IBDTransDB: a manually curated transcriptomic database for inflammatory bowel disease.

Inflammatory Bowel Disease (IBD) therapies are ineffective in at least 40% patients, and transcriptomic datasets have been widely used to reveal the pathogenesis and to identify the novel drug targets for these patients. Although public IBD transcriptomic datasets are available from many web-based tools/databases, due to the unstructured metadata and data description of these public datasets, most of these tools/databases do not allow querying datasets based on multiple keywords (e.g. colon and infliximab). Furthermore, few tools/databases can compare and integrate the datasets from the query results. To fill these gaps, we have developed IBDTransDB (https://abbviegrc.shinyapps.io/ibdtransdb/), a manually curated transcriptomic database for IBD. IBDTransDB includes a manually curated database with 34 transcriptomic datasets (2932 samples, 122 differential comparisons) and a query system supporting 35 keywords from 5 attributes (e.g. tissue and treatment). IBDTransDB also provides three modules for data analyses and integration. IBDExplore allows interactive visualization of differential gene list, pathway enrichment, gene signature and cell deconvolution analyses from a single dataset. IBDCompare supports comparisons of selected genes or pathways from multiple datasets across different conditions. IBDIntegrate performs meta-analysis to prioritize a list of genes/pathways based on user-selected datasets and conditions. Using two case studies related to infliximab treatment, we demonstrated that IBDTransDB provides a unique platform for biologists and clinicians to reveal IBD pathogenesis and identify the novel targets by integrating with other omics data. Database URL: https://abbviegrc.shinyapps.io/ibdtransdb/.

Theoretical Analysis of Selectivity Differences in Ketoreductases toward Aldehyde and Ketone Carbonyl Groups.

Lactobacillus kefir alcohol dehydrogenase (LkADH) and ketoreductase from Chryseobacterium sp. CA49 (ChKRED12) exhibit different chemoselectivity and stereoselectivity toward a substrate with both keto and aldehyde carbonyl groups. LkADH selectively reduces the keto carbonyl group while retaining the aldehyde carbonyl group, producing optically pure R-alcohols. In contrast, ChKRED12 selectively reduces the aldehyde group and exhibits low reactivity toward ketone carbonyls. This study investigated the structural basis for these differences and the role of specific residues in the active site. Molecular dynamics (MD) simulations and quantum chemical calculations were used to investigate the interactions between the substrate and the enzymes and the essential cause of this phenomenon. The present study has revealed that LkADH and ChKRED12 exhibit significant differences in the structure of their respective active pockets, which is a crucial determinant of their distinct chemoselectivity toward the same substrate. Moreover, residues N89, N113, and E144 within LkADH as well as Q151 and D190 within ChKRED12 have been identified as key contributors to substrate stabilization within the active pocket through electrostatic interactions and van der Waals forces, followed by hydride transfer utilizing the coenzyme NADPH. Furthermore, the enantioselectivity mechanism of LkADH has been elucidated using quantum chemical methods. Overall, these findings not only provide fundamental insights into the underlying reasons for the observed differences in selectivity but also offer a detailed mechanistic understanding of the catalytic reaction.

T Follicular Helper Cells in Tertiary Lymphoid Structure Contribute to Renal Fibrosis by IL-21.

Tertiary lymphoid structure (TLS) represents lymphocyte clusters in non-lymphoid organs. The formation and maintenance of TLS are dependent on follicular helper T (TFH) cells. However, the role of TFH cells during renal TLS formation and the renal fibrotic process has not been comprehensively elucidated in chronic kidney disease. Here, we detected the circulating TFH cells from 57 IgAN patients and found that the frequency of TFH cells was increased in IgA nephropathy patients with renal TLS and also increased in renal tissues from the ischemic-reperfusion-injury (IRI)-induced TLS model. The inducible T-cell co-stimulator (ICOS) is one of the surface marker molecules of TFH. Remarkably, the application of an ICOS-neutralizing antibody effectively prevented the upregulation of TFH cells and expression of its canonical functional mediator IL-21, and also reduced renal TLS formation and renal fibrosis in IRI mice in vivo. In the study of this mechanism, we found that recombinant IL-21 could directly promote renal fibrosis and the expression of p65. Furthermore, BAY 11-7085, a p65 selective inhibitor, could effectively alleviate the profibrotic effect induced by IL-21 stimulation. Our results together suggested that TFH cells contribute to TLS formation and renal fibrosis by IL-21. Targeting the ICOS-signaling pathway network could reduce TFH cell infiltration and alleviate renal fibrosis.

