Origin, loss, and regain of self-incompatibility in angiosperms.

The self-incompatibility (SI) system with the broadest taxonomic distribution in angiosperms is based on multiple S-locus F-box genes (SLFs) tightly linked to an S-RNase termed type-1. Multiple SLFs collaborate to detoxify nonself S-RNases while being unable to detoxify self S-RNases. However, it is unclear how such a system evolved, because in an ancestral system with a single SLF, many nonself S-RNases would not be detoxified, giving low cross-fertilization rates. In addition, how the system has been maintained in the face of whole-genome duplications (WGDs) or lost in other lineages remains unclear. Here we show that SLFs from a broad range of species can detoxify S-RNases from Petunia with a high detoxification probability, suggestive of an ancestral feature enabling cross-fertilization and subsequently modified as additional SLFs evolved. We further show, based on its genomic signatures, that type-1 was likely maintained in many lineages, despite WGD, through deletion of duplicate S-loci. In other lineages, SI was lost either through S-locus deletions or by retaining duplications. Two deletion lineages regained SI through type-2 (Brassicaceae) or type-4 (Primulaceae), and one duplication lineage through type-3 (Papaveraceae) mechanisms. Thus, our results reveal a highly dynamic process behind the origin, maintenance, loss, and regain of SI.

The Snapdragon Genomes Reveal the Evolutionary Dynamics of the S-Locus Supergene.

The genus Antirrhinum has been used as a model to study self-incompatibility extensively. The multi-allelic S-locus, carrying a pistil S-RNase and dozens of S-locus F-box (SLF) genes, underlies the genetic control of self-incompatibility (SI) in Antirrhinum hispanicum. However, there have been limited studies on the genomic organization of the S-locus supergene due to a lack of high-quality genomic data. Here, we present the chromosome-level reference and haplotype-resolved genome assemblies of a self-incompatible A. hispanicum line, AhS7S8. For the first time, 2 complete A. hispanicum S-haplotypes spanning ∼1.2 Mb and containing a total of 32 SLFs were reconstructed, whereas most of the SLFs derived from retroelement-mediated proximal or tandem duplication ∼122 Mya. Back then, the S-RNase gene and incipient SLFs came into linkage to form the pro-type of type-1 S-locus in the common ancestor of eudicots. Furthermore, we detected a pleiotropic cis-transcription factor (TF) associated with regulating the expression of SLFs, and two miRNAs may control the expression of this TF. Interspecific S-locus and intraspecific S-haplotype comparisons revealed the dynamic nature and polymorphism of the S-locus supergene mediated by continuous gene duplication, segmental translocation or loss, and TE-mediated transposition events. Our data provide an excellent resource for future research on the evolutionary studies of the S-RNase-based self-incompatibility system.

Cross-sectional Relationship Between Dietary Protein Intake, Energy Intake and Protein Energy Wasting in Chronic Kidney Disease Patients.

The potential threshold for dietary energy intake (DEI) that might prevent protein-energy wasting (PEW) in chronic kidney disease (CKD) is uncertain. The subjects were non-dialysis CKD patients aged ≥ 14 years who were hospitalized from September 2019 to July 2022. PEW was measured by subjective global assessment (SGA). DEI and dietary protein intake (DPI) were obtained by 3-days diet recalls. Patients were divided into adequate DEI group and inadequate DEI group according to DEI ≥ 30 or < 30 kcal/kg/d. Logistic regression analysis and restricted cubic spline (RCS) were used in this study. We enrolled 409 patients, with 53.8% had hypertension and 18.6% had diabetes. The DEI and DPI was 27.63 ± 5.79 kcal/kg/day and 1.00 (0.90,1.20) g/kg/day, respectively. 69.2% of participants in inadequate DEI group. Malnutrition occurred in 18.6% of patients. Comparing to patients in adequate DEI group, those in inadequate DEI group had significantly lower total lymphocyte count (TLC), serum cholesterol (Chol) and low-density cholesterol (LDL), and a higher prevalence of PEW. For every 1kcal/kg/day increase in DEI, the incidence of PEW was reduced by 12.0% [odds ratio (OR): 0.880, 95% confidence interval (CI): 0.830 to 0.933, P < 0.001]. There was a nonlinear curve relationship between DEI and PEW (overall P < 0.001), and DEI ≥ 27.6 kcal/kg/d may have a preventive effect on PEW in CKD. Low DPI was also significantly associated with malnutrition, but not when DEI was adequate. Decreased energy intake may be a more important factor of PEW in CKD than protein intake.

