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BackgroundPropranolol for infantile hemangiomas (IHs) is effective and relatively safe. However, propranolol has different formulations and there is no consensus on the optimal formulation for IHs. The propranolol oral solution was not used in China until 2022.ObjectiveTo evaluate the efficacy and safety of propranolol tablets and an oral solution in infants with high-risk IH.MethodsA retrospective cohort study was conducted involving 234 consecutive patients with a clinical diagnosis of high-risk IH who were treated with propranolol between August 2018 and February 2023 (propranolol tablets, 168 patients; propranolol oral solution, 66 patients). All patients were assessed in the hospital at the initiation of treatment and in the outpatient setting during treatment. The Hemangioma Activity and Severity Index was used to monitor the clinical activity of the hemangioma after propranolol treatment.ResultsBased on the Hemangioma Activity and Severity Index, 66.52% and 69.15% improvement occurred in the propranolol tablet and oral solution groups, respectively. 23.21% of patients in the propranolol tablet group and 42.42% in the oral solution group achieved >75% score improvement (X2 = 8.557; P = 0.003). Adverse reactions occurred in 34 (20.24%) and 11 patients (16.67%) in the propranolol tablet and oral solution groups, respectively. The most common adverse reaction in the propranolol tablet group was liver function abnormalities due to mild elevation of liver enzymes (X2 = 4.09; P = 0.045).ConclusionBoth propranolol tablets and oral solution had positive efficacy in patients with high-risk IHs, but more patients in the propranolol oral solution group achieve >75% score improvement compared to the propranolol tablet group. No life-threatening adverse reactions occurred in either group but liver function abnormalities were more likely to occur in patients treated with propranolol tablets.

The effects of rhizosphere microorganisms on plant growth and the associated mechanisms are a focus of current research, but the effects of exogenous combined inoculation with arbuscular mycorrhizal fungi (AMF) and plant growth-promoting rhizobacteria (PGPR) on seedling growth and the associated rhizosphere microecological mechanisms have been little reported. In this study, a greenhouse pot experiment was used to study the effects of single or double inoculation with AM fungi (Funneliformis mosseae) and two PGPR (Bacillus sp., Pseudomonas sp.) on the growth of tobacco seedlings, together with high-throughput sequencing technology to reveal associated rhizosphere microecological mechanisms. All inoculation treatments significantly increased the aboveground dry weight; root dry weight; seedling nitrogen, phosphorus, and potassium uptake; plant height; stem thickness; maximum leaf area; chlorophyll content; total root length, surface area, and volume; and average root diameter. The highest values for these indices were observed in the combined treatment of F. mosseae and Pseudomonas sp. SG29 (A_SG29). Furthermore, the A_SG29 treatment yielded the highest diversity indexes and largest percentages of significantly enriched bacterial taxa, and significantly promoted the colonization of AMF in tobacco roots and Pseudomonas in rhizosphere soil. Differential metabolic-pathway predictions using PICRUSt2 showed that the A_SG29 treatment significantly increased the metabolic pathway richness of tobacco rhizosphere microorganisms, and significantly up-regulated some metabolic pathways that may benefit plant growth. Co-inoculation with F. mosseae and Pseudomonas sp. SG29 promoted tobacco-seedling growth by significantly improving rhizosphere microbial communities' structure and function. In summary, the combined inoculation of AMF and SG29 promotes tobacco seedling growth, optimizes the rhizosphere microbial community's structure and function, and serves as a sustainable microbial co-cultivation method for tobacco seedling production.

ObjectivesTo investigate the safety and cost analysis of oral propranolol treatment for high-risk infantile hemangiomas starting from the outpatient setting.MethodsA total of 41 high-risk infantile hemangioma patients from outpatient settings and 43 from inpatient settings were selected for the study. After routine pre-treatment examinations, patients were administered propranolol in a stepwise incremental dosing regimen over three consecutive days in the outpatient clinic. Changes in heart rate, blood pressure and PR interval before and after medication were compared. On the 10th day post-medication, liver and kidney functions, fasting blood glucose, tumor ultrasonography, and electrocardiogram were re-evaluated. The costs of treatment starting from the outpatient clinic (including pre-treatment examinations and the first three days of treatment) were calculated and compared with those of similarly managed inpatient cases.ResultsThe majority of patients exhibited a reduction in heart rate and blood pressure, as well as an extended PR interval after treatment of medication (P < 0.05), which remained within normal limits without clinical symptoms. On the 10th day post-medication, statistical differences in blood biochemistry and electrocardiograms were observed when compared to pre-treatment values (P < 0.05), but all values remained within normal ranges. No severe adverse reactions such as hypoglycemia occurred. Additionally, the cost of treatment from the outpatient clinic was significantly lower than that of inpatient care.ConclusionOral propranolol treatment for high-risk infantile hemangiomas starting from the outpatient setting is associated with few adverse reactions and significantly reduced treatment costs. It is worthy of broader application in hospitals without dermatology wards.

