Differential diagnosis of pediatric cervical lymph node lesions based on simple clinical features.

This study aims to to establish a diagnosis model based on simple clinical features for children with cervical histiocytic necrotizing lymphadenitis or malignant lymphoma. Simple clinical features of pediatric patients were analyzed to develop a diagnosis model based on a comparison of classical machine-learning algorithms. This was a single-center retrospective study in a tertiary pediatrics hospital. Pediatric patients treated for cervical histiocytic necrotizing lymphadenitis or malignant lymphoma treated at our institution in recent 5 years were included. Demographic data and laboratory values were recorded and binary logistics regression analysis was applied to select possible predictors to develop diagnostic models with different algorithms. The diagnostic efficiency and stability of each algorithm were evaluated to select the best one to help establish the final model. Eighty-three children were included with 45 cases of histiocytic necrotizing lymphadenitis and 38 cases of malignant lymphoma. Peak temperature, white blood cell count, monocyte percentage, and urea value were selected as possible predictors based on the binary logistics regression analysis, together with imaging features already reported (size, boundary, and distribution of mass). In the ten-round random testing sets, the discriminant analysis algorithm achieved the best performance with an average accuracy of 89.0% (95% CI 86.2-93.6%) and an average AUC value of 0.971 (95% CI 0.957-0.995). CONCLUSION: A discriminant analysis model based on simple clinical features can be effective in differential diagnosis of cervical histiocytic necrotizing lymphadenitis and malignant lymphoma in children. Peak body temperature, white blood cell count, and short diameter of the largest mass are significant predictors. WHAT IS KNOWN: • Several multivariate diagnostic models for HNL and ML have been proposed based on B-ultrasound or CT features in adults. • The differences between children and adults are nonnegligible in the clinical featues of HNL. WHAT IS NEW: • The study firstly report a large-sample diagnostic model between the HNL and MLin pediatric patients. • Non-imaging clinical features has also been proven with quite good diagnostic value.

Roles of distinct nuclear receptors in diabetic cardiomyopathy.

Diabetes mellitus induces a pathophysiological disorder known as diabetic cardiomyopathy and may eventually cause heart failure. Diabetic cardiomyopathy is manifested with systolic and diastolic contractile dysfunction along with alterations in unique cardiomyocyte proteins and diminished cardiomyocyte contraction. Multiple mechanisms contribute to the pathology of diabetic cardiomyopathy, mainly including abnormal insulin metabolism, hyperglycemia, glycotoxicity, cardiac lipotoxicity, endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, calcium treatment damage, programmed myocardial cell death, improper Renin-Angiotensin-Aldosterone System activation, maladaptive immune modulation, coronary artery endothelial dysfunction, exocrine dysfunction, etc. There is an urgent need to investigate the exact pathogenesis of diabetic cardiomyopathy and improve the diagnosis and treatment of this disease. The nuclear receptor superfamily comprises a group of transcription factors, such as liver X receptor, retinoid X receptor, retinoic acid-related orphan receptor-α, retinoid receptor, vitamin D receptor, mineralocorticoid receptor, estrogen-related receptor, peroxisome proliferatoractivated receptor, nuclear receptor subfamily 4 group A 1(NR4A1), etc. Various studies have reported that nuclear receptors play a crucial role in cardiovascular diseases. A recently conducted work highlighted the function of the nuclear receptor superfamily in the realm of metabolic diseases and their associated complications. This review summarized the available information on several important nuclear receptors in the pathophysiology of diabetic cardiomyopathy and discussed future perspectives on the application of nuclear receptors as targets for diabetic cardiomyopathy treatment.

Intravitreal Delivery of rAAV2-hSyn-hRS1 Results in Retinal Ganglion Cell-Specific Gene Expression and Retinal Improvement in the Rs1-KO Mouse.

