Development and validation of a diagnostic nomogram to evaluate tubular atrophy/interstitial fibrosis of IgA nephropathy.

Background: IgA nephropathy (IgAN) is a cause of chronic kidney disease (CKD). Tubular atrophy/interstitial fibrosis is associated with IgAN prognosis. However, simple tools for predicting pathological lesions of IgAN remain limited. Our objective was to develop a tool for evaluating tubular atrophy/interstitial fibrosis in patients with IgAN. Methods: In this cross-sectional study, 410 biopsy-verified IgAN patients were included. The factors associated with the incident interstitial fibrosis or tubular atrophy in IgAN were confirmed by using logistic regression analysis. A nomogram was developed using logistic regression coefficients to evaluate tubular atrophy or interstitial fibrosis. Receiver operating characteristic curves (ROC) and calibration curves were used to determine the discriminative ability and predictive accuracy of the nomogram. Results: In this study, the IgAN patients with tubular atrophy or interstitial fibrosis were older and had a higher percentage of males, hypertension and urinary protein excretion (UPE), with high levels of serum cystatin C, serum creatinine, high-sensitivity C-reactive protein and serum C4. The eGFRcr-cys equation calculated using serum creatinine, cystatin C and UPE were considered independent influencing factors of tubular atrophy or interstitial fibrosis in patients with IgAN. Furthermore, the nomogram demonstrated good discrimination (AUC: 0.87, 95% CI 0.81 to 0.93) and calibration in the validation cohort. Conclusion: The eGFRcr-cys and UPE are associated with tubular atrophy or interstitial fibrosis in patients with IgAN. Diagnostic nomogram can predict tubular atrophy or interstitial fibrosis in IgAN.

Efficacy and potential mechanism of atherosclerosis prevention by the active components of leech based on network pharmacology combined with animal experiments.

Introduction: Leeches are flesh-eating and bloodsucking parasitic worms. They are being used as a traditional Chinese medicine for centuries in activating blood and dissolving statis, dreging the meridims and tick. Hirudin, an active peptide product present in leech, has blood anticoagulant property and can assist in the treatment of thrombosis and diseases related to blood circulation. The efficacy and potential mechanism of action of leeches in such diseases should be further explored. Materials and methods: First, network pharmacology was used to screen the predicted potential targets of the active constituents of leech and AS. The common targets of the active constituents of leech and AS were obtained using Venn diagram. Further, the drug-active-constituent-target network diagram, protein-protein interaction, and GO and KEGG pathway enrichment analyses were used to construct the active-constituent-AS target-pathway network diagram. Subsequently, the protein-drug molecule docking model was drawn. Finally, the results of network pharmacology were validated using a mouse model of AS. Results: In total, 34 active constituents of leech and 1172 AS-related gene targets were selected, took the drug action targets and potential disease targets to get the common targets, and took the top 10 of degree value as the main active constituents for the treatment of atherosclerosis. There were 89 common targets and 12 core targets. The main targets included MAPK, EGFR, PIK3CB, etc. Potential regulatory pathways included cancer pathways, EGFR tyrosine kinase inhibitor resistance, Rap1 signaling pathway, PPAR signaling pathway, PI3K-Akt signaling pathway, C-type lectin receptor signaling pathway, and AGE-RAGE signaling pathway in diabetic complications. Animal experiments using mouse model of AS confirmed that AS plaques were smaller after treatment with leeches. SRC level was measured using western blotting. Expression of SRC in myocardial tissue was remarkably lower in the mice treated with leech than in the mice from model group fed on high-fat chow. Conclusions: To the best of our knowledge, this is the first study to explore the mechanism of action of the active components of leech in AS prevention. The active components of leeches play a coordinated role in preventing AS through multicomponent, multitarget, and multichannel mechanism of action related to inflammatory response, oxidative stress, and lipid metabolism. This study provided a reference for subsequent cellular and animal experiments.

Demographic distribution analysis of different glomerular diseases in Southwest China from 2008 to 2022.

