Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Crescent calculator: A webtool enabling objective decision-making for assessment of IgA nephropathy immune activity throughout the disease course.

IgA nephropathy (IgAN) is an immune-mediated glomerulonephritis, posing a challenge for the long-term management. It is crucial to monitor the disease's activity over the disease course. Crescent lesions have been known as an active lesion associated with immune activity. We aimed to develop the Crescent Calculator to aid clinicians in making timely and well-informed decisions throughout the long-term disease course, such as renal biopsies and immunosuppressive therapy. 1,761 patients with biopsy-proven IgAN were recruited from four medical centers in Zhejiang Province, China. 16.9% presented crescent lesions. UPCR, URBC, eGFR and C4 were independently associated with the crescent lesions. By incorporating these variables, the Crescent Calculator was constructed to estimate the likelihood of crescent lesions. The predictor achieved AUC values of over 0.82 in two independent testing datasets. In addition, to fulfill varied clinical needs, multiple classification modes were established. The Crescent Calculator was developed to estimate the risk of crescent lesions for patients with IgAN, assisting clinicians in making timely, objective, and well-informed decisions regarding the need for renal biopsies and more appropriate use of immunosuppressive therapy in patients with IgAN.

Staminal hairs increase pollinator attraction and pollination accuracy in Tradescantia fluminensis (Commelinaceae).

Staminal hairs are the particular appendages of stamens, which may affect pollinator foraging behaviour and pollen transfer. However, experimental evidence of the functions of staminal hairs in pollination remains scarce. Here, we conducted staminal hair manipulation experiments in Tradescantia fluminensis (Commelinaceae) to investigate their effects on visitation and pollen transfer by bees. Our observations revealed that both visitation rates and visit duration of honeybees (Apis cerana) to control flowers were significantly higher than that of hairless flowers. Moreover, removing the staminal hairs significantly decreased pollen deposition by honeybees (A. cerana), but did not affect pollen removal. The staminal hair was similar in length to the stamen and the pistil of T. fluminensis. The staminal hairs provide more footholds for honeybees, and they lay prone on the staminal hairs to collect pollen, which increased the accuracy of pollination through the consistent pollen placement and pick-up on the ventral surface of honeybees. These results showed that the staminal hairs in T. fluminensis may represent an adaptation to attract pollinators and enhance pollination accuracy.

Genomic insights into biased allele loss and increased gene numbers after genome duplication in autotetraploid Cyclocarya paliurus.

BACKGROUND: Autopolyploidy is a valuable model for studying whole-genome duplication (WGD) without hybridization, yet little is known about the genomic structural and functional changes that occur in autopolyploids after WGD. Cyclocarya paliurus (Juglandaceae) is a natural diploid-autotetraploid species. We generated an allele-aware autotetraploid genome, a chimeric chromosome-level diploid genome, and whole-genome resequencing data for 106 autotetraploid individuals at an average depth of 60 × per individual, along with 12 diploid individuals at an average depth of 90 × per individual. RESULTS: Autotetraploid C. paliurus had 64 chromosomes clustered into 16 homologous groups, and the majority of homologous chromosomes demonstrated similar chromosome length, gene numbers, and expression. The regions of synteny, structural variation and nonalignment to the diploid genome accounted for 81.3%, 8.8% and 9.9% of the autotetraploid genome, respectively. Our analyses identified 20,626 genes (69.18%) with four alleles and 9191 genes (30.82%) with one, two, or three alleles, suggesting post-polyploid allelic loss. Genes with allelic loss were found to occur more often in proximity to or within structural variations and exhibited a marked overlap with transposable elements. Additionally, such genes showed a reduced tendency to interact with other genes. We also found 102 genes with more than four copies in the autotetraploid genome, and their expression levels were significantly higher than their diploid counterparts. These genes were enriched in enzymes involved in stress response and plant defense, potentially contributing to the evolutionary success of autotetraploids. Our population genomic analyses suggested a single origin of autotetraploids and recent divergence (~ 0.57 Mya) from diploids, with minimal interploidy admixture. CONCLUSIONS: Our results indicate the potential for genomic and functional reorganization, which may contribute to evolutionary success in autotetraploid C. paliurus.

ADSC-Exos outperform BMSC-Exos in alleviating hydrostatic pressure-induced injury to retinal ganglion cells by upregulating nerve growth factors.