X-linked retinoschisis (XLRS) is a monogenic recessive inherited retinal disease caused by defects in retinoschisin (RS1). It manifests clinically as retinal schisis cavities and a disproportionate reduction of b-wave amplitude compared with the a-wave amplitude. Currently there is no approved treatment. In the last decade, there has been major progress in the development of gene therapy for XLRS. Previous preclinical studies have demonstrated the treatment benefits of hRS1 gene augmentation therapy in mouse models. However, outcomes in clinical trials have been disappointing, and this might be attributed to dysfunctional assembly of RS1 complexes and/or the impaired targeted cells. In this study, the human synapsin 1 gene promoter (hSyn) was used to control the expression of hRS1 to specifically target retinal ganglion cells and our results confirmed the specific expression and functional assembly of the protein. Moreover, our results demonstrated that a single intravitreal injection of rAAV2-hSyn-hRS1 results in architectural restoration of retinal schisis cavities and improvement in vision in a mouse model of XLRS. In brief, this study not only supports the clinical development of the rAAV2-hSyn-hRS1 vector in XLRS patients but also confirms the therapeutic potential of rAAV-based gene therapy in inherited retinal diseases.

Hyperthermia improves gemcitabine sensitivity of pancreatic cancer cells by suppressing the EFNA4/ß-catenin axis and activating dCK.

Background: Previously, our investigations have underscored the potential of hyperthermia to improve the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer (PC). Nonetheless, the precise underlying mechanisms remain elusive. Methods: We engineered two GEM-resistant PC cell lines (BxPC-3/GEM and PANC-1/GEM) and treated them with GEM alongside hyperthermia. The impact of hyperthermia on the therapeutic potency of GEM was ascertained through MTT assay, assessment of the concentration of its active metabolite dFdCTP, and evaluation of deoxycytidine kinase (dCK) activity. Lentivirus-mediated dCK silencing was further employed to validate its involvement in mediating the GEM-sensitizing effect of hyperthermia. The mechanism underlying hyperthermia-mediated dCK activation was explored using bioinformatics analyses. The interplay between hyperthermia and the ephrin A4 (EFNA4)/ß-catenin/dCK axis was investigated, and their roles in GEM resistance was further explored via the establishment of xenograft tumor models in nude mice. Results: Hyperthermia restored dCK expression in GEM-resistant cell lines, concurrently enhancing GEM sensitivity and fostering DNA damage and cell death. These observed effects were negated by dCK silencing. Regarding the mechanism, hyperthermia activated dCK by downregulating EFNA4 expression and mitigating ß-catenin activation. Overexpression of EFNA4 activated the ß-catenin while suppressing dCK, thus diminishing cellular GEM sensitivity-a phenomenon remediated by the ß-catenin antagonist MSAB. Consistently, in vivo, hyperthermia augmented the therapeutic efficacy of GEM on xenograft tumors through modulation of the ephrin A4/ß-catenin/dCK axis. Conclusion: This study delineates the role of hyperthermia in enhancing GEM sensitivity of PC cells, primarily mediated through the suppression of the EFNA4/ß-catenin axis and activation of dCK.

CsiR-Mediated Signal Transduction Pathway in Response to Low Iron Conditions Promotes Escherichia coli K1 Invasion and Penetration of the Blood-Brain Barrier.

Escherichia coli K1 is the leading cause of neonatal gram-negative bacterial meningitis, but the pathogenesis of E coli K1 meningitis remains unclear. Blood-brain barrier (BBB) penetration is a crucial step in E coli meningitis development. Here, we uncovered the crucial role of CsiR, a GntR family regulator, in E coli K1 virulence. During infection, csiR expression was induced due to the derepression by Fur in the blood and human brain microvascular endothelial cells (HBMECs). CsiR positively regulated ilvB expression, which is associated with branched chain amino acid synthesis. Furthermore, we revealed that IlvB activated the FAK/PI3K pathway of HBMECs to induce actin cytoskeleton rearrangements, thereby promoting the bacterial invasion and penetration of the BBB. Overall, this study reveals a CsiR-mediated virulence regulation pathway in E coli K1, which may provide a useful target for the prevention or therapy of E coli meningitis.

The application of 3D-printed auto-stable artificial vertebral body in en bloc resection and reconstruction of thoracolumbar metastases.