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.

Spike structure of gold nanobranches induces hepatotoxicity in mouse hepatocyte organoid models.

BACKGROUND: Gold nanoparticles (GNPs) have been extensively recognized as an active candidate for a large variety of biomedical applications. However, the clinical conversion of specific types of GNPs has been hindered due to their potential liver toxicity. The origin of their hepatotoxicity and the underlying key factors are still ambiguous. Because the size, shape, and surfactant of GNPs all affect their properties and cytotoxicity. An effective and sensitive platform that can provide deep insights into the cause of GNPs' hepatotoxicity in vitro is therefore highly desired. METHODS: Here, hepatocyte organoid models (Hep-orgs) were constructed to evaluate the shape-dependent hepatotoxicity of GNPs. Two types of GNPs with different nanomorphology, gold nanospheres (GNSs) and spiny gold nanobranches (GNBs), were synthesized as the representative samples. Their shape-dependent effects on mice Hep-orgs' morphology, cellular cytoskeletal structure, mitochondrial structure, oxidative stress, and metabolism were carefully investigated. RESULTS: The results showed that GNBs with higher spikiness and tip curvature exhibited more significant cytotoxicity compared to the rounded GNSs. The spike structure of GNBs leads to a mitochondrial damage, oxidative stress, and metabolic disorder in Hep-orgs. Meanwhile, similar trends can be observed in HepG2 cells and mice models, demonstrating the reliability of the Hep-orgs. CONCLUSIONS: Hep-orgs can serve as an effective platform for exploring the interactions between GNPs and liver cells in a 3D perspective, filling the gap between 2D cell models and animal models. This work further revealed that organoids can be used as an indispensable tool to rapidly screen and explore the toxic mechanism of nanomaterials before considering their biomedical functionalities.

[Research Progress and Design Strategy of Hemostatic Adhesives].

Adhesives have emerged as an effective method for wound closure, hemostasis and tissue engineering in recent years, which not only are suitable for the adhesion of wet tissues, but also can adapt to the peristalsis and mechanical stretching of tissues and organs, especially for arteries and organize bleeding. With the further development of technology, existing adhesives can be modified through different strategies, and new materials are explored, giving new properties and uses to adhesives, such as drug delivery, temperature sensitivity, light sensitivity and so on. Nevertheless, there are many questions about the design and practical clinical application of adhesives in the future. The recent research progress of traditional adhesives and their application in hemostasis is reviewed, and the design and development ideas of future adhesives are discussed in the study.

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.

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.

The Fabrication of a Probe-Integrated Electrochemiluminescence Aptasensor Based on Double-Layered Nanochannel Array with Opposite Charges for the Sensitive Determination of C-Reactive Protein.

The effective and sensitive detection of the important biomarker, C-reactive protein (CRP), is of great significance in clinical diagnosis. The development of a convenient and highly sensitive electrochemiluminescence (ECL) aptasensor with an immobilized emitter probe is highly desirable. In this work, a probe-integrated ECL aptamer sensor was constructed based on a bipolar silica nanochannel film (bp-SNF) modified electrode for the highly sensitive ECL detection of CRP. The bp-SNF, modified on an ITO electrode, consisted of a dual-layered SNF film, including the negatively charged inner SNF (n-SNF) and the outer SNF with a positive charge and amino groups (p-SNF). The ECL emitter, tris(bipyridine) ruthenium (II) (Ru(bpy)32+), was stably immobilized in a nanochannel of bp-SNF using the dual electrostatic interactions with n-SNF attracting and p-SNF repelling. The amino groups on the outer surface of bp-SNF were aldehyde derivatized, allowing for the covalent immobilization of recognitive aptamers (5'-NH2-CGAAGGGGATTCGAGGGGTGATTGCGTGCTCCATTTGGTG-3'), leading to the recognition interface. When CRP bound to the aptamer on the recognition interface, the formed complex increased the interface resistance and reduced the diffusion of the co-reactant tripropylamine (TPA) into the nanochannels, leading to a decrease in the ECL signal. Based on this mechanism, the constructed aptamer sensor could achieve a sensitive ECL detection of CRP ranging from 0.01 to 1000 ng/mL, with a detection limit (DL) of 8.5 pg/mL. The method for constructing this probe-integrated ECL aptamer sensor is simple, and it offers a high probe stability, good selectivity, and high sensitivity.