Effect of Radiation Schedule on Transportation-Related Carbon Emissions: A Case Study in Rectal Cancer.

Purpose: The health care sector is a major contributor of worldwide greenhouse gas (GHG) emissions. Indirect emissions, including those associated with transportation, make up 82% of the US health care sector's environmental footprint. Radiation therapy (RT) treatment regimens present an opportunity for environmental health care-based stewardship owing to the high incidence of cancer diagnosis, significant utilization of RT, and myriad treatment days required for curative regimens. Because the use of short-course RT (SCRT) in the treatment of rectal cancer has demonstrated noninferior clinical outcomes compared with conventional, long-course RT (LCRT), we investigate the environmental and health equity-related outcomes. Methods and Materials: Patients treated with curative, preoperative RT for newly diagnosed rectal cancer at our institution between 2004 and 2022 and living in-state were included. Travel distance was estimated using patients' reported home address. Associated GHG emissions were calculated and reported in carbon dioxide equivalents (CO2e). Results: Of 334 patients included, the total distance traveled for the treatment course was significantly greater in patients treated with LCRT versus SCRT (median, 1417 vs 319 miles; P < .001). Total CO2e emissions for those undergoing LCRT (n = 261) and SCRT (n = 73) were 665.3 kg CO2e and 149.9 kg CO2e, respectively, per treatment course (P < .001), with a net difference of 515.4 kg CO2e. Relatively, this suggests that LCRT is associated with 4.5 times greater GHG emissions from patient transportation. Conclusions: Using treatment of rectal cancer as proof-of-principle, we advocate for the inclusion of environmental considerations in the creation of climate-resilient oncologic RT practices, especially in the context of equivocal clinical outcomes between RT fractionation schedules.

A radiomics nomogram prediction for survival of patients with "driver gene-negative" lung adenocarcinomas (LUAD).

BACKGROUND: To study the role of computed tomography (CT)-derived radiomics features and clinical characteristics on the prognosis of "driver gene-negative" lung adenocarcinoma (LUAD) and to explore the potential molecular biological which may be helpful for patients' individual postoperative care. METHODS: A total of 180 patients with stage I-III "driver gene-negative" LUAD in the First Affiliated Hospital of Sun Yat-Sen University from September 2003 to June 2015 were retrospectively collected. The Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model was used to screen radiomics features and calculated the Rad-score. The prediction performance of the nomogram model based on radiomics features and clinical characteristics was validated and then assessed with respect to calibration. Gene set enrichment analysis (GSEA) was used to explore the relevant biological pathways. RESULTS: The radiomics and the clinicopathological characteristics were combined to construct a nomogram resulted in better performance for the estimation of OS (C-index: 0.815; 95% confidence interval [CI]: 0.756-0.874) than the clinicopathological nomogram (C-index: 0.765; 95% CI: 0.692-0.837). Decision curve analysis demonstrated that in terms of clinical usefulness, the radiomics nomogram outperformed the traditional staging system and the clinicopathological nomogram. The clinical prognostic risk score of each patient was calculated based on the radiomics nomogram and divided by X-tile into high-risk (> 65.28) and low-risk (≤ 65.28) groups. GSEA results showed that the low-risk score group was directly related to amino acid metabolism, and the high-risk score group was related to immune and metabolism pathways. CONCLUSIONS: The radiomics nomogram was promising to predict the prognosis of patients with "driver gene-negative" LUAD. The metabolism and immune-related pathways may provide new treatment orientation for this genetically unique subset of patients, which may serve as a potential tool to guide individual postoperative care for those patients.