BACKGROUND: Nerve compression symptoms and spinal instability, resulting from spinal metastases, significantly impact the quality of life for patients. A 3D-printed vertebral body is considered an effective approach to reconstruct bone defects following en bloc resection of spinal tumors. The advantage of this method lies in its customized shape and innermost porous structure, which promotes bone ingrowth and leads to reduced postoperative complications. OBJECTIVE: The purpose of this study is to assess the effectiveness of 3D-printed auto-stable artificial vertebrae in the en bloc resection and reconstruction of thoracolumbar metastases. METHODS: This study included patients who underwent en bloc resection of thoracolumbar metastases based on the Weinstein-Boriani-Biagini surgical staging system, between January 2019 and April 2021. The patients were divided into two groups: the observation group, which was reconstructed using 3D-printed auto-stable vertebral bodies, and the control group, treated with titanium cages and allograft bone. Evaluation criteria for the patients included assessment of implant subsidence, instrumentation-related complications, VAS score, and Frankel grading of spinal cord injury. RESULTS: The median follow-up period was 21.8 months (range 12-38 months). Among the patients, 10 received a customized 3D-printed artificial vertebral body, while the remaining 10 received a titanium cage. The observation group showed significantly lower operation time, intraoperative blood loss, and postoperative drainage compared to the control group (P < 0.05). At the final follow-up, the average implant subsidence was 1.8 ± 2.1 mm for the observation group and 5.2 ± 5.1 mm for the control group (P < 0.05). The visual analog scale (VAS) scores were not statistically different between the two groups at preoperative, 24 h, 3 months, and 1 year after the operation (P < 0.05). There were no statistically significant differences in the improvements of spinal cord functions between the two groups. CONCLUSION: The utilization of a 3D-printed auto-stable artificial vertebra for reconstruction following en bloc resection of thoracolumbar metastases appears to be a viable and dependable choice. The low occurrence of prosthesis subsidence with 3D-printed prostheses can offer immediate and robust stability.

Epidemiology and Predictors for Cervical Burn Scar Contractures: A Multicenter Cohort Study.

Cervical burn scar contracture (BSC) affects many important neck functions and the patients' quality of life. However, it remains unclear which patients have a higher risk of neck BSCs. This study aimed to describe the epidemiology and identify the independent risks of cervical BSC formation and severity. Clinical and demographic data of 106 patients with burn scars were retrospectively collated and analyzed from 3 different Chinese hospitals between December 2016 and December 2020. Both univariate and multivariate logistic regression analyses were performed to identify the independent risks for BSC formation and severity at 12 months postburn. Lateral flexion was the most common plane of motion (POM) limited by contractures (29.4%), whereas the POM most commonly limited by severe contractures was the extension (24.6%). Most patients with contractures had those in 3 to 4 POMs (72.1%). Neck skin grafting was an independent risk factor for BSC formation, and cervical and cervicothoracic skin grafting were independent risk factors for BSC severity. These results may help to identify high-risk patients with contractures in the early stages of burns to carry out individualized early prevention and treatment.

Management of balloon dilatation in cases of subglottic stenosis in children: success and failure.

PURPOSE: To assess efficacy and prognostic factors of endoscopic balloon dilatation for the treatment of subglottic stenosis in children. METHODS: A retrospective review was performed on 49 pediatric patients with subglottic stenosis treated at the Shanghai Children's Hospital between December 2017 and December 2021. Specific demographic data, type and severity of the stenosis, number of balloon dilatations and outcomes were recorded and analyzed. RESULTS: Forty-nine children (30 male, 19 female) were included in the study with a median age at diagnosis of 24 (13-36.5) months, of which 7 (14.3%) had received open laryngotracheal reconstruction previously. The degree of subglottic stenosis was grade I in six patients, grade II in 16 patients, grade III in 20 patients and grade IV in seven patients. After various numbers of balloon dilatations (1-7 times), 29 patients showed a good outcome (decannulation or prevention of tracheostomy) and the success rate in that series was 59.2%. Overall, prognosis of balloon dilatation was not dependent on pathogeny (congenital or acquired) or open surgical history(P > 0.05), but rather on the severity grade of stenosis and the number of dilatations (P < 0.05). CONCLUSIONS: Endoscopic balloon dilatation can be safe and effective in the treatment of subglottic stenosis in children, except for more serious cases (grade IV). Open surgery should be considered if no significant improvement is observed after dilatation, especially after three or more dilatations.

Lactate attenuates astrocytic inflammation by inhibiting ubiquitination and degradation of NDRG2 under oxygen-glucose deprivation conditions.