[Network Meta-analysis of Chinese patent medicine containing Hirudo in treatment of atherosclerosis].

This study aimed to evaluate the efficacy and safety of Chinese patent medicines containing Hirudo in the treatment of atherosclerosis(AS) by network Meta-analysis, and to provide evidence-based reference for clinical treatment of AS. The clinical randomized controlled trial(RCT) on the treatment of atherosclerosis with Chinese patent medicines containing Hirudo were searched in CNKI, Wanfang, VIP, SinoMed, PubMed and EMbase from the establishment of the databases to July 1, 2022. And data extraction and quality assessment of the included RCT was performed according to the Cochrane standards. Stata 17 and ADDIS 1.16.5 were then used for Bayesian model network Meta-analysis. Finally, 67 RCTs with a total sample size of 6 826 cases were included, 3 569 cases in the experimental group and 3 257 cases in the control group, involving three oral Chinese patent medicines. Network Meta-analysis showed that in terms of reducing intima-media thickness(IMT), the top three Chinese patent medicines were Tongxinluo Capsules+sta-tins>Maixuekang Capsules+statins>Maixuekang Capsules. In terms of reducing plaque area, the top one was Maixuekang Capsules+sta-tins, and the other Chinese patent medicines had similar efficacy. For lowering AS Crouse scores, the top three were Maixuekang Capsules>Tongxinluo Capsules+statins>Naoxintong Capsules. For decreasing plaque number, the top three were Naoxintong Capsules+sta-tins>Tongxinluo Capsules+statins>Tongxinluo Capsules. With regard to adverse reactions/events, Naoxintong Capsules+statins had the lo-west incidence. In conclusion, in Chinese patent medicines containing Hirudo for the treatment of AS, Tongxinluo Capsules+statins, Maixuekang Capsules, Maixuekang Capsules+statins, and Naoxintong Capsules+statins were the primary choices to reduce IMT, AS Crouse scores, plaque area, and plaque number, respectively. The efficacy of Chinese patent medicines containing Hirudo with or without statins was more significant than that of statins alone in the four outcome indexes. Additionally, the treatment of AS should be evaluated comprehensively, and attention should be paid to Chinese patent medicines or their combination with western medicine, to optimize the treatment effect and minimize adverse reactions as the benchmark.

[Research Advances in Medical Materials and Products for Soft Tissue Repairs].

Soft tissue is an indispensable tissue in human body. It plays an important role in protecting the body from external physical, chemical or biological factors. Mild soft tissue injuries can self-heal, while severe soft tissue injuries may require related treatment. Natural polymers (such as chitosan, hyaluronic acid, and collagen) and synthetic polymers (such as polyethylene glycol and polylactic acid) exhibit good biocompatibility, biodegradability and low toxicity. It can be used for soft tissue repairs for antibacterial, hemostatic and wound healing purposes. Their related properties can be enhanced through modification or preparation of composite materials. Commonly used soft tissue repairs include wound dressings, biological patches, medical tissue adhesives, and tissue engineering scaffolds. This study introduces the properties, mechanisms of action and applications of various soft tissue repair medical materials, including chitosan, hyaluronic acid, collagen, polyethylene glycol and polylactic acid, and provides an outlook on the application prospects of soft tissue repair medical materials and products.

A high neutrophil to lymphocyte ratio is associated with poor nutritional status in chronic kidney disease patients.