Objective To investigate the clinical features of acrodermatitis enteropathica (AE). Methods A retrospective analysis was conducted on the clinical data of 20 children diagnosed with acrodermatitis enteropathica in the outpatient clinic at the dermatology department of our hospital. The serum levels of zinc and iron were compared between patients with acrodermatitis enteropathica and 20 health children. Results Among the 20 cases, the male-to-female ratio was 1∶1.22, with an average age of 10.12±7.05 months. The skin rashes commonly presented as erythemas, patches, scales, erosion and crusts, predominantly affecting the perioral, inguinal, perianal and extremity regions, and often accompanied by diarrhea and hair loss. The serum zinc levels in the patient group were lower than that in the controls [(7.39±3.51) μmol/L vs (12.40±2.57) μmol/L, t=-5.15, P

The high nutritional value of alfalfa hay makes it a widely utilized component in animal feed. However, the current prevalent drying methods for forage have a significantly detrimental impact on the quality of alfalfa during the drying process. This study investigates the effects of high-voltage corona discharge (HVCD) treatment on post-cut alfalfa. Gradient experiments are conducted by adjusting the air-gap spacing at a voltage of 25 kV. The results demonstrate that as the distance decreases, there is an observed increase in the drying rate, rehydration rate, and color intensity of the HVCD-treated material. HVCD treatment significantly enhances crude protein content, which increases with decreasing air-gap spacing. Meanwhile, it negatively affects lignin, neutral detergent fiber (NDF), and acid detergent fiber (ADF) levels. The relative forage quality (RFQ) of alfalfa reaches its peak at an air-gap spacing of 7 cm. The application of HVCD disrupts the fiber structure and induces significant electroporation effects in cells. Minimal changes in functional groups preserve nutrient integrity. Furthermore, HVCD exhibits lower energy consumption compared to hot air dryers. The HVCD treatment is a highly efficient and effective method, with a gradual improvement in alfalfa hay quality as the air-gap distance decreases.

Objective To analyze clinical manifestations and histopathological features of children patients with pigmento-genes pityriasis rosea. Methods Clinical manifestations, histopathological features and therapeutic responses were retrospectively analyzed for 5 patients, including 1 males and 4 females patients, with pigmento-genes pityriasis rosea. Results The age of onset was 5-16 years old, and the average age was 9.4 years old, the course of disease was from 1 month to 6 years. Long axes of lesions were oriented in planes of cleavage, running parallel to the dermatoglyph. Lesions were distributed over the trunk and proximal extremities. The increase of melanocyte and hyperkeratosis were the typical histopathological characteristics. Conclusions Pigmento-genes pityriasis rosea can be diagnosed according to clinical manifestations and histopathology. Vitamin c, vitamin E and antihistamine drugs are effective for children patient with pigmento-genes pityriasis rosea.

Myocardial fibrosis, a common pathophysiological consequence of various cardiovascular diseases, is characterized by fibroblast activation and excessive deposition of extracellular matrix (ECM) collagen. Accumulating evidence indicates that myocardial fibrosis contributes to ventricular stiffness, systolic and diastolic dysfunction, and ultimately leads to the development of heart failure (HF). Early detection and targeted treatment of myocardial fibrosis is critical to reverse ventricular remodeling and improve clinical outcomes in patients with cardiovascular diseases. However, despite considerable progresses made in understanding molecular mechanisms of myocardial fibrosis, non-invasive imaging to assess myocardial fibrosis and guide clinical treatment is still not widely available, limiting the development of innovative treatment strategies. This review summarizes recent progresses of imaging modalities for detecting myocardial fibrosis, with a focus on nuclear medicine, echocardiography and cardiac magnetic resonance (CMR).

