accuracy was evaluated using Harrell's Concordance Index (C-index). Results: A total of 444 patients who underwent nephrectomy were included in the study. The optimal cutoff values for RDW, PLR, NLR, and LMR were determined as 13.1, 157.3, 3.4, and 2.7, respectively. On univariate Cox regression analysis, NLR, PLR, and LMR were significant predictors for RFS, CSS, and OS. After adjusting for important prognostic factors, only NLR remained a significant prognostic marker for both CSS and OS. When NLR was added to the stage, size, grade, and necrosis (SSIGN) model, the C-index increased from 0.777 to 0.826 for CSS and from 0.703 to 0.734 for OS. Similarly, when NLR was added to the University of California, Los Angeles, Integrated Staging System (UISS), the C-index increased from 0.796 to 0.811 for CSS and from 0.735 to 0.745 for OS. Conclusion: NLR is a reliable prognostic biomarker for patients with non-metastatic ccRCC. The prognostic capabilities of UISS and SSIGN models could be improved by adding NLR to UISS and SSIGN models.

Analysis of Multimorbidity of Moderate to Severe Allergic Rhinitis in Children: A Real-World Study.

INTRODUCTION: Allergic rhinitis (AR) in children is associated with various comorbidities, posing challenges for treatment and management. There have been few investigations of these multimorbidities in Chinese children with AR. Here, we investigated the prevalence of multimorbidities in children with moderate to severe AR and analyzed the influencing factors using real-world data. METHODS: In total, 600 children who visited the outpatient clinic of our hospital and were diagnosed with moderate-severe AR were prospectively enrolled. All children underwent allergen detection and electronic nasopharyngoscopy. Parents or guardians completed a questionnaire that included age, sex, mode of delivery, feeding pattern, and familial history of allergy. The multimorbidities investigated included atopic dermatitis (AD), asthma, allergic conjunctivitis (AC), chronic rhinosinusitis (CRS), adenoid hypertrophy (AH), tonsil hypertrophy (TH), recurrent epistaxis, and recurrent respiratory tract infections (RRTIs). RESULTS: The AR multimorbidities reported in children were as follows: recurrent epistaxis (46.5%), AC (46.3%), AD (40.7%), asthma (22.5%), RRIs (21.3%), CRS (20.5%), AH (19.7%), and TH (12.5%). In univariate logistic regression analysis, age (<6 years), birth mode, familial history of allergy, and single dust mite allergy were associated with AR multimorbidity (p < 0.05). Multivariate logistic regression revealed that a familial history of allergy was an independent risk factor for AC (odds ratio [OR] = 1.539, 95% confidence interval [CI]: 1.104-2.145) and AH (OR = 1.506, 95% CI: 1.000-2.267) (p < 0.05). Age (<6 years) was independently associated with the risk of AD (OR = 1.405, 95% CI: 1.003-1.969) and RRTIs (OR = 1.869, 95% CI: 1.250-2.793) (p < 0.05), cesarean section with AR and CRS risk (OR = 1.678, 95% CI: 1.100-2.561), and single dust mite allergy with asthma (OR = 1.590, 95% CI: 1.040-2.432) and CRS (OR = 1.600, 95% CI: 1.018-2.515) risk (p < 0.05). Further, non-dust mite allergy was independently associated with AR and CRS (OR = 2.056, 95% CI: 1.084-3.899). CONCLUSION: AR was found to be accompanied by different comorbidities, including both allergic and non-allergic comorbidities, complicating disease treatment. These findings demonstrated that age (<6 years), familial history of allergy, types of allergens, and cesarean section were risk factors for different multimorbidities associated with AR.

An Integrated Method of Biomechanics Modeling for Pelvic Bone and Surrounding Soft Tissues.

The pelvis and its surrounding soft tissues create a complicated mechanical environment that greatly affects the success of fixing broken pelvic bones with surgical navigation systems and/or surgical robots. However, the modeling of the pelvic structure with the more complex surrounding soft tissues has not been considered in the current literature. The study developed an integrated finite element model of the pelvis, which includes bone and surrounding soft tissues, and verified it through experiments. Results from the experiments showed that including soft tissue in the model reduced stress and strain on the pelvis compared to when it was not included. The stress and strain distribution during pelvic loading was similar to what is typically seen in research studies and more accurate in modeling the pelvis. Additionally, the correlation with the experimental results from the predecessor's study was strong (R2 = 0.9627). The results suggest that the integrated model established in this study, which includes surrounding soft tissues, can enhance the comprehension of the complex biomechanics of the pelvis and potentially advance clinical interventions and treatments for pelvic injuries.