We aimed to investigate the relationship between the neutrophil to lymphocyte ratio (NLR) and nutritional parameters in chronic kidney disease (CKD) patients. In this cross-sectional study, 187 non-dialysis CKD patients were enrolled. Daily dietary energy intake (DEI) and daily dietary protein intake (DPI) were assessed by 3-d dietary records. Protein-energy wasting (PEW) was defined as Subjective Global Assessment (SGA) class B and C. Spearman correlation analysis, logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed. The median NLR was 2·51 (1·83, 3·83). Patients with CKD stage 5 had the highest NLR level. A total of 19·3 % (n 36) of patients suffered from PEW. The NLR was positively correlated with SGA and serum P, and the NLR was negatively correlated with BMI, waist and hip circumference, triceps skinfold thickness, mid-arm muscle circumference, DPI and Hb. Multivariate logistic regression analysis adjusted for DPI, DEI, serum creatinine, blood urea nitrogen, uric acid and Hb showed that a high NLR was an independent risk factor for PEW (OR = 1·393, 95 % CI 1·078, 1·800, P = 0·011). ROC analysis showed that an NLR ≥ 2·62 had the ability to identify PEW among CKD patients, with a sensitivity of 77·8 %, a specificity of 62·3 % and an AUC of 0·71 (95 % CI 0·63, 0·81, P < 0·001). The NLR was closely associated with nutritional status. NLR may be an indicator of PEW in CKD patients.

Serum homocysteine is associated with tubular interstitial lesions at the early stage of IgA nephropathy.

BACKGROUND: The association between homocysteine (Hcy) and IgA nephropathy (IgAN) is not well understood. We aimed to investigate the relationship between Hcy and clinicopathologic features in IgAN patients. METHODS: A total of 337 IgAN patients and 150 sex- and age- matched healthy controls were enrolled in this single-center retrospective study. According to Hcy ≤ 10 µmol/L or > 10 µmol/L, patients were divided into low and high Hcy groups. Multivariate logistic regression was performed to explore the risk factors for elevated Hcy. RESULTS: Serum Hcy was higher in IgAN patients than in healthy controls [11.6 (9.1,15.3) vs. 8.8 (7.5,10.6) µmol/L, P < 0.001], unanimously in the subgroup of 156 patients with a normal estimated glomerular filtration rate (eGFR) (≥ 90 ml/min/1.73 m2) [9.9 (7.6,12.4) vs. 8.8 (7.5,10.6) µmol/L, P < 0.001]. Compared to the low Hcy group, serum creatinine (Scr), blood urine nitrogen (BUN), uric acid (UA), endocapillary hypercellularity (E) and tubular atrophy/interstitial fibrosis lesion (T) were higher in the high Hcy group. Hcy levels were positively correlated with Scr, BUN, UA, 24-h urine protein, and E and T lesions, but negatively correlated with eGFR and superoxide dismutase (SOD). In the subgroup with normal eGFR, patients with higher Hcy were persistent with higher Scr, BUN and T lesions. A multivariate logistic regression model showed that the risk of elevated Hcy in patients with pathological T increased by 2.87-fold. T lesions could better predict high Hcy, with an odds ratio (OR) of 14.20 in the subgroup with normal eGFR. CONCLUSIONS: Pathologic T was an independent risk factor associated with elevated Hcy, especially at the early stage of IgAN.

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.

Disposable Electrochemical Sensors for Highly Sensitive Detection of Chlorpromazine in Human Whole Blood Based on the Silica Nanochannel Array Modified Screen-Printed Carbon Electrode.

Rapid and highly sensitive quantitative analysis of chlorpromazine (CPZ) in human whole blood is of great importance for human health. Herein, we utilize the screen-printed carbon electrodes (SPCE) as the electrode substrates for growth of highly electroactive and antifouling nanocomposite materials consisting of vertically ordered mesoporous silica films (VMSF) and electrochemically reduced graphene oxide (ErGO) nanosheets. The preparation of such VMSF/ErGO/SPCE could be performed by using an electrochemical method in a few seconds and the operation is controllable. Inner ErGO layer converted from graphene oxide (GO) in the growth process of VMSF provides oxygen-containing groups and two-dimensional π-conjugated planar structure for stable fabrication of outer VMSF layer. Owing to the π-π enrichment and excellent electrocatalytic abilities of ErGO, electrostatic preconcentration and antifouling capacities of VMSF, and inherent disposable and miniaturized properties of SPCE, the proposed VMSF/ErGO/SPCE sensor could be applied for quantitative determination of CPZ in human whole blood with high accuracy and sensitivity, good stability, and low sample consumption.

Anti-Biofouling Electrochemical Sensor Based on the Binary Nanocomposite of Silica Nanochannel Array and Graphene for Doxorubicin Detection in Human Serum and Urine Samples.

