Dominant dystrophic epidermolysis bullosa is associated with glycolytically active GATA3+ T helper 2 cells which may contribute to pruritus in lesional skin.

BACKGROUND: Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined. OBJECTIVES: To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. METHODS: Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients. RESULTS: The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment. CONCLUSIONS: Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus.

Dominant dystrophic epidermolysis bullosa (DDEB) is a rare inherited skin disease that causes fragile skin that blisters easily, often triggered by minor injuries. These blisters are accompanied by intense itching, which can be distressing. The underlying cause of DDEB lies in genetic mutations in a gene called COL7A1. This gene encodes 'type VII collagen', a protein crucial for attaching the outer skin layer (epidermis) to the layer beneath (dermis). Although the genetic basis of DDEB is understood, the causes of itch are not known. As well as this, effective treatments for DDEB are lacking, which has driven scientists to explore innovative approaches like repurposing existing drugs. Drug repurposing involves using medications that have already been approved for other health conditions. One such drug is dupilumab, which is used for severe atopic dermatitis (eczema). Dupilumab targets immune cells called Th2 cells, which play a role in inflammation and allergies. While dupilumab has shown promise in relieving DDEB itching, the way it works in this condition is unclear. This study, carried out by a group of researchers in Taiwan, looked at gene expression in DDEB-affected and unaffected skin, and compared it to gene expression in healthy skin samples. We found heightened activity in Th2 immune cells and abnormal gene signals related to itching, similar to atopic dermatitis. These findings support using dupilumab and other anti-inflammatory drugs to alleviate itching in DDEB. Clinical trials will be crucial to evaluate the effectiveness of these drugs for managing DDEB symptoms. This research opens doors for enhanced treatment options and improving the quality of life of people living with DDEB.

Yixin-Fumai granules modulate autophagy through the PI3K/AKT/FOXO pathway and lead to amelioration of aging mice with sick sinus syndrome.

OBJECTIVE: By employing network pharmacology alongside molecular docking techniques, we can delve into the intricate workings of Yixin-Fumai granules (YXFMs) and their impact on sick sinus syndrome (SSS) within wrinkles mice. Specifically, we aim to understand how YXFMs enhance autophagy through the PI3K/AKT/FOXO path. METHODS: The active ingredients and medicinal uses of Ginseng, ligusticum wallichii, Ophiopogon, Schisandra, salvia, and astragalus were compiled using the BATMAN-TCM database. We also used Genecards, OMIM, and Disgenet files to identify the disease goals. A hierarchical diagram of "disease-drug-key targets" was generated using the Cytoscape programs. In addition, we established a target protein interaction (PPI) network using the STRING database. Then, the Cluster Profiler R package was used to conduct GO functional enrichment evaluation and KEGG pathway enrichment analyses of the targets. Based on the PPI system, we chose the top communicating targets and substances over molecular docking. In vivo studies were performed to validate these selections further. The mouse model was induced to study the damaged sinoatrial node (SAN) in mice with lower heart rates due to age-related changes. Electrocardiogram and Masson staining assessments were performed to obtain the results. The transmission electron microscope was used to assess the autophagy level of SAN cells. Western blot was employed to analyze the impact of YXFMs on protein expression in the PI3K/AKT/FOXO signaling process throughout SSS therapy in aging mice. RESULTS: One hundred forty-two active ingredients, 1858 targets, 1226 disease targets, and 266 intersection targets were obtained. The key targets of the PPI network encompassed TP53, AKT1, CTNNB1, INS, and TNF, among others. According to GO functional analysis, the mechanism underlying YXFMs in SSS treatment may primarily be associated with the control of ion transport across membranes, cardiac contraction, regulation of blood circulation, and other biological processes. Based on the results of KEGG pathway enrichment analysis, it was determined that they were mainly enriched in multiple pathways of signaling such as the PI3K-Akt signaling route, MAPK signaling process, AGE-RAGE signaling path, FOXO signaling path, HIF-1 signaling process, and several other paths. Molecular docking demonstrated that five compounds had excellent binding to the key candidate target proteins AKT1 and INS. Through the in vivo studies, we noticed notable effects when administering YXFMs. These effects included the suppression of aging-induced SSS, a decrease in the R-R interval, a rise in heart rate, a reduction in fibrosis, a boost in the autophagy process level, and a spike in the levels of expression of key protein molecules in the PI3K/AKT/FOXO signaling path. CONCLUSION: This research has made preliminary predictions about the potential of YXFMs in treating SSS. It suggests that YXFMs may have the ability to target key proteins and critical paths associated with the condition. Further testing has been conducted to discover new findings and evidence of ideas for tackling SSS triggered by aging.