Plastic packaging has shown its advantages over ceramic packaging and metal packaging in lightweight, thin, and high-density electronic devices. In this paper, the reliability and moisture diffusion of Sop-8 (Small Out-Line Package-8) plastic packaging devices are studied, and we put forward a set of complete optimization methods. Firstly, we propose to improve the reliability of plastic packaging devices by reducing the amount of cavitation and warpage deformation. Structural and process factors were investigated in the injection molding process. An orthogonal experiment design was used to create 25 groups of simulation experiments, and Moldflow software was used to simulate the flow mode analysis. Then, the simulation results are subjected to range analysis and comprehensive weighted score analysis. Finally, different optimization methods are proposed according to different production conditions, and each optimization method can reduce cavitation or warpage by more than 9%. The moisture diffusion of the Sop-8 plastic packing devices was also investigated at the same time. It was determined that the contact surface between the lead frame and the plastic packaging material was more likely to exhibit delamination under the condition of MSL2 moisture diffusion because the humidity gradient was easily produced at the crucial points of different materials. The diffusion of moisture is related to the type of plastic packaging material and the diffusion path.

Abstract Extracellular adenosine triphosphate (ATP) and its receptor, P2X7 receptor (P2X7R), are playing an important role in the pathological process of renal ischemia-reperfusion injury, but their underlying mechanism remains unclear. Also, the effects of tubular epithelium-expressed P2X7 receptor on ischemia acute kidney injury is still unknown. The aim of this study is to clarify if this mechanism involves the activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the renal tubular epithelial cells. In our research, we used male C57BL/6 wild type and P2X7R (−/−) mice, cultured human proximal tubular epithelial cells, and kidneys from acute kidney injury patients. Mice underwent for unilateral nephrectomy combined with the lateral renal pedicle clamping. Cultured cells were subjected to hypoxia/reoxygenation or ATP. Apyrase and A438079 were used to block the extracellular ATP/P2X7 receptor pathway. We also constructed radiation-induced bone marrow (BM) chimeras by using P2X7R (−/−) mice and P2X7R (+/+) wild-type mice. P2X7 receptor deficiency protected from renal ischemia-reperfusion injury and attenuated the formation of NLRP3 inflammasome. By using BM chimeras, we found a partial reduction of serum creatinine and less histological impairment in group wild-type BM to P2X7R (−/−) recipient, compared with group wild-type BM to wild-type recipient. In renal tubular epithelial cells, hypoxia/reoxygenation induced ATP release and extracellular ATP depletion reduced the expression of active IL-1β. ATP activated the NLRP3 inflammasome in renal tubular epithelial cells, which were blunted by transient silence of P2X7 receptor, as well as by P2X7 receptor blocking with A438079. In human samples, we found that patients with Stage 3 AKI had higher levels of P2X7 receptor expression than patients with Stage 1 or Stage 2. Extracellular ATP/P2X7 receptor axis blocking may protect renal tubular epithelial cells from ischemia-reperfusion injury through the regulation of NLRP3 inflammasome.

Abstract Background The prognostic value of elevated pretreatment platelet counts remains controversial in lung cancer patients. We performed the present meta-analysis to determine its precise role in these patients. Methods We employed a multiple search strategy in the PubMed, EMBASE and Cochrane Library databases to identify eligible studies. Disease-free survival (DFS)/progression-free survival (PFS)/time to progression (TTP) and overall survival (OS) were used as outcomes with hazard ratios (HRs) and 95% confidence intervals (CIs). Heterogeneity among the studies and publication bias were also evaluated. Results A total of 40 studies including 16,696 lung cancer patients were eligible for the analysis. Overall, the pooled analysis showed that compared with normal platelet counts, elevated pretreatment platelet counts were associated with poorer OS (HR = 1.54, 95% CI: 1.37–1.72, P