BACKGROUND: Environmental and lifestyle factors play an etiological role in the pathogenesis of different glomerular diseases. Thus, exploring the epidemic characteristics of renal disease in different nationalities and regions is important. MATERIALS AND METHODS: Patients who underwent renal biopsy from October 2008 to October 2022 were included. The proportion and change tendency of glomerular diseases and the differences between the sexes and different ages and races were analyzed. RESULTS: There were 15,146 cases of glomerular diseases (98.5%), involving 7538 males (49.8%) and 7608 females (50.2%). The mean age was 37.0 years (range 0-80 years). The proportion of membranous nephropathy (MN) and diabetic nephropathy (DN) showed an increased trend. The most common primary glomerulonephritis (PGN) was IgA nephropathy (IgAN, 44.6%), followed by minimal-change disease (MCD, 24.3%) and MN (15.4%). Lupus nephritis (LN, 30%) accounted for the largest proportion of SGNs, followed by Henoch-Schonlein purpura nephritis (HSPN, 20.9%) and DN (19.8%). Compared with adults aged 18-60 years old, MCD and HSPN were more common in children and MN and DN in elderly individuals, statistically significant differences. Additionally, the sex and age distribution of PGN and SGN between the Tibetan and Han populations differed significantly, whereby LN was higher in the Han population and HSPN in the Tibetan population. CONCLUSION: The distribution of glomerular diseases showed age, sex and race differences. This research will be beneficial for providing epidemiological evidence for clinical diagnosis, disease prevention and public health decision-making.

The ratio of neutrophil to lymphocyte as a potential marker of clinicopathological activity for lupus nephritis.

INTRODUCTION: The ratio of neutrophil to lymphocyte (NLR) is a novel inflammatory factor that is elevated in systemic lupus erythematosus (SLE). However, the relationship between NLR and renal pathological manifestations in patients with lupus nephritis (LN) has not been investigated. METHODS: A retrospective study included 240 SLE patients, in which 186 patients with renal involvement and 124 LN patients underwent renal biopsy, 125 healthy volunteers and 125 chronic kidney disease (CKD) controls. Patients with SLE disease activity 2000 (SLEDAI-2 K) > 9 and ≤ 9 were defined as severely active and mildly active, respectively. Clinical parameters and renal pathological data were collected from medical records. The correlations between NLR and clinicopathological features were analyzed. RESULTS: The NLR of SLE group was significantly higher than that of the sex-age matched control groups. Patients with nephritis had higher NLR levels than those without nephritis (P = 0.044). Increased NLR was observed in severely active group compared to mildly active group (P = 0.020). NLR was significantly positively related with SLEDAI score, Renal SLEDAI score, C-reactive protein (CRP), 24-h urine protein, renal activity index (AI), cellular crescents and tubular atrophy, and negatively correlated with serum albumin. NLR was significantly decreased after treatment. Based on the receiver operating characteristic (ROC) curve, the best NLR cut-off value to predict severe activity of SLE and cellular crescents in renal pathology was 2.19 and 3.16, respectively. CONCLUSION: NLR may be a non-invasive and potential inflammatory marker in evaluating clinical and renal pathological activity in LN patients.

Autophagy protects against vocal fold injury-induced fibrosis.

Vocal fold scar formation due to vocal fold injury (VFI) is a common cause of surgery or trauma-induced voice disorders. Severe scar formation can lead to reduced voice quality or even be life-threatening. Here, we investigated the role of autophagy in VFI, focusing on fibrosis as a consequence of autophagy in inducing VFI. A VFI model was constructed in rats by dissecting the lamina propria tissue from the thyroarytenoid muscle. Real-time PCR and Western blot were used to analyze expressions of autophagy markers, including Beclin1 and Atg7, in VFI. Tgfb1 and Col1a1 were assessed to determine the correlation of fibrosis with VFI progression and autophagy levels. Rat vocal fold fibroblasts were also treated with TGF-ß1 or rapamycin, which activates and suppresses autophagy respectively, to explore how autophagy regulates fibrosis in VFI. Initially, we observed that autophagy was downregulated in vocal fold mucosa after VFI in rats. This was particularly evident by the time-dependent downregulation of Beclin1 and Atg7 following VFI. Concurrently, levels of Tgfb1 and Col1a1 also surged, hinting at elevated fibrosis levels. Furthermore, our experiments with TGF-ß1 stimulation revealed that it inhibited autophagy in rat vocal fold fibroblasts. Interestingly, when we introduced rapamycin, this effect was reversed. Our data suggest that autophagy is a suppressor of VFI by alleviating fibrosis, making targeting autophagy a potential therapeutic route in VFI.NEW & NOTEWORTHY The study has demonstrated that autophagy is a suppressor of VFI by alleviating fibrosis, making autophagy a potential therapeutic target in VFI.

Fabrication and performance evaluation of PLCL-hCOLIII small-diameter vascular grafts crosslinked with procyanidins.