Topical Skin Application of Small-Molecule Antiplatelet Agent against Pressure Injury in Rat Models.

Due to prolonged forced positioning, the incidence of intraoperative pressure injuries is high. This study aimed to explore the impact of small-molecule antiplatelet drugs on pressure injuries by locally applying them before an injury occurs. In the first part of this study, water-soluble tracers with different molecular weights were applied to normal and early-stage pressure-injured skin. Through digital cameras, spectrophotometers, and histological observations, the penetration of tracers into the epidermis was clarified. In the second part of this study, a water-soluble antiplatelet drug called Trapidil (molecular weight = 205 Da) was applied to the left side of the back of a rat before, during, and after compression, and the contralateral side served as a non-intervention control group. The differences in pressure injuries between the two groups were observed through a digital camera, an ultraviolet camera, and temperature measurement, and skin circulation and perfusion were assessed via an intravenous injection of Evans Blue. The first part of this study found that water-soluble tracers did not easily penetrate normal skin but could more easily penetrate pressure-damaged skin. The smaller the molecular weight of the tracer, the easier it penetrated the skin. Therefore, in the next step of research, water-soluble drugs with smaller molecular weights should be selected. The second part of this study found that, compared with the control group, the occurrence rates and areas of ulcers were lower, the gray value was higher, and the skin temperature was lower in the Trapidil group (p < 0.05). After the intravenous Evans Blue injection, skin circulation and perfusion in the Trapidil group were found to be better. In conclusion, this study found that the topical skin application of a small-molecule antiplatelet agent may have significant effects against pressure injuries by improving post-decompression ischemia, providing new insights into the prevention and treatment of intraoperative pressure injuries.

Fluctuations in Detection Indicators and Their Significance for the Diagnosis of Early Pressure Injury in Rat Models.

PURPOSE: The aim of this study was to identify the most meaningful diagnostic indicator for distinguishing blanchable erythema (BE) and stage 1 pressure injury (early PI) in an in vivo (rat) model. DESIGN: A prospective case-control design was used to complete a horizontal and vertical comparison of detection indicators during the process of fading of BE or the deterioration of early PI into ulcer in rat models. MATERIALS AND SETTING: The sample comprised 5 hairless rats with 20 injuries, of which 10 were BE and the other 10 were early PI. Data were collected at Nagano College of Nursing in 2020 in Nagano, Japan. METHODS: The BE and PI rat models were established by subjecting the dorsal skin of a hairless rat to compression between 2 neodymium magnets for 45 minutes and 3.45 hours, respectively. The affected skin was observed based on the following: (1) photography, (2) hardness, (3) temperature, (4) moisture, and (5) spectrophotometric (a* value and ultraviolet [UV] reflectance) measurements. All measurements of BE were performed at the beginning to 60 minutes after decompression, and those for early PI were performed until 48 hours after decompression. RESULTS: Multiple BE factors, such as the degree of erythema (macroscopy and a* value), hardness, temperature, and moisture, were found to have unstable fluctuations. Only UV reflectance gradually decreased from 6 hours and decreased significantly at 48 hours after decompression (P = .001 vs 1 hour). In contrast to early PI, erythema in BE obviously faded within 10 minutes. CONCLUSIONS: Study findings indicate that a continuous decrease in UV reflectance can reflect the worsening of hemorrhage in early (stage 1) PI. In contrast, other indicators including photography, skin hardness, temperature, and moisture fluctuated and did not prove predictive for PI progression. The obvious fading of erythema in BE a short time after decompression can be used for clinical observations.

