Blocking of amino acid transporter OsAAP7 promoted tillering and yield by determining basic and neutral amino acids accumulation in rice.

BACKGROUND: Amino acids are not only the main form of N in rice, but also are vital for its growth and development. These processes are facilitated by amino acid transporters within the plant. Despite their significance, only a few AAP amino acid transporters have been reported. RESULTS: In this study, we observed that there were differences in the expression of amino acid transporter OsAAP7 among 521 wild cultivated rice varieties, and it directly negatively correlated with tillering and grain yield per plant. We revealed that OsAAP7 protein was localized to the endoplasmic reticulum and had absorption and transport affinity for amino acids such as phenylalanine (Phe), lysine (Lys), leucine (Leu), and arginine (Arg) using subcellular localization, yeast substrate testing, fluorescent amino acid uptake, and amino acid content determination. Further hydroponic studies showed that exogenous application of amino acids Phe, Lys and Arg inhibited the growth of axillary buds in the overexpression lines, and promoted the elongation of axillary buds in the mutant lines. Finally, RNA-seq analysis showed that the expression patterns of genes related to nitrogen, auxin and cytokinin pathways were changed in axillary buds of OsAAP7 transgenic plants. CONCLUSIONS: This study revealed the gene function of OsAAP7, and found that blocking of amino acid transporter OsAAP7 with CRISPR/Cas9 technology promoted tillering and yield by determining basic and neutral amino acids accumulation in rice.

Blocking of awn development-related gene OsGAD1 coordinately boosts yield and quality of Kam Sweet Rice.

Kam Sweet Rice is a high-quality local variety of Guizhou province in China, but most varieties have awns on lemma. In this study, we aimed to obtain awnless varieties of Kam Sweet Rice by blocking the awn development-related gene OsGAD1 using CRISPR/Cas9 technology. We determined that natural variations of the OsGAD1 triggered different lengths of awns of Kam Sweet Rice. We found that the awning rate of the CRISPR lines of OsGAD1 in Guxiangnuo, Goujingao and Gouhuanggang decreased by over 65%, and the number of grains per panicle and yield per plant increased by more than 17% and 20% compared to the wild-types. Furthermore, we indicated that blocking OsGAD1 resulted in an increase of over 2% in the brown rice rate and milled rice rate in these varieties. In addition, the analysis of the transcriptome revealed that the regulation of awn development and yield formation in CRISPR lines of OsGAD1 may involve genes associated with phytohormone and nitrogen pathways. These results suggest that blocking OsGAD1 in Kam Sweet Rice using CRISPR/Cas9 technology can be used for breeding programs seeking high yield and grain quality of Kam Sweet Rice.

Astrocyte-associated fibronectin promotes the proinflammatory phenotype of astrocytes through ß1 integrin activation.

Astrocytes are key players in neuroinflammation. In response to central nervous system (CNS) injury or disease, astrocytes undergo reactive astrogliosis, which is characterized by increased proliferation, migration, and glial fibrillary acidic protein (GFAP) expression. Activation of the transcription factor nuclear factor-κB (NF-κB) and upregulation of downstream proinflammatory mediators in reactive astrocytes induce a proinflammatory phenotype in astrocytes, thereby exacerbating neuroinflammation by establishing an inflammatory loop. In this study, we hypothesized that excessive fibronectin (FN) derived from reactive astrocytes would induce this proinflammatory phenotype in astrocytes in an autocrine manner. We exogenously treated astrocytes with monomer FN, which can be incorporated into the extracellular matrix (ECM), to mimic plasma FN extravasated through a compromised blood-brain barrier in neuroinflammation. We also induced de novo synthesis and accumulation of astrocyte-derived FN through tumor necrosis factor-α (TNF-α) stimulation. The excessive FN deposition resulting from both treatments initiated reactive astrogliosis and triggered NF-κB signaling in the cultured astrocytes. In addition, inhibition of FN accumulation in the ECM by the FN inhibitor pUR4 strongly attenuated the FN- and TNF-α-induced GFAP expression, NF-κB activation, and proinflammatory mediator production of astrocytes by interrupting FN-ß1 integrin coupling and thus the inflammatory loop. In an in vivo experiment, intrathecal injection of pUR4 considerably ameliorated FN deposition, GFAP expression, and NF-κB activation in inflamed spinal cord, suggesting the therapeutic potential of pUR4 for attenuating neuroinflammation and promoting neuronal function restoration.