The Role of Slurry Reflux in a Corn Stalk Continuous Anaerobic Digestion System: Performance and Microbial Community.

Slurry reflux is a low-cost slurry reduction technology, which can solve the problem that a large amount of slurry cannot be completely consumed in a biogas plant. Anaerobic digestion (AD) of corn stalks with slurry reflux and non-reflux was compared and evaluated in continuous anaerobic digestion to clarify the effects of slurry reflux on AD with organic loading rate (OLR) variation. It was found that slurry reflux increased cumulative methane production and improved system stability. The average methane yield of the slurry reflux group was 224.19 mL/gVS, which was 41.35% higher than that of the non-reflux group. High-throughput sequencing results showed that slurry reflux increased the microbial community richness. The dominant microorganisms in the reflux group were in phylum Bacteroidetes, which have the capacity to degrade polymers, and Methanothrix, which is an aceticlastic methanogen. The relative abundances of Bacteroidetes and Methanothrix were 32.41% and 41.75%, respectively. Clostridium III and Saccharofermentans, which are related to syntrophic acetate oxidation and hydrolysis, were increased in relative abundance in the slurry reflux system. The increase of the OLR altered the main methane-producing pathway from the acetoclastic methanogenic pathway to the hydrogenotrophic methanogenic pathway in the AD system, and the slurry reflux can delay this trend. This study provided an effective way for the reduction and utilization of slurry in a biogas plant.

Administration Method and Potential Efficacy of Hyaluronidase for Hyaluronic Acid Filler-Related Vision Loss: A Systematic Review.

BACKGROUND: With the global increase in the use of injectable fillers, more cases with serious adverse events such vision loss are being reported. This article aims to review the cases of hyaluronic acid (HA) filler-related vision loss and to discuss the potential efficacy of hyaluronidase (HYASE) treatment via different given methods. METHODS: A total of 29 articles presenting 144 cases of HA filler-related vision loss were included in this study. RESULTS: Most cases of HA filler-related vision impairment were reported from China, followed by Korea. The majority of cases were seen in women. The nose, forehead and glabella were the most commonly injection sites. All cases had vision impairment and nearly all cases were unilateral with immediate onset of visual signs and symptoms. Ophthalmic artery occlusion (OAO) and central retinal artery occlusion (CRAO) were the two most commonly involved arterial obstruction patterns featured with a very poor prognosis followed by branch retinal artery occlusion (BRAO), the most favorable involved arterial pattern for a better prognosis. HYASE given subcutaneously and intra-arterially helped with visual recovery to different degrees, while retrobulbar HYASE seemed to be less helpful. CONCLUSION: Complications after HA-based filler injection are extremely rare but can cause disastrous visual impairment. HYASE given subcutaneously and intra-arterially helped with visual recovery to different extents, and the efficacy might be reinforced when performed together, while retrobulbar HYASE seemed to be less helpful. However, to accurately access the efficacy of HYASE via different administration methods, further randomized controlled trials are needed. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

[Strategies for preventing postoperative recurrence of adenoid hypertrophy].

Adenoid hypertrophy is a common disease in pediatric otorhinolaryngology. Surgical resection is the main treatment at present, but many children still face the risk of postoperative recurrence or even secondary surgery. In order to reduce the postoperative recurrence rate and provide reference information for clinical medical staff and parents of the children, this review was carried out to analyze the domestic and foreign pertinent literature in recent years and put forward overall prevention strategies base on the related factors of recurrence.

The Amomum tsao-ko Essential Oils Inhibited Inflammation and Apoptosis through p38/JNK MAPK Signaling Pathway and Alleviated Gentamicin-Induced Acute Kidney Injury.