The involvement of AtMKK1 and AtMKK3 in plant-deleterious microbial volatile compounds-induced defense responses.

KEY MESSAGE: Plant-deleterious microbial volatiles activate the transactivation of hypoxia, MAMPs and wound responsive genes in Arabidopsis thaliana. AtMKK1 and AtMKK3 are involved in the plant-deleterious microbial volatiles-induced defense responses. Microbial volatile compounds (mVCs) are a collection of volatile metabolites from microorganisms with biological effects on all living organisms. mVCs function as gaseous modulators of plant growth and plant health. In this study, the defense events induced by plant-deleterious mVCs were investigated. Enterobacter aerogenes VCs lead to growth inhibition and immune responses in Arabidopsis thaliana. E. aerogenes VCs negatively regulate auxin response and transport gene expression in the root tip, as evidenced by decreased expression of DR5::GFP, PIN3::PIN3-GFP and PIN4::PIN4-GFP. Data from transcriptional analysis suggests that E. aerogenes VCs trigger hypoxia response, innate immune responses and metabolic processes. In addition, the transcript levels of the genes involved in the synthetic pathways of antimicrobial metabolites camalexin and coumarin are increased after the E. aerogenes VCs exposure. Moreover, we demonstrate that MKK1 serves as a regulator of camalexin biosynthesis gene expression in response to E. aerogenes VCs, while MKK3 is the regulator of coumarin biosynthesis gene expression. Additionally, MKK1 and MKK3 mediate the E. aerogenes VCs-induced callose deposition. Collectively, these studies provide molecular insights into immune responses by plant-deleterious mVCs.

Interaction of glioma-associated microglia/macrophages and anti-PD1 immunotherapy.

Anti-PD-1-based therapy has resulted in a minimal clinical response in malignant gliomas. Gliomas contain numerous glioma-associated microglia/macrophages (GAMs), reported to contribute to an immunosuppressive microenvironment and promote glioma progression. However, whether and how GAMs affect anti-PD-1 immunotherapy in glioma remains unclear. Here, we demonstrated that M1-like GAMs contribute to the anti-PD-1 therapeutic response, while the accumulation of M2-like GAMs is associated with therapeutic resistance. Furthermore, we found that PD-L1 ablation reverses GAMs M2-like phenotype and is beneficial to anti-PD-1 therapy. We also demonstrated that tumor-induced impairment of the antigen-presenting function of GAMs could limit the antitumor immunity of CD4+ T cells in anti-PD-1 therapy. Our study highlights the impact of GAMs activation on anti-PD-1 treatment and provides new insights into the role of GAMs in regulating anti-PD-1 therapy in gliomas.

Computational principles and practice for decoding immune contexture in the tumor microenvironment.

Tumor-infiltrating immune cells (TIICs) have been recognized as crucial components of the tumor microenvironment (TME) and induced both beneficial and adverse consequences for tumorigenesis as well as outcome and therapy (particularly immunotherapy). Computer-aided investigation of immune cell components in the TME has become a promising avenue to better understand the interplay between the immune system and tumors. In this study, we presented an overview of data sources, computational methods and software tools, as well as their application in inferring the composition of tumor-infiltrating immune cells in the TME. In parallel, we explored the future perspectives and challenges that may be faced with more accurate quantitative infiltration of immune cells in the future. Together, our study provides a little guide for scientists in the field of clinical and experimental immunology to look for dedicated resources and more competent tools for accelerating the unraveling of tumor-immune interactions with the implication in precision immunotherapy.

Machine learning-based integrative analysis of methylome and transcriptome identifies novel prognostic DNA methylation signature in uveal melanoma.