Applying the UTAUT2 framework to patients' attitudes toward healthcare task shifting with artificial intelligence.

BACKGROUND: Increasing patient loads, healthcare inflation and ageing population have put pressure on the healthcare system. Artificial intelligence and machine learning innovations can aid in task shifting to help healthcare systems remain efficient and cost effective. To gain an understanding of patients' acceptance toward such task shifting with the aid of AI, this study adapted the Unified Theory of Acceptance and Use of Technology 2 (UTAUT2), looking at performance and effort expectancy, facilitating conditions, social influence, hedonic motivation and behavioural intention. METHODS: This was a cross-sectional study which took place between September 2021 to June 2022 at the National Heart Centre, Singapore. One hundred patients, aged ≥ 21 years with at least one heart failure symptom (pedal oedema, New York Heart Association II-III effort limitation, orthopnoea, breathlessness), who presented to the cardiac imaging laboratory for physician-ordered clinical echocardiogram, underwent both echocardiogram by skilled sonographers and the experience of echocardiogram by a novice guided by AI technologies. They were then given a survey which looked at the above-mentioned constructs using the UTAUT2 framework. RESULTS: Significant, direct, and positive effects of all constructs on the behavioral intention of accepting the AI-novice combination were found. Facilitating conditions, hedonic motivation and performance expectancy were the top 3 constructs. The analysis of the moderating variables, age, gender and education levels, found no impact on behavioral intention. CONCLUSIONS: These results are important for stakeholders and changemakers such as policymakers, governments, physicians, and insurance companies, as they design adoption strategies to ensure successful patient engagement by focusing on factors affecting the facilitating conditions, hedonic motivation and performance expectancy for AI technologies used in healthcare task shifting.

A critical review of enzymes immobilized on chitosan composites: characterization and applications.

Enzymes with industrial significance are typically used in biological processes. However, instability, high sensitivity, and impractical recovery are the major drawbacks of enzymes in practical applications. In recent years, the immobilization technology has attracted wide attention to overcoming these restrictions and improving the efficiency of enzyme applications. Chitosan (CS) is a unique functional substance with biocompatibility, biodegradability, non-toxicity, and antibacterial properties. Chitosan composites are anticipated to be widely used in the near future for a variety of purposes, including as supports for enzyme immobilization, because of their advantages. Therefor this review explores the effects of the chitosan's structure, molecular weight, degree of deacetylation on the enzyme immobilized, effect of key factors, and the enzymes immobilized on chitosan based composites for numerous applications, including the fields of biosensor, biomedical science, food industry, environmental protection, and industrial production. Moreover, this study carefully investigates the advantages and disadvantages of using these composites as well as their potential in the future.

A Higher Estimated Glomerular Filtration Rate Is Associated with Better Survival in Subjects with Coronary Artery Disease and Heart Failure with a Mildly Reduced Ejection Fraction.