Application of Cell Painting for chemical hazard evaluation in support of screening-level chemical assessments.

'Cell Painting' is an imaging-based high-throughput phenotypic profiling (HTPP) method in which cultured cells are fluorescently labeled to visualize subcellular structures (i.e., nucleus, nucleoli, endoplasmic reticulum, cytoskeleton, Golgi apparatus / plasma membrane and mitochondria) and to quantify morphological changes in response to chemicals or other perturbagens. HTPP is a high-throughput and cost-effective bioactivity screening method that detects effects associated with many different molecular mechanisms in an untargeted manner, enabling rapid in vitro hazard assessment for thousands of chemicals. Here, 1201 chemicals from the ToxCast library were screened in concentration-response up to ∼100 µM in human U-2 OS cells using HTPP. A phenotype altering concentration (PAC) was estimated for chemicals active in the tested range. PACs tended to be higher than lower bound potency values estimated from a broad collection of targeted high-throughput assays, but lower than the threshold for cytotoxicity. In vitro to in vivo extrapolation (IVIVE) was used to estimate administered equivalent doses (AEDs) based on PACs for comparison to human exposure predictions. AEDs for 18/412 chemicals overlapped with predicted human exposures. Phenotypic profile information was also leveraged to identify putative mechanisms of action and group chemicals. Of 58 known nuclear receptor modulators, only glucocorticoids and retinoids produced characteristic profiles; and both receptor types are expressed in U-2 OS cells. Thirteen chemicals with profile similarity to glucocorticoids were tested in a secondary screen and one chemical, pyrene, was confirmed by an orthogonal gene expression assay as a novel putative GR modulating chemical. Most active chemicals demonstrated profiles not associated with a known mechanism-of-action. However, many structurally related chemicals produced similar profiles, with exceptions such as diniconazole, whose profile differed from other active conazoles. Overall, the present study demonstrates how HTPP can be applied in screening-level chemical assessments through a series of examples and brief case studies.

Single cell multi-omic reference atlases of non-human primate immune tissues reveals CD102 as a biomarker for long-lived plasma cells.

In response to infection or immunization, antibodies are produced that provide protection against re-exposure with the same pathogen. These antibodies can persist at high titers for decades and are maintained by bone marrow-resident long-lived plasma cells (LLPC). However, the durability of antibody responses to immunization varies amongst vaccines. It is unknown what factors contribute to the differential longevity of serum antibody responses and whether heterogeneity in LLPC contributes to this phenomenon. While LLPC differentiation has been studied extensively in mice, little is known about this population in humans or non-human primates (NHP). Here, we use multi-omic single-cell profiling to identify and characterize the LLPC compartment in NHP. We identify LLPC biomarkers including the marker CD102 and show that CD102 in combination with CD31 identifies LLPC in NHP bone marrow. Additionally, we find that CD102 is expressed by LLPC in mouse and humans. These results further our understanding of the LLPC compartment in NHP, identify biomarkers of LLPC, and provide tissue-specific single cell references for future studies.

Non-invasive model for predicting esophageal varices based on liver and spleen volume.

BACKGROUND: Upper endoscopy is the gold standard for predicting esophageal varices in China. Guidelines and consensus suggest that patients with liver cirrhosis should undergo periodic upper endoscopy, most patients undergo their first upper endoscopy when esophageal variceal bleeds. Therefore, it is important to develop a non-invasive model to early diagnose esophageal varices. AIM: To develop a non-invasive predictive model for esophageal varices based on liver and spleen volume in viral cirrhosis patients. METHODS: We conducted a cross-sectional study based on viral cirrhosis crowd in the Second Affiliated Hospital of Xi'an Jiaotong University. By collecting the basic information and clinical data of the participants, we derived the independent risk factors and established the prediction model of esophageal varices. The established model was compared with other models. Area under the receiver operating characteristic curve, calibration plot and decision curve analysis were used to test the discriminating ability, calibration ability and clinical practicability in both the internal and external validation. RESULTS: The portal vein diameter, the liver and spleen volume, and volume change rate were the independent risk factors of esophageal varices. We successfully used the factors to establish the predictive model [area under the curve (AUC) 0.87, 95%CI: 0.80-0.95], which showed better predictive value than other models. The model showed good discriminating ability, calibration ability and the clinical practicability in both modelling group and external validation group. CONCLUSION: The developed non-invasive predictive model can be used as an effective tool for predicting esophageal varices in viral cirrhosis patients.