The clinical application of gentamicin may lead to acute kidney injury (AKI), and the nephrotoxicity of gentamicin is related to the pathological mechanism of several oxidative and inflammatory cytokines. Plant-derived essential oils have good anti-inflammatory and antioxidant properties. This study aimed to clarify the protective effect of Amomum tsao-ko essential oils (AOs) on gentamicin-induced AKI in rats and its possible mechanism. The rat AKI model was induced by intraperitoneal injection of gentamicin. After 14 days of oral AO treatment, the renal function and pathological changes of the kidney tissues were evaluated, and the level of kidney tissue oxidative stress was detected. The content of inflammatory cytokines was measured by ELISA. The expression of ERK1/2, JNK1/2, p38, NF-κB, caspase-3, and Bax/Bcl-2 proteins were estimated by Western blot analysis. The results showed that taking AO reduced the contents of serum urea and creatinine in AKI rats and improve the pathological changes and oxidative stress of the kidney tissue in rats. At the same time, AO reduced inflammation and apoptosis during AKI by regulating the MAPK pathway. The data show that AO has a protective effect on the kidneys and may be a potential drug for treating kidney injury.

Three Prognostic Biomarkers Correlate with Immune Checkpoint Blockade Response in Bladder Urothelial Carcinoma.

Aim: We aim to develop a signature that could accurately predict prognosis and evaluate the response to immune checkpoint blockade (ICB) in bladder urothelial carcinoma (BLCA). Methods: Based on comprehensive analysis of public database, we identified prognosis-related hub genes and investigated their predictive values for the ICB response in BLCA. Results: Among 69 common DEGs, three genes (AURKA, BIRC5, and CKS1B) were associated with poor prognosis, and which were related to histological subtypes, TP53 mutation status, and the C2 (IFN-gamma dominant) subtype. Three genes and their related risk model can effectively predict the response of immunotherapy. Their related drugs were identified through analysis of drug bank database. Conclusions: Three genes could predict prognosis and evaluate the response to ICB in BLCA.

[Analysis of clinical characteristics and surgical efficiency of severe laryngomalacia in children].

Objective:To analyze the clinical characteristics and factors affecting surgical efficiency in children with severe laryngomalacia. Methods:Retrospectively collect medical records of children with severe laryngomalacia who underwent supraglottoplasty in Children's Hospital of Chongqing Medical University between January 1, 2015 and May 1, 2019. And analyze the clinical characteristics, the improvement of main symptoms at different time points, and the influence factors on the surgical efficiency. Results:According to the anatomical classification of severe laryngomalacia, type Ⅳ accounted for the highest proportion（66.1%）, and type Ⅰ was the lowest（3.6%）. All children had stridor and dyspnea, 82.1% cases presented feeding difficulties, and 67.9% cases presented failure to thrive. The proportion of children with medical comorbidities was 62.5%, of which congenital heart disease had the highest incidence（39.3%） The surgical efficiency of severe laryngomalacia without comorbidities was 100.0%, with one type of comorbidity was 96.0%, with multiple comorbidities was 30.0%（P<0.01）. Stridor, dyspnea, feeding difficulties were significantly improved at one month after surgery in most cases. In the group of surgical age less than 3 months, the surgical efficiency were 61.5%, 61.5% and 69.2% at 1, 3, 6 months after surgery, respectively; the surgical efficiency of children without comorbidities were 100.0%（P>0.05） at 1, 3 ,6 months after surgery. In the group of surgical age older than 3 months, the surgical efficiency of children were 100.0% at 1, 3, 6 months after surgery regardless with or without comorbidities. The surgical failure rate and reoperation rate in children without comorbidities was 0, but in the children with comorbidities were 22.9%（P<0.05） and 20.0%（P<0.05）, respectively. The surgical failure rate and reoperation rate in children with multiple comorbidities was significantly higher than children with only one comorbidity（70.0% vs. 4.0%; 60.0% vs. 4.0%, P<0.01）. The overall operation success rate was 85.7% in severe laryngomalacia children in our hospital. Conclusion:Most children with severe laryngomalacia are associated with multiple medical comorbidities, and with more complex anatomical types. Supraglottoplasty can effectively improve the symptoms in most children with severe laryngomalacia. The existence of multiple comorbidities is the main cause of surgical failure.

DNA Repair-Related Gene Signature in Predicting Prognosis of Colorectal Cancer Patients.