Subjects with coronary artery disease (CAD) have myocardial ischemia and associated abnormal left ventricular ejection fraction (EF). Heart failure with mildly reduced EF (41-49%) (HFmrEF) is a new subgroup of EF for heart failure. Although prognostic factors for CAD and HF with reduced EF are well known, fewer studies have been conducted on factors related to the survival of CAD and HFmrEF. We recruited study subjects with significant CAD and HFmrEF from our cardiac catheterization data bank. Data were recorded from traceable chart records from our hospital. All-cause and cardiovascular mortality were recorded until December 2019 and served as a follow-up outcome. A total of 348 subjects with CAD and HFmrEF were analyzed. The median duration of follow-up was 37 months. Seventy-eight subjects died during the follow-up period and 30 of them were due to cardiovascular causes. In univariate analyses, those who died were of older ages, and with a lower estimated glomerular filtration rate (eGFR) (47 ± 30 versus 71 ± 30 mL/minute/1.73 m2, P < 0.001), and lower usage of percutaneous coronary intervention (PCI) and beta blockers. In the Cox survival regression analysis, a higher eGFR (hazard ratio 0.980, P < 0.001) was protective, while older age and a higher serum total cholesterol (hazard ratio 1.006, P = 0.048) were related to all-cause mortality for CAD with HFmrEF. Furthermore, a higher eGFR was also associated with less cardiovascular mortality. In conclusion, for subjects with CAD and HFmrEF, a higher eGFR was protective and associated with a lower all-cause and cardiovascular mortality.

High-Resolution Digital Phenotypes From Consumer Wearables and Their Applications in Machine Learning of Cardiometabolic Risk Markers: Cohort Study.

BACKGROUND: Consumer-grade wearable devices enable detailed recordings of heart rate and step counts in free-living conditions. Recent studies have shown that summary statistics from these wearable recordings have potential uses for longitudinal monitoring of health and disease states. However, the relationship between higher resolution physiological dynamics from wearables and known markers of health and disease remains largely uncharacterized. OBJECTIVE: We aimed to derive high-resolution digital phenotypes from observational wearable recordings and to examine their associations with modifiable and inherent markers of cardiometabolic disease risk. METHODS: We introduced a principled framework to extract interpretable high-resolution phenotypes from wearable data recorded in free-living conditions. The proposed framework standardizes the handling of data irregularities; encodes contextual information regarding the underlying physiological state at any given time; and generates a set of 66 minimally redundant features across active, sedentary, and sleep states. We applied our approach to a multimodal data set, from the SingHEART study (NCT02791152), which comprises heart rate and step count time series from wearables, clinical screening profiles, and whole genome sequences from 692 healthy volunteers. We used machine learning to model nonlinear relationships between the high-resolution phenotypes on the one hand and clinical or genomic risk markers for blood pressure, lipid, weight and sugar abnormalities on the other. For each risk type, we performed model comparisons based on Brier scores to assess the predictive value of high-resolution features over and beyond typical baselines. We also qualitatively characterized the wearable phenotypes for participants who had actualized clinical events. RESULTS: We found that the high-resolution features have higher predictive value than typical baselines for clinical markers of cardiometabolic disease risk: the best models based on high-resolution features had 17.9% and 7.36% improvement in Brier score over baselines based on age and gender and resting heart rate, respectively (P<.001 in each case). Furthermore, heart rate dynamics from different activity states contain distinct information (maximum absolute correlation coefficient of 0.15). Heart rate dynamics in sedentary states are most predictive of lipid abnormalities and obesity, whereas patterns in active states are most predictive of blood pressure abnormalities (P<.001). Moreover, in comparison with standard measures, higher resolution patterns in wearable heart rate recordings are better able to represent subtle physiological dynamics related to genomic risk for cardiometabolic disease (improvement of 11.9%-22.0% in Brier scores; P<.001). Finally, illustrative case studies reveal connections between these high-resolution phenotypes and actualized clinical events, even for borderline profiles lacking apparent cardiometabolic risk markers. CONCLUSIONS: High-resolution digital phenotypes recorded by consumer wearables in free-living states have the potential to enhance the prediction of cardiometabolic disease risk and could enable more proactive and personalized health management.

The amino acid transporter AAP1 mediates growth and grain yield by regulating neutral amino acid uptake and reallocation in Oryza sativa.