Over the past decades, because of large-scale bensulfuron-methyl (BSM) application, environmental residues of BSM have massively increased, causing severe toxicity in rotation-sensitive crops. The removal of BSM from the environment has become essential. In this study, the combined bioremediation of the arbuscular mycorrhizal fungi (AMF) Rhizophagus intraradices and BSM-degrading strain Hansschlegelia zhihuaiae S113 of BSM-polluted soil was investigated. BSM degradation by S113 in the maize rhizosphere could better promote AMF infection in the roots of maize, achieving an infection rate of 86.70% on the 36th day in the AMF + S113 + BSM group. Similarly, AMF enhanced the colonization and survival of S113 in maize rhizosphere, contributing 4.65 × 105 cells/g soil on the 15th day and 3.78 × 104 cells/g soil on the 20th day to a population of colonized-S113 (based possibly on the strong root system established by promoting plant-growth AMF). Both S113 and AMF coexisted in rhizosphere soil. The BSM-degrading strain S113 could completely remove BSM at 3 mg/kg from the maize rhizosphere soil within 12 days. AMF also promoted the growth of maize seedlings. When planted in BSM-contaminated soil, maize roots had a fresh weight of 2.59 ± 0.26 g in group S113 + AMF, 2.54 ± 0.20 g in group S113 + AMF + BSM, 2.02 ± 0.16 g in group S113 + BSM, and 2.61 ± 0.25 g in the AMF group, all of which exceeded weights of the control group on the 36th day except for the S113 + BSM group. Additionally, high-throughput sequencing results indicated that simultaneous inoculation with AMF and strain S113 of BSM-polluted maize root-soil almost left the indigenous bacterial community diversity and richness in maize rhizosphere soil unaltered. This represents a major advantage of bioremediation approaches resulting from the existing vital interactions among local microorganisms and plants in the soil. These findings may provide theoretical guidance for utilizing novel joint-bioremediation technologies, and constitute an important contribution to environmental pollution bioremediation while simultaneously ensuring crop safety and yield.

Abstract Background Current paradigms of detecting acute kidney injury (AKI) are insensitive and non-specific. Klotho is a pleiotropic protein that is predominantly expressed in renal tubules. In this study, we evaluated the diagnostic and prognostic roles of urine Klotho for AKI following cardiac surgery. Methods We conducted a prospective study involving 91 patients undergoing cardiac surgery. AKI was defined according to the AKIN definition. The renal outcomes within 7 days after operation were evaluated. Perioperative levels of urine Klotho and urine neutrophil gelatinase-associated lipocalin (NGAL) were measured by using ELISA. Results Of 91 participants, 33 patients (36.26%) developed AKI. Of these AKI patients, 21 (63.64%), 8 (24.24%), and 4 (12.12%) were staged 1, 2, and 3, respectively. Serum creatinine in AKI patients began to slightly increase at first postoperative time and reached the AKI diagnostic value 1 day after operation. Postoperative urine Klotho peaked at the first postoperative time (0 h after admission to the intensive care unit (ICU)) in patients with AKI, and was higher than that in non-AKI patients up to day 3. The AUC of detecting AKI for urine Klotho was higher than urine NGAL at the first postoperative time and 4 h after admission to the ICU. In a multivariate model, increased first postoperative urine Klotho may be an independent predictor for AKI occurrence following cardiac surgery. The concentrations of first postoperative urine Klotho were higher in AKI stage 2 and 3 than those in stage 1 (p

Background/Aims: LncRNA EGFR-AS1 is an antisense transcript of EGFR, which plays a key role in gastric cancer progression. This study was aimed to explore the effects of lncRNA EGFR-AS1 on GC and the underling mechanisms. Methods: The silencing of EGFR-AS1 expression was performed by using EGFR-AS1 shRNA lentivirus in MGC803 and SGC-7901 GC cell. The levels of lncRNA EGFR-AS1 and EGFR were detected by qPCR and western blot. Cell proliferation was assessed by CCK-8, EdU, and colony formation assays. The EGFR mRNA stability was explored by using RNA synthesis inhibitor α-amanitin. Results: In our study, EGFR-AS1 significantly up-regulated in GC tissues and correlated with tumor size. And the expression of EGFR-AS1 positively correlated with EGFR in tissues. Moreover, knock-down of EGFR-AS1 inhibited the proliferation of GC cells via suppressing EGFR-dependent PI3K/AKT pathway in vitro and in vivo. Mechanismly, depletion of EGFR-AS1 was found to decrease EGFR expression by reduction of EGFR mRNA stability. Conclusion: Our findings suggested that EGFR-AS1 might have an oncogenic effect on GC and serve as a potential target of GC.