Cardiovascular disease has become one of the main causes of death. It is the common goal of researchers worldwide to develop small-diameter vascular grafts to meet clinical needs. Collagen is a valuable biomaterial that has been used in the preparation of vascular grafts and has shown good results. Recombinant humanized collagen (RHC) has the advantages of clear chemical structure, batch stability, no virus hazard and low immunogenicity compared with animal-derived collagen, which can be developed as vascular materials. In this study, Poly (l-lactide- ε-caprolactone) with l-lactide/ε-caprolactone (PLCL) and type III recombinant humanized collagen (hCOLIII) were selected as raw materials to prepare vascular grafts, which were prepared by the same-nozzle electrospinning apparatus. Meanwhile, procyanidin (PC), a plant polyphenol, was used to cross-link the vascular grafts. The physicochemical properties and biocompatibility of the fabricated vascular grafts were investigated by comparing with glutaraldehyde (GA) crosslinked vascular grafts and pure PLCL grafts. Finally, the performance of PC cross-linked PLCL-hCOLIII vascular grafts were evaluated by rabbit carotid artery transplantation model. The results indicate that the artificial vascular grafts have good cell compatibility, blood compatibility, and anti-calcification performance, and can remain unobstructed after 30 days carotid artery transplantation in rabbits. The grafts also showed inhibitory effects on the proliferation of SMCs and intimal hyperplasia, demonstrating its excellent performance as small diameter vascular grafts.

Insecticidal toxicity of ω-Atypitoxin-Cs1a and its inhibitory effects on insect voltage-gated calcium channels.

BACKGROUND: Excessive use of chemical insecticides raises concerns about insecticide resistance, urging the development of novel insecticides. Peptide neurotoxins from spider venom are an incredibly rich source of ion channel modulators with potent insecticidal activity. A neurotoxin U1-Atypitoxin-Cs1a from the spider Calommata signata was annotated previously. It was of interest to investigate its insecticidal activity and potential molecular targets. RESULTS: Cs1a was heterologously expressed, purified and pharmacologically characterized here. The recombinant neurotoxin inhibited high-voltage-activated calcium channel currents with an median inhibitory concentration (IC50 ) value of 0.182 ± 0.026 µm on cockroach DUM neurons and thus was designated as ω-Atypitoxin-Cs1a. The recombinant Cs1a was toxic to three insect pests of agricultural importance, Nilaparvata lugens, Spodoptera frugiperda and Plutella xylostella with median lethal concentration (LD50 ) values of 0.121, 0.172 and 0.356 nmol g-1 , respectively, at 24 h postinjection. Cs1a was equivalently toxic to both insecticide-susceptible and -resistant insects. Cs1a exhibited low toxicity to Danio rerio with an LD50 of 2.316 nmol g-1 . CONCLUSION: Our results suggest that ω-Atypitoxin-Cs1a is a potent CaV channel inhibitor and an attractive candidate reagent for pest control and resistance management. © 2023 Society of Chemical Industry.

Reagentless Electrochemical Detection of Tumor Biomarker Based on Stable Confinement of Electrochemical Probe in Bipolar Silica Nanochannel Film.

The development of simple and probe-integrated aptamer sensors for the electrochemical detection of tumor biomarkers is of great significance for the diagnosis of tumors and evaluation of prognosis. In this work, a probe-integrated aptamer sensor is demonstrated based on the stable confinement of an electrochemical probe in a bipolar nanochannel film, which can realize the reagentless electrochemical detection of the tumor biomarker carcinoembryonic antigen (CEA). To realize the stable immobilization of a large amount of the cationic electrochemical probe methylene blue (MB), a two-layer silica nanochannel array (SNF) with asymmetric charge was grown on the supporting electrode from bipolar SNF (bp-SNF). The inner SNF is negatively charged (n-SNF), and the outer-layer SNF is positively charged (p-SNF). The dual electrostatic interaction including the electrostatic adsorption from n-SNF and the electrostatic repulsion from p-SNF achieve the stable confinement of MB in bp-SNF. The recognitive interface is fabricated by the covalent immobilization of the CEA aptamer on the outer surface of bp-SNF, followed by the blocking of non-specific binding sites. Owing to the stable and abundant immobilized probes and highly specific aptamer interface, the developed aptamer sensor enables the sensitive detection of CEA in the range of 1 pg/mL to 1 µg/mL with a low limit of detection (LOD, 0.22 pg/mL, S/N = 3). Owing to the high selectivity and stability of the developed biosensor, reagentless electrochemical detection of CEA in serum was realized.