BACKGROUND: Brain lactate concentrations are enhanced in response to cerebral ischemia and promote the formation of reactive astrocytes, which are major components of the neuroinflammatory response and functional recovery, following cerebral ischemia. NDRG2 is upregulated during reactive astrocyte formation. However, its regulation and function are unclear. We studied the relationship between lactate and NDRG2 in astrocytes under conditions of ischemia or oxygen-glucose deprivation (OGD). METHODS: We examined astrocytic NDRG2 expression after middle cerebral artery occlusion (MCAO) using western blot and immunofluorescence staining. Under hypoxia conditions, we added exogenous L-lactate sodium (lactate) to cultured primary astrocytes to explore the effects of lactate on the ubiquitination modification of NDRG2. We profiled the transcriptomic features of NDRG2 silencing in astrocytes after 8 h of OGD conditions as well as exogenous lactate treatment by performing RNA-seq. Finally, we evaluated the molecular mechanisms of NDRG2 in regulating TNFα under OGD conditions using western blot and immunohistochemistry. RESULTS: Reactive astrocytes strongly expressed NDRG2 in a rat model of MCAO. We also showed that lactate stabilizes astrocytic NDRG2 by inhibiting its ubiquitination. NDRG2 inhibition in astrocytes increased inflammation and upregulated immune-associated genes and signaling pathways. NDRG2 knockdown induced TNFα expression and secretion via c-Jun phosphorylation. CONCLUSIONS: We revealed that under OGD conditions, lactate plays an important anti-inflammatory role and inhibits TNFα expression by stabilizing NDRG2, which is beneficial for neurological functional recovery. NDRG2 may be a new therapeutic target for cerebral ischemia.

Lymph node ratio is a superior predictor in surgically treated early-onset pancreatic cancer.

Background: The prognostic performance of four lymph node classifications, the 8th American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) N stage, lymph node ratio (LNR), log odds of positive lymph nodes (LODDS), and examined lymph nodes (ELN) in early-onset pancreatic cancer (EOPC) remains unclear. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was searched for patients with EOPC from 2004 to 2016. 1048 patients were randomly divided into training (n = 733) and validation sets (n = 315). The predictive abilities of the four lymph node staging systems were compared using the Akaike information criteria (AIC), receiver operating characteristic area under the curve (AUC), and C-index. Multivariate Cox analysis was performed to identify independent risk factors. A nomogram based on lymph node classification with the strongest predictive ability was established. The nomogram's precision was verified by the C-index, calibration curves, and AUC. Kaplan-Meier analysis and log-rank tests were used to compare differences in survival at each stage of the nomogram. Results: Compared with the 8th N stage, LODDS, and ELN, LNR had the highest C-index and AUC and the lowest AIC. Multivariate analysis showed that N stage, LODDS, LNR were independent risk factors associated with cancer specific survival (CSS), but not ELN. In the training set, the AUC values for the 1-, 3-, and 5-year CSS of the nomogram were 0.663, 0.728, and 0.760, respectively and similar results were observed in the validation set. In addition, Kaplan-Meier survival analysis showed that the nomogram was also an important factor in the risk stratification of EOPC. Conclusion: We analyzed the predictive power of the four lymph node staging systems and found that LNR had the strongest predictive ability. Furthermore, the novel nomogram prognostic staging mode based on LNR was also an important factor in the risk stratification of EOPC.

Roles of the adaptor protein tumor necrosis factor receptor type 1-associated death domain protein (TRADD) in human diseases.

Cells communication in response to extracellular or biophysical stimulus relies on elaborated systems of signal transduction. In the course of most signal pathway, the cascades involve signal protein complexes, which are often assembled by adaptor proteins. Tumor necrosis factor receptor type 1-associated death domain protein (TRADD) is an adaptor molecule involved in various signal pathways and mediating multiple biological activities, including cell survival, cell proliferation, cell differentiation, apoptosis, necroptosis and inflammation. TRADD contains an N terminal tumor necrosis factor receptor-associated factor 2 (TRAF2) binding domain and a C terminal death domain (DD) for interacting with multiple DD-containing proteins. Following activation of specific receptors, such as tumor necrosis factor receptor 1 (TNFR1), death receptor 3 (DR3), tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAILR1, DR4), TRAILR1 (DR5), DR6 and p75 neurotrophin receptor (p75NTR)，TRADD can bind to the receptors, serving as a platform for the recruitment of the downstream molecules for signal propagating and thus mediating various physiological and pathological processes. In this review, we provide a brief overview of the current knowledge on TRADD and discuss the roles of TRADD in infectious and inflammatory diseases, cardiovascular diseases, central nervous system diseases, cancer, endometriosis, hepatocyte proliferation, preterm birth and perinatal development.