Uveal melanoma (UVM) is the most common primary intraocular human malignancy with a high mortality rate. Aberrant DNA methylation has rapidly emerged as a diagnostic and prognostic signature in many cancers. However, such DNA methylation signature available in UVM remains limited. In this study, we performed a genome-wide integrative analysis of methylome and transcriptome and identified 40 methylation-driven prognostic genes (MDPGs) associated with the tumorigenesis and progression of UVM. Then, we proposed a machine-learning-based discovery and validation strategy to identify a DNA methylation-driven signature (10MeSig) composing of 10 MDPGs (AZGP1, BAI1, CCDC74A, FUT3, PLCD1, S100A4, SCN8A, SEMA3B, SLC25A38 and SLC44A3), which stratified 80 patients of the discovery cohort into two risk subtypes with significantly different overall survival (HR = 29, 95% CI: 6.7-126, P < 0.001). The 10MeSig was validated subsequently in an independent cohort with 57 patients and yielded a similar prognostic value (HR = 2.1, 95% CI: 1.2-3.7, P = 0.006). Multivariable Cox regression analysis showed that the 10MeSig is an independent predictive factor for the survival of patients with UVM. With a prospective validation study, this 10MeSig will improve clinical decisions and provide new insights into the pathogenesis of UVM.

Mechanistically derived patient-level framework for precision medicine identifies a personalized immune prognostic signature in high-grade serous ovarian cancer.

An accurate prognosis assessment for cancer patients could aid in guiding clinical decision-making. Reliance on traditional clinical features alone in a complex clinical environment is challenging and unsatisfactory in the era of precision medicine; thus, reliable prognostic biomarkers are urgently required to improve a patient staging system. In this study, we proposed a patient-level computational framework from mechanistic and translational perspectives to establish a personalized prognostic signature (named PLPPS) in high-grade serous ovarian carcinoma (HGSOC). The PLPPS composed of 68 immune genes achieved accurate prognostic risk stratification for 1190 patients in the meta-training cohort and was rigorously validated in multiple cross-platform independent cohorts comprising 792 HGSOC patients. Furthermore, the PLPPS was shown to be the better prognostic factor compared with clinical parameters in the univariate analysis and retained a significant independent association with prognosis after adjusting for clinical parameters in the multivariate analysis. In benchmark comparisons, the performance of PLPPS (hazard ratio (HR), 1.371; concordance index (C-index), 0.604 and area under the curve (AUC), 0.637) is comparable to or better than other published gene signatures (HR, 0.972 to 1.340; C-index, 0.495 to 0.592 and AUC, 0.48-0.624). With further validation in prospective clinical trials, we hope that the PLPPS might become a promising genomic tool to guide personalized management and decision-making of HGSOC in clinical practice.

Computational recognition of lncRNA signature of tumor-infiltrating B lymphocytes with potential implications in prognosis and immunotherapy of bladder cancer.

Long noncoding RNAs (lncRNAs) have been associated with cancer immunity regulation and the tumor microenvironment (TME). However, functions of lncRNAs of tumor-infiltrating B lymphocytes (TIL-Bs) and their clinical significance have not yet been fully elucidated. In the present study, a machine learning-based computational framework is presented for the identification of lncRNA signature of TIL-Bs (named 'TILBlncSig') through integrative analysis of immune, lncRNA and clinical profiles. The TILBlncSig comprising eight lncRNAs (TNRC6C-AS1, WASIR2, GUSBP11, OGFRP1, AC090515.2, PART1, MAFG-DT and LINC01184) was identified from the list of 141 B-cell-specific lncRNAs. The TILBlncSig was capable of distinguishing worse compared with improved survival outcomes across different independent patient datasets and was also independent of other clinical covariates. Functional characterization of TILBlncSig revealed it to be an indicator of infiltration of mononuclear immune cells (i.e. natural killer cells, B-cells and mast cells), and it was associated with hallmarks of cancer, as well as immunosuppressive phenotype. Furthermore, the TILBlncSig revealed predictive value for the survival outcome and immunotherapy response of patients with anti-programmed death-1 (PD-1) therapy and added significant predictive power to current immune checkpoint gene markers. The present study has highlighted the value of the TILBlncSig as an indicator of immune cell infiltration in the TME from a noncoding RNA perspective and strengthened the potential application of lncRNAs as predictive biomarkers of immunotherapy response, which warrants further investigation.