Background: Increasing evidence have depicted that DNA repair-related genes (DRGs) are associated with the prognosis of colorectal cancer (CRC) patients. Thus, the aim of this study was to evaluate the impact of DNA repair-related gene signature (DRGS) in predicting the prognosis of CRC patients. Method: In this study, we retrospectively analyzed the gene expression profiles from six CRC cohorts. A total of 1,768 CRC patients with complete prognostic information were divided into the training cohort (n = 566) and two validation cohorts (n = 624 and 578, respectively). The LASSO Cox model was applied to construct a prediction model. To further validate the clinical significance of the model, we also validated the model with Genomics of Drug Sensitivity in Cancer (GDSC) and an advanced clear cell renal cell carcinoma (ccRCC) immunotherapy data set. Results: We constructed a prognostic DRGS consisting of 11 different genes to stratify patients into high- and low-risk groups. Patients in the high-risk groups had significantly worse disease-free survival (DFS) than those in the low-risk groups in all cohorts [training cohort: hazard ratio (HR) = 2.40, p < 0.001, 95% confidence interval (CI) = 1.67-3.44; validation-1: HR = 2.20, p < 0.001, 95% CI = 1.38-3.49 and validation-2 cohort: HR = 2.12, p < 0.001, 95% CI = 1.40-3.21). By validating the model with GDSC, we could see that among the chemotherapeutic drugs such as oxaliplatin, 5-fluorouracil, and irinotecan, the IC50 of the cell line in the low-risk group was lower. By validating the model with the ccRCC immunotherapy data set, we can clearly see that the overall survival (OS) of the objective response rate (ORR) with complete response (CR) and partial response (PR) in the low-risk group was the best. Conclusions: DRGS is a favorable prediction model for patients with CRC, and our model can predict the response of cell lines to chemotherapeutic agents and potentially predict the response of patients to immunotherapy.

mGluR5 promotes the progression of multiple myeloma in vitro via Ras-MAPK signaling pathway.

BACKGROUND: Multiple myeloma (MM) is a malignant plasma cancer which remains difficult to be cured. Recently, numerous research studies have appeared, exploring MM from molecular level. However, there is no study about the impact of metabotropic glutamate receptors (mGluRs), especially mGluR5, on MM progression. Thus, the present research was dedicated to the exploration of the influence of mGluR5 on MM. OBJECTIVES: In this research, we used quantitative real-time polymerase chain reaction (qRT-PCR) to check the gene expression in MM, western blot assay to check the protein expression of the gene, MTT assay to quantify the cell viability, and flow cytometry (FCM) apoptosis method to evaluate cell apoptosis in order to acquire the results. The purpose was to assess the role of mGluR5 in MM cells. MATERIAL AND METHODS: The qRT-PCR was used and it was found that mGluR5 was overexpressed in MM cell lines and MM tissues compared to normal ones. To better observe the function of mGluR5 in MM, cell viability and apoptosis were checked using MTT and FCM apoptosis assays after the treatment with agonists and antagonists. RESULTS: Agonist-induced mGluR5 upregulation could promote MM cell viability and inhibit apoptosis. The same results were obtained through MTT and FCM apoptosis assays after upregulation and downregulation of mGluR5 by transfection. To further investigate the inner mechanism, the effect of mGluR5 on Ras-MAPK pathway was checked using western blot. It was found that the upregulation of mGluR5 could activate the Ras-MAPK pathway. CONCLUSIONS: The mGluR5 might be involved in promoting cell proliferation and inhibiting cell apoptosis in MM. It can be an essential biomarker in the screening for MM and a potential part of future MM therapies.

IFNγ enhances ferroptosis by increasing JAK­STAT pathway activation to suppress SLCA711 expression in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare type of tumor with a poor prognosis. Ferroptosis is a relatively novel form of programmed cell death driven by iron­dependent lipid peroxidation accumulation. Recent evidence suggests that IFNγ facilitates erastin­induced ferroptosis, which contributed to anticancer therapy in various types of cancer. However, it has remained elusive whether the regulation of IFNγ on ferroptosis has a positive role in the treatment of ACC. Thus, the aim of the present study was to explore the effects of IFNγ on erastin­induced ferroptosis in the ACC cell line NCI­H295R and investigate the underlying mechanisms. Cell viability was assessed using a Cell Counting Kit­8 assay, an ethynyldioxyuridine proliferation assay and Live/Dead staining. The levels of iron, reactive oxygen species, lipid peroxidation and mitochondrial damage were also assessed. Western blot and reverse transcription­quantitative PCR analyses were used to determine the underlying molecular mechanisms involved in the erastin­induced ferroptosis of NCI­H295R cells. The results suggested that IFNγ promoted erastin­induced ferroptotic cell death. Furthermore, IFNγ enhanced erastin­induced ferroptosis, as evidenced by the accumulation of iron, as well as the increase in lipid peroxidation and promotion of mitochondrial damage. Further analysis suggested that IFNγ enhanced ferroptosis by suppressing the expression of solute carrier family 7 member 11, an important negative regulator of ferroptosis, and this was achieved via activation of the JAK/STAT pathway in NCI­H295R cells. The present study provided experimental evidence on the activity and mechanism of ferroptosis enhanced by IFNγ in ACC and may give critical insight into the immunotherapeutic management of ACC.