Primary inflammatory myofibroblastic tumour of the liver: a clinicopathological and genetic study including a subset with ETV6::NTRK3 fusion.

AIMS: Inflammatory myofibroblastic tumour (IMT) is an intermediate neoplasm and rarely occurs in the liver. The aim of this study was to analyse the clinicopathological and genetic features of the largest primary hepatic IMT. METHODS AND RESULTS: A total of 10 cases were identified (four males and six females aged 1-48 years, median = 35 years) from 2011 to 2021, which accounted for 2.5% of IMTs occurring in all organ systems. Histological findings revealed that myofibroblastic/fibroblastic cells with inflammatory infiltration and focal hypocellularity were observed in three children. Immunostaining showed ALK-diffuse cytoplasmic positive in six cases (six of 10; 60%) and pan-TRK nuclear positive in three cases (three of 10; 30%). Hypercellular pattern was detected in ALK-positive IMTs and obvious collagenous/myxoid matrix was observed in the pan-TRK-positive subgroup. ALK rearrangement was demonstrated in three of five interpretable ALK-positive IMTs by fluorescence in-situ hybridisation (FISH), and one case failed due to poor sample quality. Next-generation sequencing indicated an IMT with TFG::ALK and FCHSD2::ALK fusion and TP53 mutation. ETV6::NTRK3 fusion was confirmed by RT-PCR, but FISH-negative results were found in two of three cases with pan-TRK-positive IMTs. No genetic alteration was detected in one tumour. One patient died 1 year after biopsy, while nine patients survived without evidence of disease in the follow-up surveillance (17-119 months). CONCLUSIONS: This article describes the first example of primary paediatric hepatic IMTs with ETV6::NTRK3 fusion. Besides the common ALK-positive subgroup, the proportion of NTRK3 fusion is high. Recognising the association between clinicopathological and molecular alterations is critical to accurate diagnosis of hepatic IMTs.

Association between geriatric nutritional risk index and pathological phenotypes of IgA nephropathy.

Background: IgA nephropathy (IgAN) is an immune disease related to oxidative stress and inflammation. It is the most common type of glomerulonephritis in the world and is the cause of chronic kidney disease and end-stage renal disease (ESRD). The Geriatric Nutritional Risk Index (GNRI) is a practical and uncomplicated method to assess the risk of morbidity and mortality, but its ability to assess IgAN is still unclear. Here, we evaluated the association between the GNRI and clinical and histologic findings of IgAN. Methods: In a cross-sectional study, we included 348 biopsy-verified IgAN patients. The Oxford classification was used to analyze the pathological characteristics of the included patients. Based on previous studies, the participants were divided into two groups using a cutoff value of 92. Differences in clinicopathological indices between the two groups were compared. The correlation between the GNRI and the indicators was evaluated by using a bivariate correlation analysis. A binary logistic regression analysis was conducted to determine the factors associated with the crescent lesions in IgAN. Results: In this study, 138 out of 348 patients (39.7%) had low GNRI scores (GNRI < 92). Patients in the low GNRI group tended to have a significantly lower body mass index; lower hemoglobin, serum albumin, serum IgG, and serum C3 levels; and higher 24-h proteinuria. The proportions of females, Oxford M1 and Oxford C1/2 were higher in the low GNRI group. The GNRI was positively correlated with body mass index (r = 0.57, P < 0.001), hemoglobin (r = 0.35, P < 0.001), serum albumin (r = 0.83, P < 0.001), serum IgG (r = 0.32, P < 0.001), and serum C3 (r = 0.26, P < 0.001) and negatively correlated with 24-h proteinuria (r = -0.36, P < 0.001) and the proportion of crescents (r = -0.24, P < 0.001). The GNRI scores and serum IgG levels were considered independent factors influencing the crescent lesions in IgAN. Conclusions: The GNRI can reflect the severity of clinical and histologic phenotypes in IgAN patients. Lower GNRI and serum IgG levels may suggest an increased risk of crescent lesions and are potential markers for disease monitoring in IgAN.