Volatile cinnamaldehyde induces systemic salt tolerance in the roots of rice (Oryza sativa).

Cinnamaldehyde (CA) is a volatile plant secondary metabolite that exhibits strong anti-pathogenic activities. Nonetheless, less is known about the effect of CA on plant tolerance to abiotic stresses. In this study, we delineated the effects of CA fumigation on rice roots (Oryza Sativa L cv. TNG67) under salinity stress (200 mM NaCl). Our result showed that CA vapor significantly alleviated salinity-induced ROS accumulation and cell death. This CA-induced alleviation appears to be mediated primarily by the upregulation of proline metabolism genes, the rapid proline accumulation, and the decrease of Na+ /K+ ratio as early as 3 h after NaCl treatment. Of note, the activities of peroxidase (POD; EC 1.11.1.7) isozymes a and b were decreased by CA fumigation, and the activities of catalase (CAT; EC 1.11.1.6) and superoxide dismutase (SOD; EC 1.15.1.1) were not significantly affected. Our findings suggest that CA vapor might be useful for priming rice roots to withstand salinity stress, which is more prevalent due to the ongoing global climate change. To the best of our knowledge, this is the first study to show modulation of macro- and micro-elements as well as antioxidative factors after CA fumigation of salinity-stressed rice roots.

Thermal preconditioning can reduce the incidence of intraoperatively acquired pressure injuries.

Intraoperatively acquired pressure injuries (IAPIs) occur frequently among patients who undergo surgical procedures that last longer than 3 h. Several studies indicated that heat shock proteins (HSPs) play an important role in the protection of stress-induced damages in skin tissues. Hence, the aim of this study was to investigate the potential preventive effect of thermal preconditioning (TPC) on IAPIs in surgical patients and rats and to identify the differentially expressed HSP genes in response to the above treatment. TPC was performed on one group of hairless rats before the model of pressure injuries was established. Subsequently, the size of skin lesions was measured and the expression levels of mRNA and protein of HSPs of the pressured skin were detected by real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemical staining. For human studies, 118 surgical patients were randomly divided into the TPC group (n = 59) and the control group (n = 59), respectively. The temperature and pressure of sacral skin, as well as the incidence of pressure injury (PI) were detected and compared. In animal studies, TPC significantly reduced both the size and incidence of PI in rats on the second, third and fourth days post treatment. In addition, the expression levels of both mRNA and protein of HSP27 were increased in the TPC group, compared with the control group. Immunohistochemical staining showed that HSP27 was distributed in various types of dermal cells and increased in basal cells. In human studies, a significant reduction (75%) of IAPIs was observed among the patients in the TPC group. TPC can reduce the incidence of PI in rats and humans, and the upregulation of HSP27 may play an important role in this biological progress. Further studies are warranted to explore the molecular mechanism of the preventive effect in PI mediated by HSP27.

Triterpenoids from the Leaves of Cyclocarya paliurus and Their Glucose Uptake Activity in 3T3-L1 Adipocytes.

Four new dammarane triterpenoid saponins cypaliurusides Z1-Z4 (1-4) and eight known analogs (5-12) were isolated from the leaves of Cyclocarya paliurus. The structures of the isolated compounds were determined using a comprehensive analysis of 1D and 2D NMR and HRESIMS data. The docking study demonstrated that compound 10 strongly bonded with PTP1B (a potential drug target for the treatment of type-II diabetes and obesity), hydrogen bonds, and hydrophobic interactions, verifying the importance of sugar unit. The effects of the isolates on insulin-stimulated glucose uptake in 3T3-L1 adipocytes were evaluated and three dammarane triterpenoid saponins (6, 7 and 10) were found to enhance insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Furthermore, compounds 6, 7, and 10 exhibited potent abilities to promote insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner. Thus, the abundant dammarane triterpenoid saponins from C. paliurus leaves exhibited stimulatory effects on glucose uptake with application potential as a antidiabetic treatment.