[Case report of the substantial nasal mass in children and literature review].

In this article we reported 13 cases of the substantial nasal mass in children. Among 13 these patients, 3 cases were septal hemangioma, 2 cases were maxillary hemangioma, 1 case was nasal infantile fibromatosis, 1 case was osteoblastoma of the nasal cavity and sinuses, 2 cases were lymphoma of nasopharynx, 1 case was maxillary lymphoma, 1 case was rhabdomyosarcoma of nasopharynx, 1 case was maxillary squamous-cell carcinoma, 1 case was squamous-cell carcinoma of nasopharynx.All 13 cases were treated with surgery, 1 case with nasal infantile fibromatosis, 2 cases with lymphoma of nasopharynx, 1 case with rhabdomyosarcoma of nasopharynx, 1 case with nasopharyngeal carcinoma and 1 case with maxillary carcinoma were taken postoperative radiotherapy and chemotherapy. The most common substantial nasal mass in children was hemangioma. This study included 2 cases with nasal invasive benign tumors, 1 case with nasal infantile fibromatosis and 1 case with osteoblastoma of the nasal cavity and sinuses. The functional nasal endoscopic surgery of mass resection was the main method for the treatment of mass in this area and had achieved satisfied effect. Lymphoma and rhabdomyosarcoma were the most common nasal malignant tumor in children. Nasopharyngeal carcinoma and maxillary carcinoma were not uncommon.

Bacteria reduce flagellin synthesis to evade microglia-astrocyte-driven immunity in the brain.

The immune response of brain cells to invading bacteria in vivo and the mechanism used by pathogenic bacteria to escape brain immune surveillance remain largely unknown. It is believed that microglia eliminate bacteria by phagocytosis based on in vitro data. Here we find that a small percentage of microglia in the brain engulf neonatal meningitis-causing Escherichia coli (NMEC), but more microglia are activated to produce tumor necrosis factor alpha (TNFα), which activates astrocytes to secrete complement component 3 (C3) involved in anti-bacterial activity. To evade anti-bacterial activity of the immune system, NMEC senses low concentration of threonine in cerebrospinal fluid (CSF) to down-modulate the expression of flagellin and reduce microglial TNFα and astrocyte C3 production. Our findings may help develop strategies for bacterial meningitis treatment.

Protective role of hydrogen sulfide against diabetic cardiomyopathy via alleviating necroptosis.

Diabetic cardiomyopathy lacks effective and novel methods. Hydrogen sulfide (H2S) as the third gasotransmitter plays an important role in the cardiovascular system. Our study was to elucidate the protective effect and possible mechanism of H2S on diabetic cardiomyopathy from the perspective of necroptosis. Leptin receptor deficiency (db/db) mice and streptozotocin (STZ)-induced diabetic cystathionine-γ-lyase (CSE) knockout (KO) mice were investigated. In addition, cardiomyocytes were stimulated with high glucose. We found that plasma H2S level, myocardial H2S production and CSE mRNA expression was impaired in the diabetic mice. CSE deficiency exacerbated diabetic cardiomyopathy, and promoted myocardial oxidative stress, necroptosis and inflammasome in STZ-induced mice. CSE inhibitor dl-propargylglycine (PAG) aggravated cell damage and oxidative stress, deteriorated necroptosis and inflammasome in cardiomyocytes with high glucose stimulation. H2S donor sodium hydrosulfide (NaHS) improved diabetic cardiomyopathy, attenuated myocardial oxidative stress, necroptosis and the NLR family pyrin domain-containing protein 3 (NLRP3) in db/db mice. NaHS also alleviated cell damage, oxidative stress, necroptosis and inflammasome in cardiomyocytes with high glucose stimulation. In Conclusion, H2S deficiency aggravated mitochondrial damage, increased reactive oxygen species accumulation, promoted necroptosis, activated NLRP3 inflammasome, and finally exacerbated diabetic cardiomyopathy. Exogenous H2S supplementation alleviated necroptosis to suppress NLRP3 inflammasome activation and attenuate diabetic cardiomyopathy via mitochondrial dysfunction improvement and oxidative stress inhibition. Our study provides the first evidence and a new mechanism that necroptosis inhibition by a pharmacological manner of H2S administration protected against diabetic cardiomyopathy. It is beneficial to provide a novel strategy for the prevention and treatment of diabetic cardiomyopathy.

miR-124: A Promising Therapeutic Target for Central Nervous System Injuries and Diseases.