Monodomain Liquid Crystals of Two-Dimensional Sheets by Boundary-Free Sheargraphy.

Eliminating topological defects to achieve monodomain liquid crystals is highly significant for the fundamental studies of soft matter and building long-range ordered materials. However, liquid crystals are metastable and sensitive to external stimuli, such as flow, confinement, and electromagnetic fields, which cause their intrinsic polycrystallinity and topological defects. Here, we achieve the monodomain liquid crystals of graphene oxide over 30 cm through boundary-free sheargraphy. The obtained monodomain liquid crystals exhibit large-area uniform alignment of sheets, which has the same optical polarized angle and intensity. The monodomain liquid crystals provide bidirectionally ordered skeletons, which can be applied as lightweight thermal management materials with bidirectionally high thermal and electrical conductivity. Furthermore, we extend the controllable topology of two-dimensional colloids by introducing singularities and disclinations in monodomain liquid crystals. Topological structures with defect strength from - 2 to + 2 were realized. This work provides a facile methodology to study the structural order of soft matter at a macroscopic level, facilitating the fabrication of metamaterials with tunable and highly anisotropic architectures.

Detection of cell-cell interactions via photocatalytic cell tagging.

The growing appreciation of immune cell-cell interactions within disease environments has led to extensive efforts to develop immunotherapies. However, characterizing complex cell-cell interfaces in high resolution remains challenging. Thus, technologies leveraging therapeutic-based modalities to profile intercellular environments offer opportunities to study cell-cell interactions with molecular-level insight. We introduce photocatalytic cell tagging (PhoTag) for interrogating cell-cell interactions using single-domain antibodies (VHHs) conjugated to photoactivatable flavin-based cofactors. Following irradiation with visible light, the flavin photocatalyst generates phenoxy radical tags for targeted labeling. Using this technology, we demonstrate selective synaptic labeling across the PD-1/PD-L1 axis in antigen-presenting cell-T cell systems. In combination with multiomics single-cell sequencing, we monitored interactions between peripheral blood mononuclear cells and Raji PD-L1 B cells, revealing differences in transient interactions with specific T cell subtypes. The utility of PhoTag in capturing cell-cell interactions will enable detailed profiling of intercellular communication across different biological systems.

Scalable production of ultrafine polyaniline fibres for tactile organic electrochemical transistors.

The development of continuous conducting polymer fibres is essential for applications ranging from advanced fibrous devices to frontier fabric electronics. The use of continuous conducting polymer fibres requires a small diameter to maximize their electroactive surface, microstructural orientation, and mechanical strength. However, regularly used wet spinning techniques have rarely achieved this goal due primarily to the insufficient slenderization of rapidly solidified conducting polymer molecules in poor solvents. Here we report a good solvent exchange strategy to wet spin the ultrafine polyaniline fibres. The slow diffusion between good solvents distinctly decreases the viscosity of protofibers, which undergo an impressive drawing ratio. The continuously collected polyaniline fibres have a previously unattained diameter below 5 µm, high energy and charge storage capacities, and favorable mechanical performance. We demonstrated an ultrathin all-solid organic electrochemical transistor based on ultrafine polyaniline fibres, which operated as a tactile sensor detecting pressure and friction forces at different levels.

Low-Carbohydrate-Diet Score and Mortality in Adults With and Without Chronic Kidney Disease: Results From the Third National Health and Nutrition Examination Survey.