Background/Aims: Klotho is a multifunctional protein expressed predominantly in kidney tubular epithelium. Here, we investigated the protective effects of Klotho on necroptosis in renal ischemic-reperfusion injury (IRI) and the role of oxidative stress in this process. Methods: Mice were subjected to bilateral renal pedicle clamping. Mouse renal tubular epithelial (TCMK-1) cells were exposed to hypoxia/reoxygenation (H/R) or H2O2. Kidney samples from acute kidney injury (AKI) patients and controls were examined by immunofluorescence. Klotho protein and N-acetyl-L-cysteine (NAC) were used to define their roles in mediating necroptosis. Necroptosis was assessed by TUNEL staining, immunoblotting, and real-time PCR. Oxidative stress was studied via ELISA, immunoblotting, colorimetric, and thiobarbituric acid reactive substances assays. Results: Renal IRI induced Klotho deficiency in the serum and kidney, but an increase in the urine. The levels of the necroptotic markers receptor-interacting protein kinase (RIP) 1, RIP3, IL-1β, and TUNEL-positive cells increased after IRI; all increases were ameliorated by Klotho. In TCMK-1 cells, Klotho and NAC attenuated the elevation in RIP1, RIP3, and LDH release induced by H/R or H2O2. Moreover, Klotho decreased the levels of oxidative stress biomarkers and elevated superoxide dismutase 2 expression in both in vivo and in vitro experiments. Studies in human samples further confirmed the Klotho deficiency and increased formation of RIP3 puncta in AKI kidneys. Conclusion: Klotho protects tubular epithelial cells from IRI and its anti-necroptotic role may be associated with oxidative stress inhibition.

After the publication of this work [1],

Purpose The Shanghai Preconception Cohort (SPCC) was initially established to investigate the associations of parental periconceptional nutritional factors with congenital heart disease (CHD) but has further analysed child growth and development and paediatric diseases.Participants Preparing-for-pregnancy couples who presented at Shanghai preconception examination clinics and early-pregnancy women before 14 gestational weeks were enrolled to comprise the periconceptional baseline study population. General characteristics, routine clinical data and consumption of diet supplements, such as folic acid and multivitamins, were collected. Blood samples were obtained at preconception and early, middle and late gestations using standard procedures. Multiple nutritional factors, including folate, homocysteine, vitamin A, vitamin D, vitamin E and metals, in the blood samples of participants selected using a case–control design were examined. Genomic DNA was extracted.Findings to date The baseline population included 8045 preconception couples, 3054 single women and 15 615 early-pregnancy women. Data from 12 402 births were collected, and follow-up of the cohort for other outcomes is ongoing. Currently, 151 cases of CHD were identified after birth. The pilot analysis in a small subgroup showed that approximately 20.0% of preconception women and 44.9% of early-pregnancy women had red blood cell (RBC) folate levels that met the international recommendation for preventing neural tube defects.Future plans Once a sufficient number of CHD cases are achieved, we will investigate the quantitative association of preconception RBC folate levels with CHD using a nested case–control design. The SPCC will be followed up for 18 years to investigate extensive outcomes of growth, development, obesity, and common and rare diseases during childhood and adolescence according to our plan. Blood nutritional factors will be examined in participants selected for specific aims. The SPCC will also allow for prospective cohort studies on extensive research questions.Trial registration number NCT 02737644

Background/Aims: Autophagy is a dynamic catabolic process that maintains cellular homeostasis. Whether it plays a role in promoting cell survival or cell death in the process of renal ischemia/reperfusion (I/R) remains controversial, partly because renal autophagy is usually examined at a certain time point. Therefore, monitoring of the whole time course of autophagy and apoptosis may help better understand the role of autophagy in renal I/R. Methods: Autophagy and apoptosis were detected after mice were subjected to bilateral renal ischemia followed by 0-h to 7-day reperfusion, exposure of TCMK-1 cells to 24-h hypoxia, and 2 to 24-h reoxygenation. The effect of autophagy on apoptosis was assessed in the presence of autophagy inhibitor 3-methyladenine (3-MA) and autophagy activator rapamycin. Results: Earlier than apoptosis, autophagy increased from 2-h reperfusion, reached the maximum at day 2, and then began declining from day 3 when renal damage had nearly recovered to normal. Exposure to 24-h hypoxia induced autophagy markedly, but it decreased drastically after 4 and 8-h reoxygenation, which was accompanied with increased cell apoptosis. Inhibition of autophagy with 3-MA increased the apoptosis of renal tubular cells during I/R in vivo and hypoxia/reoxygenation (H/R) in vitro. In contrast, activation of autophagy by rapamycin significantly alleviated renal tissue damage and tubular cell apoptosis in the two models. Conclusion: Autophagy was induced in a time-dependent manner and occurred earlier than the onset of cell apoptosis as an early response that played a renoprotective role during renal I/R and cell H/R. Up-regulation of autophagy may prove to be a potential strategy for the treatment of acute kidney injury.