Central nervous system injuries and diseases, such as ischemic stroke, spinal cord injury, neurodegenerative diseases, glioblastoma, multiple sclerosis, and the resulting neuroinflammation often lead to death or long-term disability. MicroRNAs are small, non-coding, single-stranded RNAs that regulate posttranscriptional gene expression in both physiological and pathological cellular processes, including central nervous system injuries and disorders. Studies on miR-124, one of the most abundant microRNAs in the central nervous system, have shown that its dysregulation is related to the occurrence and development of pathology within the central nervous system. Herein, we review the molecular regulatory functions, underlying mechanisms, and effective delivery methods of miR-124 in the central nervous system, where it is involved in pathological conditions. The review also provides novel insights into the therapeutic target potential of miR-124 in the treatment of human central nervous system injuries or diseases.

A Nomogram Based on the Log Odds of Positive Lymph Nodes Predicts the Prognosis of Patients With Distal Cholangiocarcinoma After Surgery.

Background: Lymph node (LN) metastasis is considered one of the most important risk factors affecting the prognosis of distal cholangiocarcinoma (DCC). This study aimed to demonstrate the superiority of log odds of positive lymph nodes (LODDS) compared with other LN stages, and to establish a novel prognostic nomogram to predict the cancer-specific survival (CSS) of DCC. Methods: From the Surveillance, Epidemiology and End Results (SEER) database, the data of 676 patients after DCC radical operation were screened, and patients were randomly divided into training (n = 474) and validation sets (n = 474). The prognostic evaluation performance of the LODDS and American Joint Commission on Cancer (AJCC) N stage and lymph node ratio (LNR) were compared using the Akaike information criteria, receiver operating characteristic area under the curve (AUC), and C-index. Multivariate Cox analysis was used to screen independent risk factors, and a LODDS-based nomogram prognostic staging model was established. The nomogram's precision was verified by C-index, calibration curves, and AUC, and the results were compared with those of the AJCC TNM staging system. Results:Compared with the other two stages of LN metastasis, LODDS was most effective in predicting CSS in patients with DCC. Multivariate analysis proved that LODDS, histologic grade, SEER historic stage, and tumor size were independent risk factors for DCC. The C-index of the nomogram, based on the above factors, in the validation set was 0.663. The 1-, 3-, and 5-y AUCs were 0.735, 0.679, and 0.745, respectively. Its good performance was also verified by calibration curves. In addition, the C-index and Kaplan-Meier analysis showed that the nomogram performed better than the AJCC TNM staging system. Conclusion:For postoperative patients with DCC, the LODDS stage yielded better prognostic efficiency than the AJCC N and LNR stages. Compared with the AJCC TNM staging system, the nomogram, based on the LODDS, demonstrated superior performance.

Construction of a Prognostic Model for Hepatocellular Carcinoma Based on Immunoautophagy-Related Genes and Tumor Microenvironment.

BACKGROUND: The aim of this study was to screen and identify immunoautophagy-related genes (IARGs) in HCC patients and clarify their potential prognostic value in HCC patients. METHODS: Immune-related genes and autophagy-related gene were downloaded from public databases. Cox regression analysis was used to selected several immunoautophagy-related genes to establish a prognostic model, and patients were divided into high- and low-risk groups based on median risk score. We analyzed the overall survival and clinicopathological characteristics between two groups. Meanwhile, internal validation dataset and external ICGC dataset were used to verify robustness of the model. Associations between six immune cells infiltrates and risk score were analyzed. RESULTS: A prognostic model was established based on CANX and HDAC1. The prognoses of the high-risk group were worse than low-risk group in both TCGA and ICGC datasets. Multivariate Cox regression analysis showed that risk score was an independent prognostic factor for HCC patients. Results showed that the risk score in young group was higher than elderly group. Patients with poorly differentiated tumor may have high risk score and poor survival. The score was positively correlated with immune cells. CONCLUSION: Our study shows that immunoautophagy-related genes have potential prognostic value for patients with HCC and may provide new information and direction for targeted therapy.

Declines in PDE4B activity promote myopia progression through downregulation of scleral collagen expression.