Jinhua Qinggan granules attenuates acute lung injury by promotion of neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is one of the fatal complications of respiratory virus infections such as influenza virus and coronavirus, which has high clinical morbidity and mortality. Jinhua Qinggan granules (JHQG) has been approved by China Food and Drug Administration in the treatment of H1N1 influenza and mild or moderate novel coronavirus disease 2019 (COVID-19), which is an herbal formula developed based on Maxingshigan decoction and Yinqiao powder that have been used to respiratory diseases in China for thousands of years. However, the underlying mechanism of JHQG in treating infectious diseases remains unclear. AIM OF THE STUDY: This study investigated the effects of JHQG on neutrophil apoptosis and key signaling pathways in lipopolysaccharide (LPS) -induced ALI mice in order to explore its mechanism of anti-inflammation. MATERIALS AND METHODS: The effect of JHQG on survival rate was observed in septic mouse model by intraperitoneal injection of LPS (20 mg/kg). To better pharmacological evaluation, the mice received an intratracheal injection of 5 mg/kg LPS. Lung histopathological changes, wet-to-dry ratio of the lungs, and MPO activity in the lungs and total protein concentration, total cells number, TNF-α, IL-1ß, IL-6, and MIP-2 levels in BALF were assessed. Neutrophil apoptosis rate was detected by Ly6G-APC/Annexin V-FITC staining. Key proteins associated with apoptosis including caspase 3/7 activity, Bcl-xL and Mcl-1 were measured by flow cytometry and confocal microscope, respectively. TLR4 receptor and its downstream signaling were analyzed by Western blot assay and immunofluorescence, respectively. RESULTS: JHQG treatment at either 6 or 12 g/kg/day resulted in 20% increase of survival in 20 mg/kg LPS-induced mice. In the model of 5 mg/kg LPS-induced mice, JHQG obviously decreased the total protein concentration in BALF, wet-to-dry ratio of the lungs, and lung histological damage. It also attenuated the MPO activity and the proportion of Ly6G staining positive neutrophils in the lungs, as well as the MIP-2 levels in BALF were reduced. JHQG inhibited the expression of Mcl-1 and Bcl-xL and enhanced caspase-3/7 activity, indicating that JHQG partially acted in promoting neutrophil apoptosis via intrinsic mitochondrial apoptotic pathway. The levels of TNF-α, IL-1ß, and IL-6 were significantly declined in LPS-induced mice treated with JHQG. Furthermore, JHQG reduced the protein expression of TLR4, MyD88, p-p65 and the proportion of nuclei p65, suggesting that JHQG treatment inhibited TLR4/MyD88/NF-κB pathway. CONCLUSION: JHQG reduced pulmonary inflammation and protected mice from LPS-induced ALI by promoting neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway, suggesting that JHQG may be a promising drug for treatment of ALI.

Electrochemical aptasensor fabricated by anchoring recognition aptamers and immobilizing redox probes on bipolar silica nanochannel array for reagentless detection of carbohydrate antigen 15-3.

Timely, convenient, and efficient detection of carbohydrate antigen 15-3 (CA15-3) levels in serum holds significant importance in early screening, diagnostic assistance and prognosis prediction of breast cancer. The development of efficient and convenient electrochemical aptasensors with immobilized redox probes for label-free detection of CA15-3 is highly desirable. In this work, a bipolar silica nanochannel array film (bp-SNA) with two distinct functional domains including nanochannels and an outer surface was employed for the immobilization of recognition ligands and electrochemical redox probes, enabling the construction of a probe-integrated aptasensor for reagentless electrochemical detection of CA15-3. Cost-effective and readily available indium tin oxide (ITO) was used as the supporting electrode for sequential growth of a negatively charged inner layer (n-SNA) followed by a positively charged outer layer (p-SNA). The preparation process of bp-SNA is convenient. Functionalization of amino groups on the outer surface of bp-SNA was modified by aldehyde groups for covalent immobilization of recognition aptamers, further establishing the recognition interface. Within the nanochannels of bp-SNA, the electrochemical redox probe, tri (2,2'-dipyridyl) cobalt (II) (Co(bpy)3 2+) was immobilized, which experienced a dual effect of electrostatic attraction from n-SNA and electrostatic repulsion from p-SNA, resulting in high stability of the immobilized probes. The constructed aptasensor allowed for reagentless electrochemical detection of CA15-3 ranged from 0.001 U/mL to 500 U/mL with a low detection limit (DL), 0.13 mU/mL). The application of the constructed aptasensor for CA15-3 detection in fetal bovine serum was also validated. This sensor offers advantages of a simple and readily obtainable supporting electrode, easy bp-SNA fabrication, high probe stability and good stability.

Dermatofibrosarcoma protuberans im Gesicht: Klinisch-pathologische und molekulare Studie mit 34 Fällen.