Effect of preconditioning exercise on biceps brachii myotendinous junction displacement during elbow flexor eccentric exercise.

The present study tested the hypothesis that 30 low-intensity (10%) eccentric contractions (10%EC) or two maximal voluntary isometric contractions at a long muscle length (2MVIC) that were performed at two days before maximal eccentric exercise of the elbow flexors consisting of five sets of six maximal eccentric contractions (MaxEC) would reduce increases in biceps brachii distal myotendinous junction displacement (MTJd) over the eccentric contractions during MaxEC. Sedentary young men were randomly placed (n = 12/group) to a control group that performed two bouts of MaxEC (CONT-1st, CONT-2nd) separated by two weeks, or one of two preconditioning groups that performed 10%EC or 2MVIC at 20° elbow flexion at two days prior to MaxEC. All exercises were performed by the non-dominant arm. MTJd of each contraction was assessed by B-mode ultrasound, and its changes over sets were compared among the groups. The average MTJd from the start to the end of six eccentric contractions in the first set was similar among the groups (6.4 ± 0.7 mm). The MTJd increased from the first to fifth set, but the increase was smaller (P < .05) for the 10%EC (13 ± 6%) and 2MVIC (16 ± 9%) groups, and CONT-2nd (3 ± 6%) when compared with CONT-1st (60 ± 12%). Both 10%EC and 2MVIC groups showed smaller (P < .05) changes in all muscle damage markers after MaxEC similarly when compared with CONT-1st, but the changes were greater than those after CONT-2nd. These results supported the hypothesis that protective effect was associated with less MTJd changes, suggesting that this is associated with the mechanisms underpinning the preconditioning effect on muscle damage.

Future Directions in Diagnosis, Prognosis and Disease Monitoring of Adrenocortical Carcinoma: Novel Non-Invasive Biomarkers.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with frequent metastatic spread and poor prognosis. The disease can occur at any age with unexpected biological behavior. Recent genome-wide studies of ACC have contributed to our understanding of the disease, but diagnosis of ACC remains a challenge, even for multidisciplinary expert teams. Patients with ACC are frequently diagnosed in advanced stages and have limited therapeutic options. Therefore, for earlier diagnosis and better clinical management of adrenocortical carcinoma, specific, sensitive, and minimal invasive markers are urgently needed. Over several decades, great efforts have been made in discovering novel and reliable diagnostic and prognostic biomarkers including microRNAs, steroid profilings, circulating tumor cells, circulating tumor DNAs and radiomics. In this review, we will summarize these novel noninvasive biomarkers and analyze their values for diagnosis, predicting prognosis, and disease monitoring. Current problems and possible future application of these non-invasive biomarkers will also be discussed.

The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation.

The transcription factor forkhead box P3 (FOXP3) is essential for the development of regulatory T cells (Tregs) and their function in immune homeostasis. Previous studies have shown that in natural Tregs (nTregs), FOXP3 can be regulated by polyubiquitination and deubiquitination. However, the molecular players active in this pathway, especially those modulating FOXP3 by deubiquitination in the distinct induced Treg (iTreg) lineage, remain unclear. Here, we identify the ubiquitin-specific peptidase 44 (USP44) as a novel deubiquitinase for FOXP3. USP44 interacts with and stabilizes FOXP3 by removing K48-linked ubiquitin modifications. Notably, TGF-ß induces USP44 expression during iTreg differentiation. USP44 co-operates with USP7 to stabilize and deubiquitinate FOXP3. Tregs genetically lacking USP44 are less effective than their wild-type counterparts, both in vitro and in multiple in vivo models of inflammatory disease and cancer. These findings suggest that USP44 plays an important role in the post-translational regulation of Treg function and is thus a potential therapeutic target for tolerance-breaking anti-cancer immunotherapy.