OBJECTIVE: The long-term safety of consuming low-carbohydrate diets (LCDs) remains controversial. As high protein and high fat might accelerate chronic kidney disease (CKD) progression, the impact of LCD on mortality might be different in subjects with CKD and subjects without CKD. Therefore, the objective of this study was to assess the association of LCD with mortality among individuals with and without CKD. METHODS: Data from 1158 subjects with CKD and 9523 subjects without CKD in the Third National Health and Nutrition Examination Survey were analyzed. The LCD score was calculated based on a 24-hour dietary recall interview. Mortality was from baseline until 31 December 2015. Cox proportional hazards regression models were fitted to estimate multivariable-adjusted hazard ratios and 95% confidence intervals. RESULTS: During the median follow-up of 24 years, 751 (65%) deaths and 2624 (28%) deaths were recorded in the CKD group and the non-CKD group, respectively. The multivariable-adjusted hazard ratio for all-cause mortality comparing the highest versus lowest quarters of LCD score was 1.51 (95% confidence interval, 1.01-2.25, P for trend = 0.045) in the CKD group. However, there were no association between the LCD score and all-cause mortality in the non-CKD group. CONCLUSIONS: The LCD scores were found significantly positively associated with all-cause mortality in adults with CKD, but not in adults without CKD.

Mapping QTLs for spring green-up, plant vigor, and plant biomass in two lowland switchgrass populations.

Switchgrass (Panicum virgatum L.) is an important perennial C4 species due to its large potential for cellulosic bioenergy feedstock production. Identification of quantitative trait loci (QTL) controlling important developmental traits is valuable to understanding the genetic basis and using marker-assisted selection (MAS) in switchgrass breeding. One F1 hybrid population derived from NL94 (♀) × SL93 (♂) and one S1 (first-generation selfed) population from NL94 were used in this study. Both the populations showed significant variations for genotype and genotype by environment interactions for three traits studied: plant vigor, spring green-up, and plant biomass. Plant vigor had strong and positive correlations with plant biomass in both populations. Broad-sense heritability estimates for plant vigor ranged from 0.46 to 0.74 and 0.45 to 0.74 in the hybrid and selfed population, respectively. Spring green-up had similar heritability estimates, 0.42-0.78 in the hybrid population, and 0.47-0.82 in the selfed population. Heritability of plant biomass was 0.54-0.64 in the hybrid population and 0.64-0.74 in the selfed population. Fifteen QTLs for spring green-up, 6 QTLs for plant vigor, and 3 QTLs for biomass yield were detected in the hybrid population, whereas 4 QTLs for spring green-up, 4 QTLs for plant vigor, and 1 QTL for biomass yield were detected in the selfed population. Markers associated with these QTLs can be used in MAS to accelerate switchgrass breeding program. This study provided new information in understanding the genetic control of biomass components and demonstrated substantial heterotic vigor that could be explored for breeding hybrid cultivars in switchgrass. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-022-01296-7.

Novel adjuvants enhance immune responses elicited by a replication-defective human cytomegalovirus vaccine in nonhuman primates.

Adjuvants have long been explored to enhance vaccine efficacy. Current adjuvants approved for human vaccines are mostly studied for their ability to improve antibody responses. There remains a need for development of novel adjuvants, especially those able to enhance cell-mediated immunity (CMI). In this preclinical study we assessed the effect of two novel adjuvants, a delta inulin microparticle Advax formulated with or without a toll-like receptor 9 (TLR9) agonist CpG oligonucleotide, and a Merck & Co., Inc., Kenilworth, NJ, USA proprietary lipid nanoparticle (LNP), on immune responses elicited by V160, an experimental replication-defective human cytomegalovirus vaccine. Adult rhesus macaques were immunized with a low dose of V160 (10 units) either alone or in combination with the adjuvants as compared to those immunized with a high dose of V160 alone (100 units). While neither adjuvant conferred a significant benefit to vaccine-elicited humoral immune responses at the dose tested, both enhanced cellular immune responses to V160, where Advax promoted both CD4+ and CD8+ T cells and LNP predominantly impacted the CD4+ T cell response. Transcriptome analyses of peripheral blood samples demonstrated different modes of action for these adjuvants. One day post vaccination, LNP induced upregulation of a large number of genes involved in the innate immune response similar to those triggered by viral infection. In contrast, Advax did not activate any known inflammatory pathways and did not significantly impact gene expression pattern until day 7 post administration, suggesting a unique, non-inflammatory mechanism. These data warrant further exploration of Advax and LNP as adjuvants in clinical trials for vaccines desiring to elicit both humoral and T cell responses.