Nitrogen (N) is a major element necessary for crop yield. In most plants, organic N is primarily transported in the form of amino acids. Here, we show that amino acid permease 1 (AAP1) functions as a positive regulator of growth and grain yield in rice. We found that the OsAAP1 gene is highly expressed in rice axillary buds, leaves, and young panicles, and that the OsAAP1 protein is localized to both the plasma membrane and the nuclear membrane. Compared with the wild-type ZH11, OsAAP1 overexpression (OE) lines exhibited increased filled grain numbers as a result of enhanced tillering, while RNAi and CRISPR (clustered regularly interspaced short palindromic repeat; Osaap1) knockout lines showed the opposite phenotype. In addition, OsAAP1-OE lines had higher concentrations of neutral and acidic amino acids, but lower concentrations of basic amino acids in the straw. An exogenous treatment with neutral amino acids promoted axillary bud outgrowth more strongly in the OE lines than in the WT, RNAi, or Osaap1 lines. Transcriptome analysis of Osaap1 further demonstrated that OsAAP1 may affect N transport and metabolism, and auxin, cytokinin, and strigolactone signaling in regulating rice tillering. Taken together, these results support that increasing neutral amino acid uptake and reallocation via OsAAP1 could improve growth and grain yield in rice.

The application of exercise stress cardiovascular magnetic resonance in patients with suspected dilated cardiomyopathy.

OBJECTIVES: The imaging features of dilated cardiomyopathy (DCM) overlap with physiological exercise-induced cardiac remodeling in active and otherwise healthy individuals. Distinguishing the two conditions is challenging. This study examined the diagnostic and prognostic roles of exercise stress imaging in asymptomatic patients with suspected DCM. METHODS: Exercise stress cardiovascular magnetic resonance (CMR) was performed in 60 asymptomatic patients with suspected DCM (dilated left ventricle and/or impaired systolic function on CMR), who also underwent DNA sequencing for DCM-causing genetic variants. Confirmed DCM was defined as genotype- and phenotype-positive (G+P+). Another 100 healthy subjects were recruited to establish normal exercise capacities (peak exercise cardiac index; PeakCI). The primary outcome was a composite of all-cause mortality, cardiac decompensation and ventricular arrhythmic events. RESULTS: No patients with confirmed G+P+ DCM had PeakCI exceeding the 35th percentile specific for age and sex. Applying this threshold in G-P+ patients, those with PeakCI below 35th percentile had characteristics similar to confirmed DCM while patients with higher PeakCI were younger, more active and higher longitudinal strain. Adverse cardiovascular events occurred only in patients with low exercise capacity (P = 0.004). CONCLUSIONS: In individuals with suspected DCM, exercise stress CMR demonstrates diagnostic and prognostic potential in distinguishing between pathological DCM and physiological exercise-induced cardiac remodeling.

Blocking amino acid transporter OsAAP3 improves grain yield by promoting outgrowth buds and increasing tiller number in rice.

Amino acid transporters (AATs) play indispensable roles in nutrient allocation during plant development. In this study, we demonstrated that inhibiting expression of the rice amino acid transporter OsAAP3 increased grain yield due to a formation of larger numbers of tillers as a result of increased bud outgrowth. Elevated expression of OsAAP3 in transgenic plants resulted in significantly higher amino acid concentrations of Lys, Arg, His, Asp, Ala, Gln, Gly, Thr and Tyr, and inhibited bud outgrowth and rice tillering. However, RNAi of OsAAP3 decreased significantly Arg, Lys, Asp and Thr concentrations to a small extent, and thus promoted bud outgrowth, increased significantly tiller numbers and effective panicle numbers per plant, and further enhanced significantly grain yield and nitrogen use efficiency (NUE). The promoter sequences of OsAAP3 showed some divergence between Japonica and Indica rice, and expression of the gene was higher in Japonica, which produced fewer tillers than Indica. We generated knockout lines of OsAAP3 on Japonica ZH11 and KY131 using CRISPR technology and found that grain yield could be increased significantly. These results suggest that manipulation of OsAAP3 expression could be used to increase grain yield in rice.