Circ-ZEB1 promotes PIK3CA expression by silencing miR-199a-3p and affects the proliferation and apoptosis of hepatocellular carcinoma.

BACKGROUND: Although the prognostic outcomes of liver cancer (LC) cases have improved with the advancement in diagnostic technology and treatment methods, the transferability and recurrence of HCC and the 5-year and 10-year survival rates of patients have remained unsatisfactory. As a result, there is a need for more accurate diagnostic indicators that can detect liver cancer early, effectively improving the prognosis of patients. Whole-genome sequencing (WGS) revealed that circ-ZEB1 and PIK3CA are highly expressed in HCC tissues, whereas miR-199a-3p is significantly downregulated in HCC. Multiple databases search and biological analysis revealed that elevated expression of circ-ZEB1 and PIK3CA was related to poor prognosis of HCC. In vitro and in vivo studies revealed that upregulated levels of PIK3CA and circ-ZEB1 were closely associated with HCC proliferation and apoptosis. Based on these results, we believe that circ-ZEB1 and PIK3CA could be used as biomarkers to diagnose and treat patients with HCC. More importantly, circ-ZEB1 can promotes the expression of PIK3CA by silencing miR-199a-3p and affecting the progression of HCC. METHODS AND RESULTS: Postoperative specimens from 56 patients with HCC who had not undergone chemotherapy from 2015 to 2018 were collected from the Department of Hepatobiliary Surgery, Second Affiliated Hospital of Nanchang University. WGS revealed differential expression of genes in HCC. Furthermore, RT-qPCR detected the expression of circ-ZEB1, miR-199a-3p, and PIK3CA in HCC tissues. MTT, EdU, and plate cloning experiments were conducted to detect cell proliferation, whereas flow cytometry analysis was used to detect apoptosis. FISH was used to co-localize circ-ZEB1 and miR-199a-3p, and biotin-coupled probe pull-down assay was used to detect the specific binding of circ-ZEB1 and miR-199a-3p. The dual-luciferase report assay detected the association of miR-199a-3p with PIK3CA. Western blotting was used to study the expression of PIK3CA protein. Circ-ZEB1 and PIK3CA were upregulated in HCC and predicted a poor prognosis. MiR-199a-3p showed low expression in HCC, whereas downregulation of circ-ZEB1 reduced HCC cell proliferation and promoted cell apoptosis. MiR-199a-3p blocked the effect of circ-ZEB1 on HCC. Circ-ZEB1 served as a biomarker of HCC. Circ-ZEB1 promoted the expression of PIK3CA by silencing miR-199a-3p to affect the progress of HCC. CONCLUSIONS: Circ-ZEB1 promoted the expression of PIK3CA by depleting miR-199a-3p, thereby affecting HCC proliferation and apoptosis.

Knockdown of UCA1 attenuated the progression of alcoholic fatty disease by sponging miR-214.

Alcoholic fatty liver (AFL) is the initial manifestation of Alcoholic liver disease which can develop into alcoholic cirrhosis even extensive necrosis of liver cells, which induces liver failure finally. This study aims to focus on the role of long noncoding RNA UCA1 in AFL and further explored possible mechanism of this disease. We first downloaded GSE28619 to identify the expression of UCA1 in patients with AFL and use lncRNAs microarray to confirm UCA1 expression in serum of patients with AFL. Then we established ethanol-induced L02 cell model to mimic hepatocyte injury condition. By conducting qRT-PCR, we measured the expression of LncRNA UCA1 and miR-214 in serum of patients and ethanol-induced L02 cell. MTT assay, transwell migration, ELISA, qRT-PCR, and western blotting analysis were applied to evaluating the effect of UCA1 on ethanol-induced L02 cell. The bioinformatics analysis and the rescue experiment were devoted to the underlying mechanism. In this study, we first detected the expression of UCA1 was up-regulated in serum of patients with AFL and ethanol-induced L02 cells. And knockdown of UCA1 reversed the inhibiting effect of ethanol on the biological behavior of L02 cells including cell proliferation, migration, and apoptosis. Besides, lncRNA UCA1 regulated the expression of KLF5 by sponging miR-214. LncRNA UCA1 regulated the biological behavior of ethanol-induced L02 cells by sponging miR-214, which may provide novel therapeutic strategies for alcoholic fatty liver.