Precise Thermoplastic Processing of Graphene Oxide Layered Solid by Polymer Intercalation.

The processing capability is vital for the wide applications of materials to forge structures as-demand. Graphene-based macroscopic materials have shown excellent mechanical and functional properties. However, different from usual polymers and metals, graphene solids exhibit limited deformability and processibility for precise forming. Here, we present a precise thermoplastic forming of graphene materials by polymer intercalation from graphene oxide (GO) precursor. The intercalated polymer enables the thermoplasticity of GO solids by thermally activated motion of polymer chains. We detect a critical minimum containing of intercalated polymer that can expand the interlayer spacing exceeding 1.4 nm to activate thermoplasticity, which becomes the criteria for thermal plastic forming of GO solids. By thermoplastic forming, the flat GO-composite films are forged to Gaussian curved shapes and imprinted to have surface relief patterns with size precision down to 360 nm. The plastic-formed structures maintain the structural integration with outstanding electrical (3.07 × 105 S m-1) and thermal conductivity (745.65 W m-1 K-1) after removal of polymers. The thermoplastic strategy greatly extends the forming capability of GO materials and other layered materials and promises versatile structural designs for more broad applications.

Physiological and Proteomic Responses of Contrasting Alfalfa (Medicago sativa L.) Varieties to High Temperature Stress.

High temperature (HT) is an important factor for limiting global plant distribution and agricultural production. As the global temperature continues to rise, it is essential to clarify the physiological and molecular mechanisms of alfalfa responding the high temperature, which will contribute to the improvement of heat resistance in leguminous crops. In this study, the physiological and proteomic responses of two alfalfa (Medicago sativa L.) varieties contrasting in heat tolerance, MS30 (heat-tolerant) and MS37 (heat-sensitive), were comparatively analyzed under the treatments of continuously rising temperatures for 42 days. The results showed that under the HT stress, the chlorophyll content and the chlorophyll fluorescence parameter (Fv/Fm) of alfalfa were significant reduced and some key photosynthesis-related proteins showed a down-regulated trend. Moreover, the content of Malondialdehyde (MDA) and the electrolyte leakage (EL) of alfalfa showed an upward trend, which indicates both alfalfa varieties were damaged under HT stress. However, because the antioxidation-reduction and osmotic adjustment ability of MS30 were significantly stronger than MS37, the damage degree of the photosynthetic system and membrane system of MS30 is significantly lower than that of MS37. On this basis, the global proteomics analysis was undertaken by tandem mass tags (TMT) technique, a total of 6,704 proteins were identified and quantified. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that a series of key pathways including photosynthesis, metabolism, adjustment and repair were affected by HT stress. Through analyzing Venn diagrams of two alfalfa varieties, 160 and 213 differentially expressed proteins (DEPs) that had dynamic changes under HT stress were identified from MS30 and MS37, respectively. Among these DEPs, we screened out some key DEPs, such as ATP-dependent zinc metalloprotease FTSH protein, vitamin K epoxide reductase family protein, ClpB3, etc., which plays important functions in response to HT stress. In conclusion, the stronger heat-tolerance of MS30 was attributed to its higher adjustment and repair ability, which could cause the metabolic process of MS30 is more conducive to maintaining its survival and growth than MS37, especially at the later period of HT stress. This study provides a useful catalog of the Medicago sativa L. proteomes with the insight into its future genetic improvement of heat-resistance.