Demethoxycurcumin-Loaded Chitosan Nanoparticle Downregulates DNA Repair Pathway to Improve Cisplatin-Induced Apoptosis in Non-Small Cell Lung Cancer.

Demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanoyl chitosan (CHC) nanomatrix has been successfully developed and used as a therapeutic approach to inhibit cisplatin-induced drug resistance by suppressing excision repair cross-complementary 1 (ERCC1) in non-small cell lung carcinoma cells (NSCLC). Previously, DMC significantly inhibited on-target cisplatin resistance protein, ERCC1, via PI3K-Akt-snail pathways in NSCLC. However, low water solubility and bioavailability of DMC causes systemic elimination and prevents its clinical application. To increase its bioavailability and targeting capacity toward cancer cells, a DMC-polyvinylpyrrolidone core phase was prepared, followed by encapsulating in a CHC shell to form a DMC-loaded core-shell hydrogel nanoparticles (DMC-CHC NPs). We aimed to understand whether DMC-CHC NPs efficiently potentiate cisplatin-induced apoptosis through downregulation of ERCC1 in NSCLC. DMC-CHC NPs displayed good cellular uptake efficiency. Dissolved in water, DMC-CHC NPs showed comparable cytotoxic potency with free DMC (dissolved in DMSO). A sulforhodamine B (SRB) assay indicated that DMC-CHC NPs significantly increased cisplatin-induced cytotoxicity by highly efficient intracellular delivery of the encapsulated DMC. A combination of DMC-CHC NPs and cisplatin significantly inhibited on-target cisplatin resistance protein, ERCC1, via the PI3K-Akt pathway. Also, this combination treatment markedly increased the post-target cisplatin resistance pathway including bax, and cytochrome c expressions. Thymidine phosphorylase (TP), a main role of the pyrimidine salvage pathway, was also highly inhibited by the combination treatment. The results suggested that enhancement of the cytotoxicity to cisplatin via administration of DMC-CHC NPs was mediated by down-regulation of the expression of TP, and ERCC1, regulated via the PI3K-Akt pathway.

Role of Transient Receptor Potential Channels in Heart Transplantation: A Potential Novel Therapeutic Target for Cardiac Allograft Vasculopathy.

Heart transplantation has evolved as the criterion standard therapy for end-stage heart failure, but its efficacy is limited by the development of cardiac allograft vasculopathy (CAV), a unique and rapidly progressive form of atherosclerosis in heart transplant recipients. Here, we briefly review the key processes in the development of CAV during heart transplantation and highlight the roles of transient receptor potential (TRP) channels in these processes during heart transplantation. Understanding the roles of TRP channels in contributing to the key procedures for the development of CAV during heart transplantation could provide basic scientific knowledge for the development of new preventive and therapeutic approaches to manage patients with CAV after heart transplantation.

Wenckebach pattern in right bundle branch block - benign or not?

A Mobitz type I block (Wenckebach phenomenon) with narrow QRS complex is almost always due to a lesion in the AV node. In a type I block with wide QRS complex (>0.12sec), the block can be in the His-Purkinje system in 60-70% of the cases. Even though the progressive PR prolongation with every conducted beat suggests Wenckebach phenomenon, one needs to pay attention to the accompanying QRS complex. In the setting of persistent right bundle branch block, axis change of subsequent conducted beat before an unconducted p suggests alternating fascicular block, giving clue to unreliable infra-Hisian conduction; and in the setting of symptoms, a pacemaker should be implanted. Infra-Hisian Wenckebach block is rare with only sparse literature reports. The present case report adds to these, suggesting that wide QRS with Wenckebach block on surface ECG may indicate infra-Hisian conduction abnormalities.

Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling.