Abstract Background Schistosomiasis is a chronic parasitic disease that affects approximately 200 million people. In Schistosomiasis japonica and mansoni, parasite eggs were trapped in host liver and stimulated the CD4+T cell responses to regulate the formation of the granulomas. Subsequently, excessive granulomatous response in some heavily, and/or repeatedly infected individuals could result in chronic liver fibrosis and circulatory impairment. Thus, elucidation of the mechanisms of these responses will not only provide more information to better understand the mechanisms of the immunoregulation in schistosomiasis, but also help to design new therapies to control granuloma-associated immunopathology. The role of aquaporin-4 (AQP4) in water transport has been extensively investigated in the central nervous system (CNS). Recently, studies have shown that AQP4 expresses in immune system and lack of AQP4 in mice results in significantly less CD4+CD25+ T regulatory cells (Treg cells) under physiological condition, one of the subpopulations of CD4+T cells which restrains immunopathology in hosts with schistosomiasis. However, little information exists regarding the contribution of AQP4 to the immune regulation in schistosome infection. Methods The liver granulomatous response in S. japonicum-infected AQP4 knockout (KO) mice and its wild-type (WT) littermates were detected by staining liver sections with hematoxylin and eosin. The generation of various CD4+ T subsets, including Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry. In addition, the levels of total IgG, IgG1, IgG2a in serum of infected mice were detected by ELISA assay. Results Our results showed an enhanced granulomatous response with increased accumulation of eosinophils and macrophages around eggs in the liver of AQP4 KO mice with Schistosomiasis japonica. In addition, our study demonstrated enhanced Th2 but reduced Th1 and Treg cells generation in AQP4 KO mice with Schistosomiasis japonica, which may, at least partly, account for the enhancement of the liver granuloma formation. Conclusion Our study for the first time provides evidences that AQP4 has an association with the immunoregulation of the liver granuloma formation, which may confer a new option for schistosomiasis treatment.

Root is important in acquiring nutrients from soils. Developing marker-assisted selection for wheat root traits can help wheat breeders to select roots desirable for efficient acquisition of nutrients. A recombinant inbred line (RIL) population derived from wheat varieties Xiaoyan 54 and Jing 411 was used to detect QTLs for maximum root length and root dry weight (RDW) under control, low nitrogen and low phosphorus conditions in hydrophobic culture (HC). We totally detected 17 QTLs for the investigated root traits located at 13 loci on 11 chromosomes. These loci differentially expressed under different nutrient supplying levels. The RILs simultaneously harboring positive alleles or negative alleles of the most significant three QTLs for RDW, qRDW.CK-2A, qRDW.CK-2D, and qRDW.CK-3B, were selected for soil column culture (SC) trial to verify the effects of these QTLs under soil conditions. The RILs pyramiding the positive alleles not only had significantly higher shoot dry weight, RDW, nitrogen and phosphorus uptake in all the three treatments of the HC trial, but also had significantly higher RDW distribution in both the top- and sub-soils in the SC trial than those pyramiding the negative alleles. These results suggested that QTL analysis based on hydroponic culture can provide useful information for molecular design of wheat with large and deep root system.

Resistance to TKI treatment is a major obstacle in effective treatment of NSCLC. Besides EGFR mutation status, the mechanisms involved are largely unknown. Some evidence supports a role for microRNA 21 in modulating drug sensitivity of chemotherapy but its role in NSCLC TKI resistance still remains unexplored. This study aimed to investigate whether NSCLC miR-21 mediated resistance to TKIs also results from Pten targeting. Here, we show miR-21 promotes cancer by negatively regulating Pten expression in human NSCLC tissues: high miR-21 expression levels were associated with shorter DFS in 47 NSCLC patients; high miR-21/low Pten expression levels indicated a poor TKI clinical response and shorter overall survival in another 46 NSCLC patients undergoing TKI treatment. In vitro assays showed that miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERK pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AKT and ERK pathways, in vivo and in vitro. We propose alteration of miR-21/Pten expression as a novel mechanism for TKI resistance in NSCLC cancer. Our findings provide a new basis for using miR 21/Pten-based therapeutic strategies to reverse gefitinib resistance in NSCLC.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), gefitinib and erlotinib have been tested as maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC). The studies are quite heterogenous regarding study size and populations, and a synopsis of these data could give some more insight in the role of maintenance therapy with TKI.In September 2012 we performed a search in the pubmed, EMBASE and Cochrane library databases for randomized phase III trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through a rigorous selection process with specific criteria, five trials (n = 2436 patients) were included for analysis. Standard statistical methods for meta-analysis were applied.TKIs (gefitinib and erlotinib) significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.76, I(2) = 78.1%] and overall survival (HR 0.84, 95% CI 0.76-0.93, I(2) = 0.0%) compared with placebo or observation. The PFS benefit was consistent in all subgroups including stage, sex, ethnicity, performance status, smoking status, histology, EGFR mutation status, and previous response to chemotherapy. Patients with clinical features such as female, never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced PFS benefit. Overall survival benefit was observed in patients with clinical features such as female, non-smoker, smoker, adenocarcinoma, and previous stable to induction chemotherapy. Severe adverse events were not frequent. Main limitations of this analysis are that it is not based on individual patient data, and not all studies provided detailed subgroups analysis.The results show that maintenance therapy with erlotinib or gefitinib produces a significant PFS and OS benefit for unselected patients with advanced NSCLC compared with placebo or observation. Given the less toxicity of TKIs than chemotherapy and simple oral administration, this treatment strategy seems to be of important clinical value.