Cerebrovascular Reactivity Mapping Using Resting-State Functional MRI in Patients With Gliomas.

BACKGROUND: Recently, a data-driven regression analysis method was developed to utilize the resting-state (rs) blood oxygenation level-dependent signal for cerebrovascular reactivity (CVR) mapping (rs-CVR), which was previously optimized by comparing with the CO2 inhalation-based method in health subjects and patients with neurovascular diseases. PURPOSE: To investigate the agreement of rs-CVR and the CVR mapping with breath-hold MRI (bh-CVR) in patients with gliomas. STUDY TYPE: Retrospective. POPULATION: Twenty-five patients (12 males, 13 females; mean age ± SD, 48 ± 13 years) with gliomas. FIELD STRENGTH/SEQUENCE: Dynamic T2*-weighted gradient-echo echo-planar imaging during a breath-hold paradigm and during the rs on a 3-T scanner. ASSESSMENT: rs-CVR with various frequency ranges and resting-state fluctuation amplitude (RSFA) were assessed. The agreement between each rs-based CVR measurement and bh-CVR was determined by voxel-wise correlation and Dice coefficient in the whole brain, gray matter, and the lesion region of interest (ROI). STATISTICAL TESTS: Voxel-wise Pearson correlation, Dice coefficient, Fisher Z-transformation, repeated-measure analysis of variance and post hoc test with Bonferroni correction, and nonparametric repeated-measure Friedman test and post hoc test with Bonferroni correction were used. Significance was set at P < 0.05. RESULTS: Compared with bh-CVR, the highest correlations were found at the frequency bands of 0.04-0.08 Hz and 0.02-0.04 Hz for rs-CVR in both whole brain and the lesion ROI. RSFA had significantly lower correlations than did rs-CVR of 0.02-0.04 Hz and a wider frequency range (0-0.1164 Hz). Significantly higher correlations and Dice coefficient were found in normal tissues than in the lesion ROI for all three methods. DATA CONCLUSION: The optimal frequency ranges for rs-CVR are determined by comparing with bh-CVR in patients with gliomas. The rs-CVR method outperformed the RSFA. Significantly higher correlation and Dice coefficient between rs- and bh-CVR were found in normal tissue than in the lesion. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Prediction and management of strangulated bowel obstruction: a multi-dimensional model analysis.

BACKGROUND: Distinguishing strangulated bowel obstruction (StBO) from simple bowel obstruction (SiBO) still poses a challenge for emergency surgeons. We aimed to construct a predictive model that could distinctly discriminate StBO from SiBO based on the degree of bowel ischemia. METHODS: The patients diagnosed with intestinal obstruction were enrolled and divided into SiBO group and StBO group. Binary logistic regression was applied to identify independent risk factors, and then predictive models based on radiological and multi-dimensional models were constructed. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were calculated to assess the accuracy of the predicted models. Via stratification analysis, we validated the multi-dimensional model in the prediction of transmural necrosis both in the training set and validation set. RESULTS: Of the 281 patients with SBO, 45 (16.0%) were found to have StBO, while 236(84.0%) with SiBO. The AUC of the radiological model was 0.706 (95%CI, 0.617-0.795). In the multivariate analysis, seven risk factors including pain duration ≤ 3 days (OR = 3.775), rebound tenderness (OR = 5.201), low-to-absent bowel sounds (OR = 5.006), low levels of potassium (OR = 3.696) and sodium (OR = 3.753), high levels of BUN (OR = 4.349), high radiological score (OR = 11.264) were identified. The AUC of the multi-dimensional model was 0.857(95%CI, 0.793-0.920). In the stratification analysis, the proportion of patients with transmural necrosis was significantly greater in the high-risk group (24%) than in the medium-risk group (3%). No transmural necrosis was found in the low-risk group. The AUC of the validation set was 0.910 (95%CI, 0.843-0.976). None of patients in the low-risk and medium-risk score group suffered with StBO. However, all patients with bowel ischemia (12%) and necrosis (24%) were resorted into high-risk score group. CONCLUSION: The novel multi-dimensional model offers a useful tool for predicting StBO. Clinical management could be performed according to the multivariate score.

