Real-time arrhythmia detection using convolutional neural networks.

Cardiovascular diseases, such as heart attack and congestive heart failure, are the leading cause of death both in the United States and worldwide. The current medical practice for diagnosing cardiovascular diseases is not suitable for long-term, out-of-hospital use. A key to long-term monitoring is the ability to detect abnormal cardiac rhythms, i.e., arrhythmia, in real-time. Most existing studies only focus on the accuracy of arrhythmia classification, instead of runtime performance of the workflow. In this paper, we present our work on supporting real-time arrhythmic detection using convolutional neural networks, which take images of electrocardiogram (ECG) segments as input, and classify the arrhythmia conditions. To support real-time processing, we have carried out extensive experiments and evaluated the computational cost of each step of the classification workflow. Our results show that it is feasible to achieve real-time arrhythmic detection using convolutional neural networks. To further demonstrate the generalizability of this approach, we used the trained model with processed data collected by a customized wearable sensor from a lab setting, and the results shown that our approach is highly accurate and efficient. This research provides the potentials to enable in-home real-time heart monitoring based on 2D image data, which opens up opportunities for integrating both machine learning and traditional diagnostic approaches.

Latexin regulates sex dimorphism in hematopoiesis via gender-specific differential expression of microRNA 98-3p and thrombospondin 1.

Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate to all blood cell types. HSCs and their differentiated progeny show sex/gender differences. The fundamental mechanisms remain largely unexplored. We previously reported that latexin (Lxn) deletion increased HSC survival and repopulation capacity in female mice. Here, we find no differences in HSC function and hematopoiesis in Lxn knockout (Lxn-/-) male mice under physiologic and myelosuppressive conditions. We further find that Thbs1, a downstream target gene of Lxn in female HSCs, is repressed in male HSCs. Male-specific high expression of microRNA 98-3p (miR98-3p) contributes to Thbs1 suppression in male HSCs, thus abrogating the functional effect of Lxn in male HSCs and hematopoiesis. These findings uncover a regulatory mechanism involving a sex-chromosome-related microRNA and its differential control of Lxn-Thbs1 signaling in hematopoiesis and shed light on the process underlying sex dimorphism in both normal and malignant hematopoiesis.

Whole-Transcriptome Analysis Highlights Adenylyl Cyclase Toxins-Derived Modulation of NF-κB and ERK1/2 Pathways in Macrophages.

Edema toxin (ET), one of the main toxic factors of Bacillus anthracis (B. anthracis), is a kind of potent adenylate cyclase (AC). B. anthracis has adapted to resist macrophage microbicidal mechanisms in part by secreting ET. To date, there is limited information on the pathogenic mechanisms used by ET to manipulate macrophage function, especially at the transcriptome level. We used RNA sequencing to study transcriptional changes in RAW264.7 cells treated with ET. We aimed to identify molecular events associated with the establishment of infection and followed changes in cellular proteins. Our results indicate that ET inhibited TNF-α expression in the RAW264.7 mouse macrophage cell line by activating the cAMP/PKA pathway. ET challenge of macrophages induced a differential expression of genes that participate in multiple macrophage effector functions such as cytokine production, cell adhesion, and the inflammatory response. Furthermore, ET influenced the expression of components of the ERK1/2, as well as the NF-αB signaling pathways. We also showed that ET treatments inhibit the phosphorylation of the ERK1/2 protein. ET also attenuated NF-αB subunit p65 phosphorylation and transcriptional activity of NF-αB via the cAMP/PKA pathway in macrophages. Since the observed modulatory effects were characteristic only of the bacterial exotoxin ET, we propose this may be a mechanism used by B. anthracis to manipulate macrophages and establish systemic infection.

Recent Advances in Lipid Nanoparticles for Delivery of mRNA.