Glucagon-like peptide-1 (GLP-1) analogs are approved for treatment of type 2 diabetes and are in clinical trials for disorders including neurodegenerative diseases. GLP-1 receptor (GLP-1R) is expressed in many peripheral and neuronal tissues and is activated by circulating GLP-1. Other than food intake, little is known about factors regulating GLP-1 secretion. Given a normally basal circulating level of GLP-1, knowledge of mechanisms regulating GLP-1R signaling, which has diverse functions in extrapancreatic tissues, remains elusive. In this study, we found that the potency of GLP-1, not exendin 4, is specifically enhanced by the endocannabinoid-like lipids oleoylethanolamide (OEA) and 2-oleoylglycerol but not by stearoylethanolamide (SEA) or palmitoylethanolamide. 9.2 µM OEA enhances the potency of GLP-1 in stimulating cAMP production by 10-fold but does not affect its receptor binding affinity. OEA and 2-oleoylglycerol, but not SEA, bind to GLP-1 in a dose-dependent and saturable manner. OEA but not SEA promoted GLP-1(7-36) amide to trypsin inactivation in a dose-dependent and saturable manner. Susceptibility of GLP-1(7-36) amide to trypsin inactivation is increased 40-fold upon binding to OEA but not to SEA. Our findings indicate that OEA binds to GLP-1(7-36) amide and enhances the potency that may result from a conformational change of the peptide. In conclusion, modulating potency of GLP-1 by physiologically regulated endocannabinoid-like lipids allows GLP-1R signaling to be regulated spatiotemporally at a constant basal GLP-1 level.

The PTEN-AKT-mTOR/RICTOR Pathway in Nasal Natural Killer Cell Lymphoma Is Activated by miR-494-3p via PTEN But Inhibited by miR-142-3p via RICTOR.

Nasal natural killer (NK) cell lymphoma (NNL) is an Epstein-Barr virus-associated lymphoma of cytotoxic NK cell origin. The Epstein-Barr virus-encoded miR-BART20-5p inhibits T-bet (TBX21), the master transcription factor of cytotoxic NK cells. To further explore the roles of miRNAs in NNLs, we measured the miRNA expression profiles of 36 NNLs. miR-21, miR-142-3p, miR-126, miR-451, and miR-494-3p were the top five miRNAs with the highest expression levels. By using pathway analysis, we identified associations between all of the five miRNAs with the PTEN-AKT-mTOR pathway, in which PTEN suppresses the oncogenic AKT, and mTOR mediates the oncogenic effects of AKT. YT and NK92 cells derived from NK cell lymphomas were used. miR-494-3p inhibited PTEN with secondary activation of AKT in NK92 cells, and miR-142-3p inhibited RICTOR, a key component of the mTOR complex, with secondary suppression of AKT in YT cells. Significantly, T-bet inhibited the PTEN-AKT-mTOR/RICTOR pathway through induction of PTEN and suppression of RICTOR. Therefore, a molecular circuit of T-bet, PTEN, AKT, and RICTOR is regulated by miR-BART20-5p, miR-494-3p, and miR-142-3p. This circuit is involved in the pathogenesis of NNL. Hence, antagomirs to miR-BART20-5p or miR-494-3p, miR-142-3p mimics, or AKT inhibitors may be useful in NNL therapy.

EBV-encoded miR-BART20-5p and miR-BART8 inhibit the IFN-γ-STAT1 pathway associated with disease progression in nasal NK-cell lymphoma.