BACKGROUND: Mesenchymal stem cells (MSCs) have protective effects on the cornea, lacrimal gland, retina, and photoreceptor cell damage, which may be mediated by exosomes (exos) released by MSCs. AIM: To investigate the ameliorating effect of exos derived from different MSCs on retinal ganglion cell (RGC) injury induced by hydrostatic pressure. METHODS: The RGC injury model was constructed by RGC damage under different hydrostatic pressures (40, 80, 120 mmHg). Then RGCs were cultured with adipose-derived stem cell (ADSC)-Exos and bone marrow-derived stem cell (BMSC)-Exos. Cell Counting Kit-8, transmission electron microscopy, flow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction, and western blotting were performed to detect the ameliorating effect of exos on pressure-induced RGC injury. RESULTS: ADSC-Exos and BMSC-Exos were successfully isolated and obtained. The gibbosity of RGCs was lower, the cells were irregularly ellipsoidal under pressure, and the addition of ADSC-Exos and BMSC-Exos significantly restored RGC morphology. Furthermore, the proliferative activity of RGCs was increased and the apoptosis of RGCs was inhibited. Moreover, the levels of lactate dehydrogenase and apoptosis-related proteins were increased, and the concentrations of antiapoptotic proteins and neurotrophic factors were decreased in damaged RGCs. However, the above indicators were significantly improved after ADSC-Exos and BMSC-Exos treatment. CONCLUSION: These findings indicated that ADSC-Exos and BMSC-Exos could ameliorate RGC injury caused by hydrostatic pressure by inhibiting apoptosis and increasing the secretion of neurotrophic factors.

[Efficacy prediction of acupuncture in treatment of moderate-to-severe allergic rhinitis based on miRNA expression profile].

OBJECTIVE: To investigate the differential characteristics of plasma mircoRNA (miRNA) expression profile in the patients of moderate-to-severe allergic rhinitis treated with acupuncture so as to provide an index for screening the potential biomarkers of acupuncture efficacy. METHODS: Of 33 patients of moderate-to-severe allergic rhinitis underwent acupuncture, the superior efficacy patients (superior efficacy group, 3 cases) and the inferior efficacy patients (inferior efficacy group, 3 cases) were selected. Using human miRNA microarray technology, the differences in plasma miRNA expression before and after treatment were analyzed in the patients of two groups. Besides, 10 cases of superior efficacy and 10 cases of inferior one were selected respectively among the patients of moderate-to-severe allergic rhinitis treated with same acupuncture regimen; and the real-time PCR was used to validate miRNAs of differential expression determined by microarray technology. The bioinformatics analysis was performed for miRNAs of significant differences in expression so as to predict the potential functional target genes, and then, the predicted target genes were annotated in reference with the databases of gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG). RESULTS: Before treatment, there were 51 miRNAs of differential expression between two groups, of which, the expression levels of 26 miRNAs were up-regulated and those of 25 miRNAs were down-regulated. Compared with before treatment, 33 miRNAs presented differential expression in the superior efficacy group after treatment. The results of real-time PCR showed that the expression levels of hsa-miR-126-3p, hsa-miR-15a-5p, hsa-miR-494-3p and hsa-miR-574-5p were consistent with the results of microarray analysis in tendency. GO/KEGG analysis indicated that miRNAs with significant differences of expression between two groups were involved in regulating various biological processes, molecular functions and signaling pathways. CONCLUSION: Plasma miRNA-mediated biological processes may be associated with the efficacy response of acupuncture in treatment of moderate-to-severe allergic rhinitis. Plasma miRNAs of differential expression may be the potential non-invasive biomarkers to predict the effectiveness of acupuncture on moderate-to-severe allergic rhinitis.

Homochiral Chemistry Strategy To Trigger Dielectric Switching and Second-Harmonic Generation Response on Spirocyclic Derivatives.

Organic-inorganic hybrid materials with switchable properties have significant potential applications in intelligent devices. There are some conventional ways to obtain optical and/or electric multiple responses, such as asymmetric design, chirality, doping, and structural dimension in hybrid materials. Among them, the homochirality strategy is one of the best ways to regulate the molecular structure and symmetry, thereby ensuring second-harmonic generation (SHG) and dielectric dual response characteristics. Here, we report a homochiral design strategy to obtain noncentrosymmetric [R-(HASD)][Cd(SCN)3] (HASD = 7-hydroxy-5-azaspiro[4.5]decan) and [S-(HASD)][Cd(SCN)3]; [Rac-(HASD)][Cd(SCN)3] was also synthesized as a comparative experiment to illustrate the relationship between structural chirality and physical properties. With the help of homochiral regulation, the SHG response is excited and dielectric phase transition temperature (Tc) is also highly improved. In addition, both the optical SHG and dielectric phase change show an optical/electric switchable response. This work is of great significance for the further exploration of multifunctional molecular switching materials through homochiral chemistry.