BACKGROUND: Recent evidence indicates that microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. Our objective was to investigate the association of SNPs in deregulated miRNAs with clinical outcome in patients with non-small cell lung cancer (NSCLC) in a Chinese population. METHODS: Deregulated miRNAs in NSCLC and their SNPs were identified through public databases. A single SNP, rs895819 in pre-miR-27a, was found suitable for selection. TaqMan assays were performed for genotyping and to assess the effect on the overall survival (OS) and chemotherapy response in 576 NSCLC patients. RESULTS: Log-rank test and Cox regression analysis indicated that the G allele of rs895819 was associated with shorter survival and increased risk of death in NSCLC [dominant model: 22.0 vs. 46.0 months, P

Amphenicol antibiotics, such as chloramphenicol (CHL), thiamphenicol (TAP), and florfenicol (Ff), are high-risk emerging pollutants. Their extensive usage in aquaculture, livestock, and poultry farming has led to an increase in bacterial antibiotic resistance and facilitated the spread of resistance genes. Yet, limited research has been conducted on the co-resistance of CHL, TAP, and Ff. Herein, a novel amidase AphA was identified from a pure cultured strain that can concurrently mediate the hydrolytic inactivation of CHL, TAP, and Ff, yielding products p-nitrophenylserinol, thiamphenicol amine (TAP-amine), and florfenicol amine (Ff-amine), respectively. The antibacterial activity of these antibiotic hydrolysates exhibited a significant reduction or complete loss in comparison to the parent compounds. Notably, AphA shared less than 26% amino acid sequence identity with previously reported enzymes and exhibited high conservation within the sphingomonad species. Through enzymatic kinetic analysis, the AphA exhibited markedly superior affinity and catalytic activity toward Ff in comparison to CHL and TAP. Site-directed mutagenesis analysis revealed the indispensability of catalytic triad residues, particularly serine 153 and histidine 277, in forming crucial hydrogen bonds essential for AphA’s hydrolytic activity. Comparative genomic analysis showed that aphA genes in some species are closely adjacent to various transposable elements, indicating that there is a high potential risk of horizontal gene transfer (HGT). This study established a hydrolysis resistance mechanism of amphenicol antibiotics in sphingomonads, which offers theoretical guidance and a novel marker gene for assessing the prevalent risk of amphenicol antibiotics in the environment. IMPORTANCE Amphenicol antibiotics are pervasive emerging contaminants that present a substantial threat to ecological systems. Few studies have elucidated resistance genes or mechanisms that can act on CHL, TAP, and Ff simultaneously. The results of this study fill this knowledge gap and identify a novel amidase AphA from the bacterium Sphingobium yanoikuyae B1, which mediates three typical amphenicol antibiotic inactivation, and the molecular mechanism is elucidated. The diverse types of transposable elements were identified in the flanking regions of the aphA gene, indicating the risk of horizontal transfer of this antibiotic resistance genes (ARG). These findings offer new insights into the bacterial resistance to amphenicol antibiotics. The gene reported herein can be utilized as a novel genetic diagnostic marker for monitoring the environmental fate of amphenicol antibiotics, thereby enriching risk assessment efforts within the context of antibiotic resistance. [ABSTRACT FROM AUTHOR]