HINTERGRUND: Dermatofibrosarcoma protuberans (DFSP) ist eines der häufigsten dermalen Sarkome, kommt aber im Gesicht nur selten vor. PATIENTEN UND METHODEN: Die klinisch-pathologischen Charakteristika von insgesamt 34 fazialen DFSP wurden näher untersucht. Hierzu wurden zusätzlich eine Immunmarkierung (CD34) sowie eine PDGFB/COL1A1-PDGFB Fluoreszenz-in situ-Hybridisierung (FISH) durchgeführt. ERGEBNISSE: Die untersuchten Patienten waren zwischen 24 und 64 Jahre alt (im Mittel 42,9 Jahre), das Verhältnis Mäner zu Frauen betrug 4,7 : 1. Morphologisch fanden sich "klassische" DFSP (25/34; 73,5 %), pigmentierte DFSP (2/34; 5,9 %), DFSP mit myoider Differenzierung (1/34; 2,9 %) und fibrosarkomatös transformierte DFSP (DFSP-FS) (6/34; 17,6 %). Zusätzlich zeigte sich bei drei Fällen mit DFSP-FS eine myxoide Degeneration (3/6; 50,0 %). In allen 29 Fällen mit CD34-Immunhistochemie-Untersuchung fand sich eine positive Anfärbung (100 %). In der genetischen Untersuchung wiesen 94,1 % (16/17) der Patienten eine PDGFB-Rearrangement/COL1A1-PDGFB-Fusion auf. Die Raten an Rezidiven (83,3 % vs. 59,1 %) und Metastasierung (33,3 % vs. 0) lagen bei den DFSP-FS deutlich höher als bei den gewöhnlichen DFSP. In allen Fällen von Rezidiven waren die Schnittränder vorher als positiv eingestuft worden. Umgekehrt waren alle Patienten mit negativen Schnitträndern (bei der Exzision oder Re-Exzision) noch am Leben, ohne weitere Krankheitszeichen aufzuweisen (Mittel 81,8 Monate, Median 81 Monate). SCHLUSSFOLGERUNG: DFSP tritt vor allem bei Männern auf. Bei DFSP-FS besteht eine höhere Wahrscheinlichkeit für myxoide Degeneration bei insgesamt schlechterer Prognose. Ein negativer Status der chirurgischen Schnittränder zeigte eine gute Prognose an.

Dermatofibrosarcoma protuberans of the face: A clinicopathologic and molecular study of 34 cases.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is one of the most common dermal sarcomas, but facial DFSP is rare. PATIENTS AND METHODS: The clinicopathological characteristics of 34 facial DFSPs were reviewed. Additional immunostaining (CD34) and PDGFB/COL1A1-PDGFB fluorescence in situ hybridization (FISH) detection were performed. RESULTS: Patients were aged from 24 to 64 years (mean 42.9 years), with a male-to-female ratio of 4.7 : 1. Morphologically, classic DFSP (25/34, 73.5 %), pigmented DFSP (2/34, 5.9 %), DFSP with myoid differentiation (1/34, 2.9 %) and fibrosarcomatous DFSP (FS-DFSP) (6/34, 17.6 %) were found. Moreover, myxoid degeneration was observed in three FS-DFSP cases (3/6, 50.0 %). All 29 cases that underwent CD34 immunohistochemistry exhibited positive staining (100 %). Genetically, PDGFB rearrangement/COL1A1-PDGFB fusion was detected in 94.1 % (16/17) of patients. Regarding prognosis, the recurrence (83.3 % vs. 59.1 %) and metastasis (33.3 % vs. 0 %) rates were higher in FS-DFSPs than that in ordinary DFSPs. All available surgical margins were positive before DFSPs recurrence. All patients with negative excision or re-excision margins were alive without evidence of disease (mean, 81.8 months; median, 81 months). CONCLUSIONS: Facial DFSP occurs predominantly in males, while FS-DFSPs are more likely to exhibit myxoid degeneration and a worse prognosis. Notably, negative surgical margin status determined a satisfactory prognosis.

Umbilical Cord Mesenchymal Stem Cells Seeded on Small Intestinal Submucosa to Repair the Uterine Wall Injuries.