Clinicopathologic features of Good's syndrome: Two cases and literature review.

BACKGROUND: Good's syndrome (GS) is an immunodeficiency disease, causing thymoma, low or absent B-cells, hypogammaglobulinemia, and defects in cell-mediated immunity. The most common clinical presentation is recurrent infection, followed by refractory diarrhea, due to the immunodeficiency. However, there are only few reports on intestinal endoscopy and pathology. CASE SUMMARY: We report here two typical GS cases with diarrhea as the prominent manifestation. Both cases presented with thymoma combined with immunodeficiency, characterized by hypogammaglobulinemia, low or absent B lymphocytes, and decreased T-cells with inverted CD4+/CD8+ T-cell ratio, while two GS patients were evaluated by endoscopy revealed mucosal edema and fine-granular or nodular appearance changes in the small intestine. Histological examination showed chronic inflammation and villous atrophy. A very interesting finding is that the inflammatory cell infiltration in the two GS cases was different. In one case, predominantly CD138+ plasma cells with only scattered CD3+ T-cells infiltration were revealed, while in another, it showed predominantly T-cells infiltration without plasma cells in the lamina propria. Although GS cases shared various clinical characteristics with common variable immunodeficiency (CVID) cases, they still differed from CVID cases in terms of its late onset, lack of familial clusters, low or absent peripheral blood B lymphocytes, absence of lymphoid hyperplasia, and plasma cells infiltration in the lamina propria in some patients. Although both patients had been diagnosed previously with recurrent diarrhea, respiratory infection, and thymoma, the association between these conditions and the possibility of GS was not recognized. The patients had remained misdiagnosed for 2 and 4 years, respectively, even after receiving the diagnosis of thymoma. The rarity of GS was likely the primary cause for the lack of disease recognition. Reporting of these cases will help to alert clinicians and raise awareness of this disease. CONCLUSION: GS should be considered among the differential diagnoses for patients with unexplained recurrent diarrhea and opportunistic infection. Although it was regarded as a subset of CVID with thymoma, GS had a different clinical-pathological feature from CVID.

[Ginger-separated moxibustion for chronic fatigue syndrome and its effect on intestinal flora].

OBJECTIVE: To observe the effect of ginger-separated moxibustion on fatigue state and intestinal flora in patients with chronic fatigue syndrome (CFS). METHODS: A total of 62 patients with CFS were randomly divided into an observation group (31 cases, 3 cases dropped off) and a control group (31 cases, 2 cases dropped off). The patients in the control group were treated with normal diet and moderate exercise; on the basis of the control group, the patients in the observation group were treated with ginger-separated moxibustion at Zhongwan (CV 12), Shenque (CV 8) and Guanyuan (CV 4), 30 min each time, once every other day, three times a week. Both groups were intervened for 4 weeks. Before and after treatment, the fatigue scale-14 (FS-14) was used to observe the improvement of fatigue state, and 16S rRNA detection technology was used to detect the distribution of intestinal flora. RESULTS: Compared before treatment, the FS-14 score was reduced after treatment in the observation group (P<0.01), and the reduction in the observation group was larger than that in the control group (P<0.01). The relative abundance of intestinal flora was similar between the observation group and control group at the phylum and genus level before treatment. After treatment, there was no significant change of intestinal flora in the control group. However, the enterobacteriaceae, corynebacterium, erysipelothrix, actinomycetes were increased in the observation group (P<0.05), and actinomycetes, ruminococcus, lactarius had obvious flora advantages compared with the control group (P<0.05). CONCLUSION: The ginger-separated moxibustion could significantly improve the fatigue state in CFS patients, which may be related to the regulation of intestinal flora structure and the repair of intestinal barrier.

[Effect of ginger-separated moxibustion on fatigue, sleep quality and depression in patients with chronic fatigue syndrome: a randomized controlled trial].