Nasal NK-cell lymphoma (NNL) is an Epstein-Barr virus (EBV)-associated lymphoma of cytotoxic natural killer (NK) cell origin. Because normal NK cells secrete the principal cytotoxic cytokine IFN-γ to suppress both tumor growth and viral replication, we investigated how EBV may have used miRNAs of viral origin to inhibit the IFN-γ-STAT1 pathway to facilitate viral replication and tumor growth. In EBV(-) Jurkat cells, transfection of miR-BART20-5p and miR-BART8 inhibited translation of luciferase-IFN-γ-3'-UTR and luciferase-STAT1-3'-UTR, respectively. In EBV(+) IFN-γ(weak)/STAT1(strong) YT leukemic cells and IFN-γ(strong)/STAT1(weak) NK92 cells, relative endogenous levels between miR-BART20-5p and IFN-γ mRNAs or between miR-BART8 and STAT1 mRNAs determined expression of the targets. Chromatin immunoprecipitation studies showed that STAT1 regulates the transcription of the tumor suppressor TP53 (encoding p53) and miR-let7a. Consistent with these findings, overexpression of miR-BART8 in YT cells or of miR-BART20-5p in NK92 cells inhibited p53 and increased resistance to doxorubicin. In 36 NNLs, the levels of miR-BART20-5p or miR-BART8 correlated inversely with the expression of STAT1. Additionally, in 46 NNLs, expression of both miR-BART20-5p and miR-BART8 identified a group of NNLs with decreased p53 mRNAs and evidence of disease progression. We conclude that miR-BART20-5p and miR-BART8 cause progression of nasal NK-cell lymphomas through inhibition of the IFN-γ-STAT1 pathway.

Demethoxycurcumin-carrying chitosan-antibody core-shell nanoparticles with multitherapeutic efficacy toward malignant A549 lung tumor: from in vitro characterization to in vivo evaluation.

Targeting controlled release core-shell nanocarriers with the potential to overcome multidrug resistant (MDR) lung cancer were prepared based on demethoxycurcumin (DMC) loaded amphiphilic chitosan nanoparticles coated with an anti-EGFR antibody layer. The nanocarriers were characterized with regard to size with dynamic light scattering, SEM, and TEM. The characterization confirmed the nanocarriers to have a surface coating of the anti-EGFR antibody and a final size excellently suited for circulating targeting nanocarriers, i.e., <200 nm in diameter. In vitro drug release revealed extended quasi-Fickian release from the nanocarriers, with the anti-EGFR layer further reducing the release rate. Cell culture experiments using normoxic and MDR hypoxic cells overexpressing EGFR confirmed improved DMC delivery for anti-EGFR coated particles and revealed that the DMC was delivered to the cytoplasmic region of the cells, forming nanoprecipitates in lysosomes and endosomes. The effective endocytosis and targeting of the core-shell nanoparticles resulted in the nanocarriers achieving high cytotoxicity also against MDR cells. The therapeutic potential was further confirmed in an A549 xenograft lung tumor mouse model, where DMC loaded core-shell nanocarriers achieved about 8-fold reduction in tumor volume compared with control group over the 8 weeks of the investigation. Both in vitro and in vivo data suggest the anti-EGFR coated core-shell nanocarriers as highly promising for treatment of hypoxic MDR cancers, especially for non-small cell lung cancer.

The Clot Strikes Thrice: Case Report of a Patient with 3 Concurrent Embolic events.

PURPOSE: Concurrent cerebral and systemic embolism are unusual occurrences. Acute myocardial infarction secondary to coronary embolism are particularly rare with only isolated reports in the literature. CASE REPORT: A 49-year old Chinese man presented with right posterior cerebral artery infarction to our hospital. He developed chest pain and ST-elevation on ECG the next morning. Urgent cardiac catheterization showed a right coronary artery as well as a right profunda femoris artery occlusion. The cause of these 3 concurrent emboli was a large mobile left ventricular thrombus seen on echocardiography. Urgent anticoagulation was initiated, and the patient returned home after 1 month of rehabilitation with no further ischemic events. CONCLUSION: In selected patients with high embolic risks, urgent anticoagulation after acute ischemic stroke can be a possible treatment option.

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior.