Objective: The effectiveness of tissue engineering materials combining porcine small intestine submucosa (SIS) and umbilical cord mesenchymal stem cells (UC-MSCs) on uterine injury in female rat after full-thickness uterine resection was evaluated as a basis for clinical treatment of postoperative uterine injury. Methods: After complex culture with SIS and UC-MSCs, cell adhesion, growth, and proliferation were assessed. Before the implantation, a surgical procedure of bilateral full-thickness uterine resection (0.5-2.0 cm long and 0.3 cm wide) was performed to obtain the rat uterine injury model, while the sham-operated rats were used as controls. Hematoxylin-eosin (H&E) staining results and fertility of female rats in each group were assessed to determine the critical resection length of the full-thickness uterine resection. Then SIS or UC-MSCs-SIS were implanted into the female rats from the uterine injury group, followed by assessments of H&E staining, the expression of ki67, α-SMA, and leukemia inhibitory factor (LIF), and fertility to determine the effectiveness of SIS and UC-MSCs-SIS on uterine injury in female rat. Results: At 24, 48, and 72 h, the cells grew progressively on the SIS material. In the 1.5 cm and 2.0 cm groups, the pregnancy rate, proportion of the uterus supporting live embryo growth, number of live embryos, and proportion of live embryos were all significantly less than those in the 0.5 cm and sham-operated groups. In the 2.0 cm group, there was little tissue regeneration at the center of the injury and not conducive to subsequent assessment. The UC-MSCs-SIS and SIS groups were better on morphological development, cell proliferation, LIF expression, and fertility than the control group. Conclusions: UC-MSCs show good adhesion, growth, and proliferation on the SIS scaffold material. The optimal resection length in full-thickness uterine resection on female rat is 1.5 cm. UC-MSCs-SIS is the effective treatment for repairing a injury after the full-thickness resection of the uterus in this research. Impact Statement The acquired severe uterus injury is a serious condition, which prone to uterine adhesions. Postoperative endometrial repairment and prevention of intrauterine adhesion recurrence are two major clinical challenges. Fortunately, the development of tissue engineering technology makes repairing a uterine injury possible. There are two main contributions from this study. First, due to ethical requirements, it is difficult to assess the repairing effect on uterus by invasive experiments in a clinical practice. Therefore, we constructed a full-thickness uterine injury rat model, which allows us to assess the repairing effect of treatments after severe uterine injuries in vivo. Second, it explored the effect of using a combination of and umbilical cord mesenchymal stem cells and small intestine submucosa materials on improving uterine repairments, providing a potential possibility for a future clinical practice.

Identifying DUSP-1 and FOSB as hub genes in immunoglobulin A nephropathy by WGCNA and DEG screening and validation.

Background: The mechanism of immunoglobulin A nephropathy (IgAN) is still unknown. A bioinformatics analysis is a powerful method to identify the biomarkers and possible therapeutic targets of a certain disease from related datasets. Methods: The GSE93973 dataset, obtained from the Gene Expression Omnibus (GEO) database, was used to construct a weighted gene co-expression network (WGCNA) and filter differentially expressed genes (DEGs). The biological process (BP) enrichment among all the genes in the key modules was analyzed through a Gene Ontology (GO) enrichment analysis. We selected the overlap of hub genes in the WGCNA and Protein-Protein Interaction (PPI) network as the final hub genes in IgAN. We verified the final hub genes in two other datasets and in clinical kidney tissue specimens. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of hub genes for IgAN. Results: The turquoise module, which contained 1,806 genes, was the module with the highest correlation coefficient with IgAN in the GSE93973 dataset. The GO enrichment analysis showed that these 1,806 genes were mainly enriched in inflammation and immune responses. There were five hub genes identified by WGCNA and 34 hub genes identified in a DEG analysis in the GSE93973 dataset. DUSP1 and FOSB were identified as the final hub genes in IgAN. The validation results of the final hub genes in two other databases and clinical kidney tissue specimens validated the result that, compared to the control group, FOSB and DUSP1 were expressed at lower levels in the glomerulus of IgAN patients. The ROC curve indicated that DUSP1 and FOSB were good diagnostic indicators for IgAN. Conclusions: Our analysis identified two hub genes that might be potential targets for the intervention and treatment of IgAN.

Effect of modified endoscopic sinus surgery combined with middle turbinate resection on olfactory function and stress response in patients with refractory chronic rhinosinusitis with nasal polyps.