A disposable and portable electrochemical sensor was fabricated by integrating vertically-ordered silica mesoporous films (VMSF) and electrochemically reduced graphene (ErGO) on a screen-printed carbon electrode (SPCE). Such VMSF/ErGO/SPCEs could be prepared by a simple and controllable electrochemical method. Stable growth of VMSF on SPCE could be accomplished by the introduction of an adhesive ErGO nanolayer owing to its oxygen-containing groups and two-dimensional (2D) planar structure. An outer VMSF layer acting as a protective coating is able to prevent the leakage of the inner ErGO layer from the SPCE surface. Thanks to the electrostatic permselectivity and anti-fouling capacity of VMSF and to the good electroactive activity of ErGO, binary nanocomposites of VMSF and ErGO endow the SPCE with excellent analytical performance, which could be used to quantitatively detect doxorubicin (DOX) in biological samples (human serum and urine) with high sensitivity, good long-term stability, and low sample amounts.

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.

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.

The synthetic cannabinoid dehydroxylcannabidiol restores the function of a major GABAA receptor isoform in a cell model of hyperekplexia.

The functions of the glycine receptor (GlyR) and GABAA receptor (GABAAR) are both impaired in hyperekplexia, a neurological disorder usually caused by GlyR mutations. Although emerging evidence indicates that cannabinoids can directly restore normal GlyR function, whether they affect GABAAR in hyperekplexia remains unknown. Here we show that dehydroxylcannabidiol (DH-CBD), a synthetic nonpsychoactive cannabinoid, restores the GABA- and glycine-activated currents (IGABA and IGly , respectively) in HEK293 cells coexpressing a major GABAAR isoform (α1ß2γ2) and GlyRα1 carrying a human hyperekplexia-associated mutation (GlyRα1R271Q). Using coimmunoprecipitation and FRET assays, we found that DH-CBD disrupts the protein interaction between GABAAR and GlyRα1R271Q Furthermore, a point mutation of GlyRα1, changing Ser-296 to Ala-296, which is critical for cannabinoid binding on GlyR, significantly blocked DH-CBD-induced restoration of IGABA and IGly currents. This S296A substitution also considerably attenuated DH-CBD-induced disruption of the interaction between GlyRα1R271Q and GABAAR. These findings suggest that, because it restores the functions of both GlyRα1 and GABAAR, DH-CBD may represent a potentially valuable candidate drug to manage hyperekplexia.

TLR-4 targeting contributes to the recovery of osteoimmunology in periodontitis.

OBJECTIVE: The aim of this study was to determine the potential role of TLR-4 in the osteoimmunological imbalance of periodontitis. BACKGROUND: Although current evidence supports that TLR-4 plays an important role in the inflammatory response of periodontal tissues triggered by microorganisms, little information is available regarding the function of TLR-4 in the osteoimmune regulation of homeostasis in periodontitis. METHODS: Human gingival epithelial cells (HGEC) were isolated from the gingival tissues of 3 healthy volunteers and the expression of osteoclastogenic cytokines was evaluated by ELISA and real time RT-PCR. In addition, 30 C57BL/6 mice were used and randomly divided into three groups: control group, periodontitis group (CP) and periodontitis+TAK-242 (a specific inhibitor of TLR-4) group (TAK-242) and the expression of osteoclastogenic cytokines and the osteoclast density in the periodontal tissue were evaluated by immunohistochemical staining and tartrate resistant acid phosphatase staining. Moreover, micro-computed tomography (Micro-CT) was used to assess bone resorption. RESULTS: The in vitro results showed that TAK-242 blocked the overproduction of IL-1, IL-6, TNF-α and RANKL in HGEC treated with LPS. The in vivo results revealed that TAK-242 also effectively decreased these osteoclastogenic cytokines in periodontal tissue of mice with periodontitis. More importantly, Micro-CT analysis showed a significant reduction of the alveolar bone loss in the TAK-242 group compared with the CP group. Furthermore, the TRAP staining showed a significant lower density of osteoclasts in the alveolar bone area of the TAK-242 group. CONCLUSION: TLR-4 inhibition decreased the differentiation of osteoclast through the inhibition of the overproduction of osteoclastogenic cytokines and the prevention of the alveolar bone absorption in mouse periodontitis models. Therefore, the use of TAK-242 might contribute to the recovery of the osteoimmunological homeostasis and might provide a potential strategy to treat periodontal diseases.