Protective effect of Dachengqi decoction on the pancreatic microcirculatory system in severe acute pancreatitis by down-regulating HMGB-TLR-4-IL-23-IL-17A mediated neutrophil activation by targeting SIRT1.

BACKGROUND: Dachengqi decoction (DCQD), one of classic prescription of Chinese herbal medicine has been widely used in clinic to treat severe acute pancreatitis (SAP). The damage of pancreatic microcirculation plays key pathogenesis of SAP. However, little is known about the molecular pharmacological activity of DCQD on pancreatic microcirculation in SAP. METHODS: Sodium taurodeoxycholate and cerulein were used to establish model of SAP in vitro and in vivo, respectively. The pancreatic pathological morphology, wet weight ratio, myeloperoxidase (MPO) activity, cell viability and microcirculatory function of the pancreas, as well as serum lipase and amylase expressions were evaluated. The expression levels of SIRT1, acety-HMGB1, TLR-4, HMGB1, IL-23, IL-17A, neutrophil chemokines (KC, LIX, and MIP-2), and inflammation-related factors (IL-6, IL-1ß, and TNF-α), the translocation of HMGB1 and the interaction of SIRT-HMGB1 in the pancreas and serum were determined by ELISA real-time PCR, western blotting and immunoprecipitation. RESULTS: In vivo studies showed that DCQD or neutralizing antibody (anti-23p19 or anti-IL-17A) could all significantly decrease lipase, amylase activity, down-regulate the expression of CD68, Myeloperoxidase (MPO), wet/weight, IL-1ß, IL-6, TNF-α, and neutrophil chemokines (KC, LIX, MIP-2), alleviate pathological injury and improve pancreatic microcirculatory function in rats with SAP. Furthermore, DCQD remarkably increased SIRT1 expression, promoted SIRT1 and HMGB1 combination, reduced HMGB1 translocation from nuclear to cytoplasm, and alleviated the expression of acetyl-HMGB1, HMGB1, IL-17A, TLR-4, and IL-23 in vitro and in vivo with SAP. However, the intervention with EX527 (SIRT1 inhibitor) or r-HMGB1 (recombinant HMGB1) obliviously reverses the above mentioned influence mentioned above of DCQD in SAP. In vitro, we confirmed that DCQD could decrease HMGB1 acetylation, migration, and release, and improve the decline of cell viability, SIRT1 expression and SIRI-HMGB1 combination induced by cerulean with promoting macrophage to release IL-23 by relying on the HMGB1/TLR-4 way. CONCLUSIONS: DCQD treatment improves SAP-induced pancreatic microcirculatory dysfunction by inhibiting neutrophil-mediated inflammation via inactivating HMGB1-TLR-4-IL-23-IL-17A signaling by targeting SIRT1.

Efficacy and safety of rituximab for childhood refractory nephrotic syndrome: A meta-analysis of randomized controlled trials / Eficacia y seguridad de rituximab para el síndrome nefrótico refractario infantil: un meta-análisis de ensayos controlados aleatorios

Background: Idiopathic nephrotic syndrome is the most common glomerular disease in children, but there are still some difficulties in treating childhood steroid-dependent or steroid-resistant nephrotic syndrome (SDNS/SRNS). Rituximab (RTX) might be an effective and safe choice.MethodsStudies were searched from PubMed, Web of Science, Cochrane library and some Chinese databases up to April 2020. Only randomized controlled trials (RCT) were included.ResultsOf 1383 screened articles, 6 RCTs with 334 participants were included. RTX was better than the control group at improving relapse-free rate in the short term [RR (risk ratio) (95% CI (confidence interval)), 1.84(1.41, 2.39)]. As for long-term, RTX did not show significant improvement [RR (95% CI), 4.43(.57, 34.67)]; but in subgroup analysis, RTX was still better than conventional drugs and tacrolimus [RR (95% CI), 9.91(1.95, 50.52) and 1.42(1.15, 1.75), respectively]. And there was a difference between the two groups of prednisolone dose after treatment [MD (mean difference) (95% CI), −.22(−.36, −.09) mg/kg/d)]. However, RTX did not significantly improve serum albumin and creatinine [MD (95% CI), 3.46(−1.40, 8.32)g/L and −3.66(−11.79, 4.48)μmol/L, respectively]. No significant differences between the RTX and the control group were found in total adverse events (AEs) or serious AEs.ConclusionChildhood SDNS/SRNS patients appear to benefit from RTX in relapse-free rate and dose of prednisolone use. Also, RTX did not significantly increase the incidence of AEs. But RTX did not show improvements in biological indicators, more studies are required to explain the effect of RTX. (AU)