Primary gastric diffuse large B-cell lymphomas may or may not have a concurrent component of mucosa-associated lymphoid tissue lymphoma. Diffuse large B-cell lymphoma/mucosa-associated lymphoid tissue lymphomas are often associated with Helicobacter pylori (H. pylori) infection, suggesting that the large cells are transformed from mucosa-associated lymphoid tissue lymphomas. In contrast, only limited data are available on the clinical and molecular features of pure gastric diffuse large B-cell lymphomas. In 102 pure gastric diffuse large B-cell lymphomas, we found H. pylori infection in 53% of the cases. H. pylori-positive gastric diffuse large B-cell lymphomas were more likely to present at an earlier stage (73% vs 52% at stage I/II, P=0.03), to achieve complete remission (75% vs 43%, P=0.001), and had a better 5-year disease-free survival rate (73% vs 29%, P<0.001) than H. pylori-negative gastric diffuse large B-cell lymphomas. Through genome-wide expression profiles of both miRNAs and mRNAs in nine H. pylori-positive and nine H. pylori-negative gastric diffuse large B-cell lymphomas, we identified inhibition of ZEB1 (zinc-finger E-box-binding homeobox 1) by miR-200 in H. pylori-positive gastric diffuse large B-cell lymphomas. ZEB1, a transcription factor for marginal zone B cells, can suppress BCL6, the master transcription factor for germinal center B cells. In 30 H. pylori-positive and 30 H. pylori-negative gastric diffuse large B-cell lymphomas, we confirmed that H. pylori-positive gastric diffuse large B-cell lymphomas had higher levels of miR-200 by qRT-PCR, and lower levels of ZEB1 and higher levels of BCL6 using immunohistochemistry. As BCL6 is a known predictor of a better prognosis in gastric diffuse large B-cell lymphomas, our data demonstrate that inhibition of ZEB1 by miR-200, with secondary increase in BCL6, is a molecular event that characterizes H. pylori-positive gastric diffuse large B-cell lymphomas with a less aggressive behavior.

Impact of different surgical and postoperative adjuvant treatment modalities on survival of sinonasal malignant melanoma.

BACKGROUND: The role of postoperative adjuvant treatment for sinonasal malignant melanoma remains unclear. This study evaluates the impact of three different surgical and postoperative adjuvant treatment modalities: surgery alone(open and endoscopic approaches), surgery plus radiotherapy and surgery, radiotherapy plus chemotherapy on survival of patients with primary sinonasal malignant melanoma (SMM). METHODS: The data of 69 patients who underwent primary surgical treatments at Eye & ENT hospital of Fudan University between January 1st, 2000 and December 31st, 2010 were retrospectively reviewed. Survival comparison of different surgical and postoperative adjuvant treatment modalities (surgery alone, surgery plus radiotherapy and surgery, radiotherapy plus chemotherapy), as well as survival comparison between open and endoscopic surgical approaches were performed. Curves depicting survival were performed using Kaplan-Meier method. Statistical analysis was performed using log-rank test software SPSS19 and p < .05 is considered as statistically significant. RESULTS: The median overall survival time was found to be 18 months for surgery alone (27 cases), 32 months for surgery plus radiotherapy (24 cases), 42 months for surgery, radiotherapy plus chemotherapy (18 cases). The 3 and 5 year survival rates for groups mentioned above were 14.8% and 5.6%, 45.1% and 31.6%, 55% and 32.1%, respectively. Statistical significances were found not only between surgery alone and surgery plus radiotherapy treatment group (P = 0.012), but also surgery alone and surgery, radiotherapy plus chemotherapy group (P = 0.002). There was no statistically significant survival difference found between the two different surgical approaches (41 cases for open approach and 28 cases for endoscopic approach). CONCLUSIONS: Sinonasal malignant melanoma is a disease with a poor prognosis. Patients who underwent surgery plus radiotherapy or surgery, radiotherapy plus chemotherapy had better survival outcomes than those underwent surgery alone. Endoscopic approach provided similar survival outcome as an open approach.