OBJECTIVE: To observe the effect of ginger-separated moxibustion on fatigue, sleep quality and depression in the patients with chronic fatigue syndrome. METHODS: A total of 62 patients with chronic fatigue syndrome were randomized into an observation group (31 cases, 3 cases dropped off) and a control group (31 cases, 2 cases dropped off). In the control group, the patients had normal diet and proper physical exercise. In the observation group, on the basis of the control group, the ginger-separated moxibustion was added at Zhongwan (CV 12), Shenque (CV 8) and Guanyuan (CV 4), 30 min each time, once every two days, 3 times weekly. Separately, before treatment and after 4 weeks of treatment, the MOS item short form health survey (SF-36), the Pittsburgh sleep quality index (PSQI) scale and the self-rating depression scale (SDS) were adopted to evaluate the degrees of fatigue, sleep quality and depression in the patients of the two groups. RESULTS: In the observation group, the score of each item of SF-36, the score of each item of PSQI and SDS score after treatment were all improved significantly as compared with those before treatment respectively (P<0.05, P<0.01). In the control group, the scores of overall health, vitality and mental health in SF-36 and the score of sleep time of PSQI after treatment were improved as compared with those before treatment respectively (P<0.05). After treatment, the score of each item of SF-36, the scores of sleep quality, sleep time, sleep efficiency and sleep disorders of PSQI, as well as SDS score in the observation group were all better than those in the control group respectively (P<0.01, P<0.05). The score of SF-36 was relevant to the scores of PSQI and SDS in the patients of chronic fatigue syndrome (r =0.331, P<0.05; r =-0.706, P<0.01). The improvement value of SF-36 score was closely related to the improvement value of SDS score in the observation group (r =-0.657, P<0.01). CONCLUSION: The ginger-separated moxibustion effectively relieves fatigue and depression condition and improves sleep quality in the patients with chronic fatigue syndrome. The fatigue condition is relevant with sleep quality and depression condition to a certain extent in the patients.

[A Retrospective Analysis of Clinical Features of Interstitial Pneumonia with Autoimmune Features].

OBJECTIVE: To analyze the clinical features of interstitial pneumonia with autoimmune features (IPAF) and the correlation between them. METHODS: We respectively analyzed the patients with interstitial lung disease (ILD) admitted in our hospital from January 2014 to January 2017. The patients who met all priori requirements and at least one feature of one domain were recuited, and the clinical features and autoimmune diseases related prognosis were analyzed. RESULTS: There were 90 patients recruited,including 38 patients completely met IPAF classification criteria and 52 patients who incompletely met. The average age was (62.34±14.98) yr.. The pneumonia pattern of complete IPAF patients was non-specific interstitial pneumonia (NSIP), while it was usually interstitial pneumonia (UIP) in the incomplete IPAF patients. During follow-up,11 patients were diagnosed with autoimmune diseases (4 with complete IPAF,and 7 with incomplete IPAF) . According to Cox regression analysis,completely meet the criteria of IPAF was related to the relapse of disease. CONCLUSION: There exist relation between IPAF and autoimmune diseases. The patients with IPAFmay finally develop into autoimmune diseases. The IPAF classification criteria provide basic structure for this disease,but the limitation of the criteria call for revising by more clinical trials.

Characterization of transcriptional modules related to fibrosing-NAFLD progression.

Based on the severity of liver fibrosis, low or high-risk profile of developing end-stage liver disease was present in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms inducing transition from mild to advanced NAFLD are still elusive. We performed a system-level study on fibrosing-NAFLD by weighted gene co-expression network analysis (WGCNA) to identify significant modules in the network, and followed by functional and pathway enrichment analyses. Moreover, hub genes in the module were analyzed by network feature selection. As a result, fourteen distinct gene modules were identified, and seven modules showed significant associations with the status of NAFLD. Module preservation analysis confirmed that these modules can also be found in diverse independent datasets. After network feature analysis, the magenta module demonstrated a remarkably correlation with NAFLD fibrosis. The top hub genes with high connectivity or gene significance in the module were ultimately determined, including LUM, THBS2, FBN1 and EFEMP1. These genes were further verified in clinical samples. Finally, the potential regulators of magenta module were characterized. These findings highlighted a module and affiliated genes as playing important roles in the regulation of fibrosis in NAFLD, which may point to potential targets for therapeutic interventions.

Potential Regulators Driving the Transition in Nonalcoholic Fatty Liver Disease: a Stage-Based View.