Messenger RNA (mRNA), which is composed of ribonucleotides that carry genetic information and direct protein synthesis, is transcribed from a strand of DNA as a template. On this basis, mRNA technology can take advantage of the body's own translation system to express proteins with multiple functions for the treatment of various diseases. Due to the advancement of mRNA synthesis and purification, modification and sequence optimization technologies, and the emerging lipid nanomaterials and other delivery systems, mRNA therapeutic regimens are becoming clinically feasible and exhibit significant reliability in mRNA stability, translation efficiency, and controlled immunogenicity. Lipid nanoparticles (LNPs), currently the leading non-viral delivery vehicles, have made many exciting advances in clinical translation as part of the COVID-19 vaccines and therefore have the potential to accelerate the clinical translation of gene drugs. Additionally, due to their small size, biocompatibility, and biodegradability, LNPs can effectively deliver nucleic acids into cells, which is particularly important for the current mRNA regimens. Therefore, the cutting-edge LNP@mRNA regimens hold great promise for cancer vaccines, infectious disease prevention, protein replacement therapy, gene editing, and rare disease treatment. To shed more lights on LNP@mRNA, this paper mainly discusses the rational of choosing LNPs as the non-viral vectors to deliver mRNA, the general rules for mRNA optimization and LNP preparation, and the various parameters affecting the delivery efficiency of LNP@mRNA, and finally summarizes the current research status as well as the current challenges. The latest research progress of LNPs in the treatment of other diseases such as oncological, cardiovascular, and infectious diseases is also given. Finally, the future applications and perspectives for LNP@mRNA are generally introduced.

Sex differences in normal and malignant hematopoiesis.

Hematopoiesis is a continuous and well-regulated process requiring both the capacity for self-renewal and the potential for differentiation of hematopoietic stem cells. Multiple studies indicate that sex hormones exert significant effects on not only hematopoietic stem and progenitor cells, but also the development of hematopoietic lineages, resulting in sexual dimorphisms in normal hematopoiesis. Hematologic malignancies comprise a wide variety of cancers affecting the blood, bone marrow, and lymphatic system, such as leukemia, lymphoma, myeloma, myelodysplastic syndrome, and myeloproliferative diseases. Overall, males are at greater risk and have worse prognosis for most of these malignancies compared with females. A better understanding of the differences between male and female could be of substantial value in research as well as clinical management.

Tylvalosin demonstrates anti-parasitic activity and protects mice from acute toxoplasmosis.

AIMS: Toxoplasmosis, caused by Toxoplasma gondii (Tg), is one of the most prevalent zoonotic diseases worldwide. Currently, safe and efficient therapeutic options for this disease are still being developed, and are urgently needed. Tylvalosin (Tyl), a broad-spectrum third-generation macrolide, exhibits anti-bacterial, anti-viral, and anti-inflammatory properties. The present study aims to explore the anti-parasitic and immunomodulation activities of Tyl against Tg, and the underlying mechanism. MAIN METHODS: Adhesion, invasion, replication, proliferation, plaque, reversibility, immunofluorescence assays and transmission electron microscopy were utilized to determine the anti-Toxoplasma effect of Tyl. With acute toxoplasmosis model and rabies virus-induced brain inflammation model, the anti-toxoplasmosis and immunomodulation activities of Tyl were assessed by colorimetric assay, histopathological and Oil red O staining, and real-time quantitative PCR. The involved molecular mechanisms were investigated by western blotting and immunohistochemical staining. KEY FINDINGS: Tyl (5 and 10 µg/ml) can inhibit Tg propagation, and damage its ultrastructure irreversibly. The combination of Tyl and Pyrimethamine (Pyr) exhibits a better synergistic effect. Tyl (50 and 100 mg/kg) treatment intraperitoneally can delay mice death and improve survival rate, accompanying the reduced histopathological score and parasite load in the indicated tissues, espically for ileum, liver, spleen, lung and brain. Furthermore, Tg can modulate host phospho-p38 MAPK (pp38), subtilisin/kexin-isozyme-1 (SKI-1)-sterol regulatory element binding protein-1 (SREBP-1) (SKI-1-SREBP-1) pathway and peroxisome proliferators-activated receptor δ (PPARδ), while Tyl is able to reverse these signal pathways close to normal levels. SIGNIFICANCE: Our findings indicate that Tyl exhibits anti-Toxoplasma activity and protects mice from acute toxoplasmosis.