Myopia is the most common cause of a visual refractive error worldwide. Cyclic adenosine monophosphate (cAMP)-linked signaling pathways contribute to the regulation of myopia development, and increases in cAMP accumulation promote myopia progression. To pinpoint the underlying mechanisms by which cAMP modulates myopia progression, we performed scleral transcriptome sequencing analysis in form-deprived mice, a well-established model of myopia development. Form deprivation significantly inhibited the expression levels of genes in the cAMP catabolic pathway. Quantitative real-time polymerase chain reaction analysis validated that the gene expression level of phosphodiesterase 4B (PDE4B), a cAMP hydrolase, was downregulated in form-deprived mouse eyes. Under visually unobstructed conditions, loss of PDE4B function in Pde4b-knockout mice increased the myopic shift in refraction, -3.661 ± 1.071 diopters, more than that in the Pde4b-wildtype littermates (P < 0.05). This suggests that downregulation and inhibition of PDE4B gives rise to myopia. In guinea pigs, subconjunctival injection of rolipram, a selective inhibitor of PDE4, led to myopia in normal eyes, and it also enhanced form-deprivation myopia (FDM). Subconjunctival injection of dibutyryl-cyclic adenosine monophosphate, a cAMP analog, induced only a myopic shift in the normal visually unobstructed eyes, but it did not enhance FDM. As myopia developed, axial elongation occurred during scleral remodeling that was correlated with changes in collagen fibril thickness and distribution. The median collagen fibril diameter in the FDM + rolipram group, 55.09 ± 1.83 nm, was thinner than in the FDM + vehicle group, 59.33 ± 2.06 nm (P = 0.011). Thus, inhibition of PDE4 activity with rolipram thinned the collagen fibril diameter relative to the vehicle treatment in form-deprived eyes. Rolipram also inhibited increases in collagen synthesis induced by TGF-ß2 in cultured human scleral fibroblasts. The current results further support a role for PDE enzymes such as PDE4B in the regulation of normal refractive development and myopia because either loss or inhibition of PDE4B function increased myopia and FDM development through declines in the scleral collagen fibril diameter.

Assessment of Systemic Inflammation and Nutritional Indicators in Predicting Recurrence-Free Survival After Surgical Resection of Gastrointestinal Stromal Tumors.

BACKGROUND: Recent studies have shown that the systemic inflammation and nutritional indicators are prognostic for a variety of malignancies. However, only limited data have so far demonstrated their usefulness in gastrointestinal mesenchymal tumors (GIST). METHODS: We retrospectively analyzed the data of GIST patients who underwent radical surgery in Beijing hospital from October 2004 to July 2018. The area under the receiver operating characteristic curve (AUC) was used to compare several commonly used inflammatory and nutritional indicators. The indicators with largest AUC were further analysis. Optimal cut-off values of those indicators in predicting recurrence-free survival (RFS) were determined. Kaplan-Meier curve and the time-dependent receiver operating characteristic (ROC) curve were used to assess the prognostic values. We then used univariate and multivariate Cox regression analyses to identify prognostic factors that were associated with RFS. RESULTS: In total, 160 patients who underwent surgery for GIST were included in the study. The median survival time was 34.5 months, with 1-, 3-, and 5-year RFS rates of 96.1%, 84.7%, and 80.8%, respectively. The inflammatory and nutritional indicators with largest AUC were Systemic immunoinflammatory Index (SII) and Geriatric Nutrition Risk Index (GNRI), reached 0.650 and 0.713, respectively. The optimal cutoff of GNRI and SII were 98.3, and 820.0, respectively. Univariate analysis showed that GNRI, SII, KI67, surgery method, tumor location, tumor size, and mitotic index were all significant prognostic indicators of RFS. After multivariate Cox analysis, independent prognostic factors for RFS in GIST included tumor location, mitotic index, tumor size, and GNRI (HR=2.802,95% CI: 1.045 to 7.515, p = 0.041). Besides, SII also tended to be associated with RFS (HR = 2.970, 95% CI: 0.946 to 9.326, p = 0.062). CONCLUSIONS: High GNRI is an independent prognostic factor for RFS in GIST, while SII can be considered as a prognostic factor. GNRI and SII can be used as tools to evaluate the prognosis of patients before surgery, helping doctors to better treat high-risk patients.