OBJECTIVE: To investigate the effects of modified endoscopic sinus surgery combined with middle turbinate resection on olfactory function and stress response in patients with refractory chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: We prospectively selected 92 patients with refractory CRSwNP who were treated in Tianjin 4th Central Hospital from June 2019 to June 2020 as the research subjects. According to the simple randomization of "flipping a coin", they were divided into the observation group (n=50) and the control group (n=42). The observation group was treated with modified endoscopic sinus surgery combined with middle turbinectomy and the control group underwent conventional surgery. The overall response rate, olfactory function, and stress responses of the two groups were compared. RESULTS: A generalized linear model showed that the overall response rate at 2, 4, and 6 months after surgery in the observation group was higher than that in the control group (Wald χ2 group =4.301, Wald χ2 time =91.677, P group =0.038, P time <0.001). Repeated measurements of variance showed no significant differences in olfactory function scores before surgery (P=0.485). After 2, 4, and 6 months, the olfactory function scores of the observation group were higher than those of the control group (P<0.001). After surgery, patients in the observation group had lower Lund-Mackey, Lund-Kennedy, and SNOT-20 scores, and lower epinephrine (E), norepinephrine (NE), and cortisol (Cor) levels than those in the control group (all P<0.001). The observation group had a significantly lower incidence of complications than the control group (10.00% vs. 28.57%, χ2 =5.226, P=0.022). CONCLUSION: Modified endoscopic sinus surgery combined with middle turbinate resection significantly improved the olfactory function and reduced the perioperative stress response of patients with CRSwNP.

Case Report: Early Distant Metastatic Inflammatory Myofibroblastic Tumor Harboring EML4-ALK Fusion Gene: Study of Two Typical Cases and Review of Literature.

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm that frequently arises in the lung and accounts for ~1% of lung tumors. Distant metastatic IMT is extremely rare and has been poorly investigated. This analysis was specifically performed to explore the clinicopathological and genetic features of early distant metastatic IMT. Two typical patients with distant metastatic IMTs were selected, which accounted for 1.13% of all diagnosed IMTs in the last 5 years. One patient was a 55 year-old male, and the other patient was a 56 year-old female. Both primary tumors arose from the lung, and the initial clinical symptoms of the two patients involved coughing. Both of the imaging examinations showed low-density nodular shadows in the lungs with enhancement around the mass. Microscopically, dense arranged tumor cells, prominent cellular atypia, and high mitotic activity with atypical form were more prominent in the metastatic lesions than in the primary lesions. All of the primary and metastatic tumors in both cases showed positive anaplastic lymphoma kinase (ALK) immunostaining and ALK rearrangement via fluorescence in situ hybridization. The EML4 (exon 6)-ALK (exon 20) fusion variant (v3a/b) was identified by using next-generation sequencing (NGS) and was verified by using reverse transcription polymerase chain reaction (RT-PCR). Furthermore, intronic variants of NOTCH1 and synonymous variants of ARAF were also detected via NGS in one IMT for the first time and were verified in all of the primary and metastatic lesions via PCR. Distant metastasis occurred during a short period of time (1 and 2 months) after the first surgery. One patient presented with multiple metastases to the subcutaneous tissue and bone that responded to ALK inhibitor alectinib therapy, and the tumor was observed to regress 10 months after the initial ALK inhibitor therapy. In contrast, the other patient presented with subcutaneous neck metastasis without ALK inhibitor treatment and succumbed to the disease within 3 months after the surgery. This study demonstrated the possible role of EML4-ALKv3a/b in the malignant progression of IMT and proposed certain therapeutic effects of ALK inhibitors on multiple metastatic IMTs.

Addition of glomerular lesion severity improves the value of anemia status for the prediction of renal outcomes in Chinese patients with type 2 diabetes.

We aimed to determine the utility of biopsy data and anemia for the prediction of renal outcomes in Chinese patients with type 2 diabetes. In total, 441 Chinese patients with type 2 diabetes and biopsy-confirmed diabetic nephropathy (DN) were enrolled in a retrospective study. Their renal pathology was assessed using the Renal Pathology Society system. Cox proportional hazards models were used to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), and immunofluorescence staining was used to assess the expression of hypoxia-inducible factor (HIF)-α in patients' kidneys. We found that glomerular pathology classification was an independent pathological predictor of low hemoglobin concentration, according to linear and logistic regression analyses. Each 1 g/dL decrease in baseline hemoglobin concentration was associated with a 42% higher risk of an adverse renal outcome, after adjustment for clinical and pathologic covariates. In patients with severe glomerular lesions, the risk of progression to ESRD was significantly higher if mild or moderate/severe anemia was present, but in patients with mild glomerular lesions, the risk was only significantly higher in those with moderate or severe anemia than in the absence of anemia. Harrell's C Concordance was improved, but the Akaike information criterion was worsened by adding the glomerular pathology classification to the use of anemia status and clinical data. Immunofluorescence staining revealed that renal HIF-1α and HIF-2α expression was significantly higher in classes II-IV than class I. Thus, the addition of glomerular pathology classification increases the value of anemia status for the prediction of the progression to ESRD.