Antecedentes: El síndrome nefrótico idiopático es la enfermedad glomerular más común en niños, pero aún existen algunas dificultades para tratar el síndrome nefrótico infantil dependiente de esteroides o resistente a esteroides. El rituximab (RTX) podría ser una opción efectiva y segura.MétodosSe realizaron búsquedas en los estudios de PubMed, Web of Science, Cochrane Library y algunas bases de datos chinas hasta abril de 2020. Sólo se incluyó ensayo controlado aleatorio (ECA).ResultadosDe 1.383 artículos seleccionados, se incluyeron 6 ECA con 334 participantes. RTX fue mejor que el grupo control para mejorar la tasa libre de recaídas a corto plazo [Relación de riesgo (IC95%), 1,84 (1,41, 2,39)]. En cuanto a largo plazo, RTX no mostró una mejora significativa [4,43 (0,57, 34,67)]; pero en el análisis de subgrupos, RTX fue aún mejor que los fármacos convencionales y el tacrolimus [9,91 (1,95, 50,52) y 1,42 (1,15, 1,75), respectivamente]. Se encontró una diferencia entre los dos grupos de dosis de prednisolona después del tratamiento [Diferencia media (IC95%), -0,22 (-0,36, -0,09) mg/kg/d)]. Sin embargo, RTX no mejoró significativamente la albúmina sérica y la creatinina [3,46 (-1,40, 8,32) g/L y -3,66 (-11,79, 4,48) μmol/L, respectivamente]. No se encontraron diferencias significativas entre RTX y el grupo de control en los eventos adversos totales (EA) o los EA graves.ConclusiónLos niños con síndrome nefrótico refractario parecen beneficiarse de RTX en la tasa libre de recaídas y la dosis de uso de prednisolona. Además, RTX no aumentó significativamente la incidencia de EA. Pero RTX no mostró mejoras en los indicadores biológicos, se requieren más estudios para explicar el efecto de RTX. (AU)

Predicting response to immunotherapy plus chemotherapy in patients with esophageal squamous cell carcinoma using non-invasive Radiomic biomarkers.

OBJECTIVES: To develop and validate a radiomics model for evaluating treatment response to immune-checkpoint inhibitor plus chemotherapy (ICI + CT) in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: A total of 64 patients with advance ESCC receiving first-line ICI + CT at two centers between January 2019 and June 2020 were enrolled in this study. Both 2D ROIs and 3D ROIs were segmented. ComBat correction was applied to minimize the potential bias on the results due to different scan protocols. A total of 788 features were extracted and radiomics models were built on corrected/uncorrected 2D and 3D features by using 5-fold cross-validation. The performance of the radiomics models was assessed by its discrimination, calibration and clinical usefulness with independent validation. RESULTS: Five features and support vector machine algorithm were selected to build the 2D uncorrected, 2D corrected, 3D uncorrected and 3D corrected radiomics models. The 2D radiomics models significantly outperformed the 3D radiomics models in both primary and validation cohorts. When ComBat correction was used, the performance of 2D models was better (p = 0.0059) in the training cohort, and significantly better (p < 0.0001) in the validation cohort. The 2D corrected radiomics model yielded the optimal performance and was used to build the nomogram. The calibration curve of the radiomics model demonstrated good agreement between prediction and observation and the decision curve analysis confirmed the clinical utility. CONCLUSIONS: The easy-to-use 2D corrected radiomics model could facilitate noninvasive preselection of ESCC patients who would benefit from ICI + CT.