Who would avoid severe adverse events from nasointestinal tube in small bowel obstruction? A matched case-control study.

BACKGROUND: Nasointestinal tubes (NITs) have been increasingly used in patients with small bowel obstruction (SBO); However, severe adverse events (SAEs) of NITs might threaten the lives of patients. The indications of NITs need to be identified. This study was designed to explore the indications for the insertion of NITs in patients with SBO and to suggest the optimal strategies for individuals based on the outcomes of SAEs. METHODS: After propensity score matching, 68 pairs were included (Success group and failure group). The occurrence of SAEs and the clinical parameters were compared between the SAE group and the non-SAE group. Independent risk factors were evaluated among the subgroups. A novel scoring system was established to detect the subgroups that would benefit from NITs insertion. RESULTS: Successful implementation of NITs could avoid hypochloremia (p = 0.010), SAEs (p = 0.001), pneumonia (p = 0.006). SAEs occurred in 13 of 136 (9.6%) patients who accepted NITs insertion treatment. Risk factors for SAEs included tumors (p = 0.002), reduced BMI (p = 0.048), reduced hemoglobin (p = 0.001), abnormal activated partial thromboplastin time (p = 0.015) and elevated white blood cells (p = 0.002). A novel risk scoring system consists of hemoglobin before NITs insertion (95% CI 0.685, 0.893) and bowel obstruction symptoms relieved after NITs insertion (95% CI 0.575, 0.900) had the highest area under curve for predicting the occurrence of SAEs. We divided the risk score system into 3 grades, with the increasing grades, the rates of SAEs surged from 1.3% (1/74) to (6/11) 54.5%. CONCLUSION: NITs successfully insertion could avoid SAEs occurrence in SBO conservative treatment. SBO patients without anemia and could be relieved after NITs insertion could be the potential benefit group for this therapy.

Variation of body regional responses to Ustekinumab and Secukinumab in psoriasis patients: A real-world retrospective study and literature review.

Psoriasis in different body regions displays varying therapeutic responses to biologics, whereas currently relevant studies remain scarce. We retrospectively reviewed the treatment responses of patients with moderate-to-severe psoriasis, who completed the two-year reimbursed ustekinumab or secukinumab treatment in two medical centers in Southern Taiwan. Demographic profiles and body regional PASI scores (head/neck, trunk, upper and lower limbs) along the treatment course were recorded. The proportions of patients attaining PASI 75, 90, 100 and the extent of body regional PASI score improvements were compared in biologic naïve or experienced patients. A total of 57 and 67 patients receiving ustekinumab and secukinumab injections, respectively, were included. Overall, patients receiving secukinumab showed higher degrees of PASI score improvements along the two-year treatment course. The lower limbs had the highest, and the upper extremities and head/neck had the lowest post-treatment PASI scores regardless of prior biologic use in the groups of ustekinumab and secukinumab. The upper limbs showed the highest, while the lower limbs had the lowest complete remission rate (regional specific PASI 100) in response to ustekinumab (upper limbs 48.7%, lower limbs 25.6%) and secukinumab (upper limbs 77.1%, lower limbs 42.8%) in biologic naïve groups. Our study demonstrated that lower limbs were the most treatment-refractory area in response to ustekinumab and secukinumab injections, while the upper limbs and head/neck region had a better response.

Interaction between GALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy.

BACKGROUND: Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established. METHODS: To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis. RESULTS: We discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; ß=0.26, P=1.20×10-9); the locus we identified at GALNT12 (rs7856182; ß=0.73, P=2.38×10-9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10-2) and disease risk (P=6.55×10-3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls. CONCLUSIONS: Our data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.