BACKGROUND AND AIM: The incidence of nonalcoholic fatty liver disease (NAFLD), ranging from mild steatosis to hepatocellular injury and inflammation, increases with the rise of obesity. However, the implications of transcription factors network in progressive NAFLD remain to be determined. METHODS: A co-regulatory network approach by combining gene expression and transcription influence was utilized to dissect transcriptional regulators in different NAFLD stages. In vivo, mice models of NAFLD were used to investigate whether dysregulated expression be undertaken by transcriptional regulators. RESULTS: Through constructing a large-scale co-regulatory network, sample-specific regulator activity was estimated. The combinations of active regulators that drive the progression of NAFLD were identified. Next, top regulators in each stage of NAFLD were determined, and the results were validated using the different experiments and bariatric surgical samples. In particular, Adipocyte enhancer-binding protein 1 (AEBP1) showed increased transcription activity in nonalcoholic steatohepatitis (NASH). Further characterization of the AEBP1 related transcription program defined its co-regulators, targeted genes, and functional organization. The dynamics of AEBP1 and its potential targets were verified in an animal model of NAFLD. CONCLUSIONS: This study identifies putative functions for several transcription factors in the pathogenesis of NAFLD and may thus point to potential targets for therapeutic interventions.

Acupuncture for moderate to severe allergic rhinitis: A non-randomized controlled trial.

OBJECTIVE: To evaluate the effect and safety of acupuncture therapy on patients with moderate to severe allergic rhinitis. METHODS: A non-randomized controlled design was used to compare between the acupuncture group and the medication group. The acupuncture group received 8-week acupuncture therapy, and the medication group received budesonide nasal spray with cetirizine tablets for 8 weeks. The clinical symptoms and signs were analyzed before treatment, at 4 and 8 weeks after the start of treatment, and at 12 weeks after the end of treatment. Furthermore, the clinical efficacy and safety indicators were compared between the two groups. RESULTS: A total of 76 participants consisting of 38 in each of the two groups were enrolled. The scores of each clinical symptom and sign, including sneezing, runny nose, stuffy nose, nasal itching, and turbinate edema, and the total scores decreased over time in both groups (all P<0.05); and no difference was found in the scores between the two groups (P>0.05). There was no statistically significant difference in the effective rates of the acupuncture group at 4 and 8 weeks after the start of treatment as well as at 12-week follow-up compared with those of the medication group (83.3% vs. 91.2%, and 94.4 % vs. 85.3%; and 80.6 % vs. 82.4%, all P>0.05). Experimental items including blood routine, urine routine, aspartate transaminase, alanine aminotransferase, urea nitrogen and creatinine were all in the normal reference ranges during the treatment in the acupuncture group. CONCLUSIONS: Acupuncture therapy has a comparable effect to the medication treatment on patients with moderate to severe allergic rhinitis, and it is safe with no severe adverse effects.

[Anaerobic Biodegradability of Perfluorooctanoic Acid (PFOA)].

Perfluorooctanoic acid (PFOA), one of the most typical representatives of perfluoroalkyl surfactants (PASs), has relatively high detection rate and level of pollution, and the accumulation of PFOA in the environment has been a serious threat to human health and security of the whole ecological environment. Therefore, studies on anaerobic biodegradability of PFOA are very important for elucidation of its environmental fate. This study used anaerobic sludge from municipal sewage treatment plant (WWTP) and 5.0 mg·L-1 vitamin B12 (VB12) as catalysts for the degradation of PFOA in the anaerobic environment. The anaerobic biodegradability of PFOA was examined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and ion chromatography while some indictors, such as molar recoveries of PFOA as well as concentrations of fluoride, acetate, 2H-PFOA (F(CF2)6CHFCOOH), and shorter chain (

Development of oral dispersible tablets containing prednisolone nanoparticles for the management of pediatric asthma.

The purpose of the present study was to develop oral dispersible tablets containing prednisolone (PDS)-loaded chitosan nanoparticles using microcrystalline cellulose (MCC 101), lactose, and croscarmellose sodium (CCS). The PDS-loaded chitosan nanoparticles were formulated by ionotropic external gelation technique in order to enhance the solubility of PDS in salivary pH. Prepared nanoparticles were used for the development of oral fast disintegrating tablets by direct compression method. The prepared tablets were evaluated for disintegration time (DT), in vitro drug release (DR), thickness, weight variation, drug content uniformity, friability, and hardness. The effect of concentrations of the dependent variables (MCC, lactose, CCS) on DT and in vitro DR was studied. Fast disintegrating tablets of PDS can be prepared by using MCC, CCS, and lactose with enhanced solubility of PDS. The minimum DT was found to be 15 seconds, and the maximum DR within 30 minutes was 98.50%. All independent variables selected for the study were statistically significant. Oral fast disintegrating tablets containing PDS nanoparticles could be the better choice for the pediatric patients that would result in better patient compliance. From this study, it can be concluded that fast disintegrating tablets could be a potential drug delivery technology for the management of asthma in pediatrics.