Lipid metabolism is a novel and practical source of potential targets for antiviral discovery against porcine parvovirus.

How parvovirus manipulates host lipid metabolism to facilitate its propagation, pathogenicity and consequences for disease, is poorly characterized. Here, we addressed this question using porcine parvovirus (PPV) to understand the complex interactions of parvovirus with lipid metabolism networks contributing to the identification of novel and practical antiviral candidates. PPV significantly alters host lipid composition, characteristic of subclasses of phospholipids and sphingolipids, and induces lipid droplets (LDs) formation via regulating calcium-independent PLA2ß (iPLA2ß), phospholipase Cγ2 (PLCγ2), diacylglycerol kinase α (DKGα), phosphoinositide 3-kinase (PI3K), lysophosphatidic acid acyltransferase θ (LPAATθ), and sphingosine kinases (SphK1 and SphK2). PPV utilizes and exploits these enzymes as well as their metabolites and host factors including MAPKs (p38 and ERK1/2), protein kinase C (PKC) and Ca2+ to induce S phase arrest, apoptosis and incomplete autophagy, all benefit to PPV propagation. PPV also suppresses prostaglandin E2 (PGE2) synthesis via downregulating cyclooxygenase-1 (COX-1), indicating PPV hijacks COX-1-PGE2 axis to evade immune surveillance. Our data support a model where PPV to establishes an optimal environment for its propagation and pathogenicity via co-opting host lipid metabolism, being positioned as a source of potential targets.

Identification of serum biomarkers to predict pemetrexed/platinum chemotherapy efficacy for advanced lung adenocarcinoma patients by data-independent acquisition (DIA) mass spectrometry analysis with parallel reaction monitoring (PRM) verification.

BACKGROUND: Pemetrexed/platinum chemotherapy has been the standard chemotherapy regimen for lung adenocarcinoma patients, but the efficacy varies considerably. METHODS: To discover new serum biomarkers to predict the efficacy of pemetrexed/platinum chemotherapy, we analyzed 20 serum samples from advanced lung adenocarcinoma patients who received pemetrexed/platinum chemotherapy with the data-independent acquisition (DIA) quantitative mass spectrometry (MS). RESULTS: The 20 patients were categorized as "good response" [12 patients achieving partial response (PR)] and "poor response" [8 patients with progressive disease (PD)] groups. Altogether 23 significantly different expressed proteins were identified, which had relative ratios higher than 1.2 or lower than -0.83, with 7 proteins having an area under the curve (AUC) above 0.8. To further validate the DIA results, we used the parallel reaction monitoring (PRM) method to examine 16 candidate serum biomarkers in the study cohort of 20 patients and another cohort of 22 advanced lung adenocarcinoma patients (16 PR and 6 PD). Quantitative validation using PRM correlated well with the DIA results, and 10 promising proteins exhibited a similar up- or downregulation. It is worth noting that glutathione peroxidase 3 (GPX3) exhibits significant upregulation in the poor response group compared with the good response group, which was validated by both DIA and PRM methods. CONCLUSIONS: Our study confirmed that combined DIA MS and PRM approaches were effective in identifying serum predictive biomarkers for advanced lung adenocarcinoma patients. Further studies are needed to explore the potential biological mechanism underlying these biomarkers.

Plasma cytokines interleukin-18 and C-X-C motif chemokine ligand 10 are indicative of the anti-programmed cell death protein-1 treatment response in lung cancer patients.

BACKGROUND: Although programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint inhibitors have shown prominent efficacy for treatment of advanced lung cancer, the outcomes of metastatic lung cancer remain poor throughout the world. Although progression-free survival (PFS) and overall survival (OS) have improved in the first- and second-line therapy settings for advanced lung cancer, the response rates to PD-1/PD-L1 inhibition range from 20% to 40%. Furthermore, patients may be at risk for immune-related adverse events (irAEs); hence, appropriate patient selection is crucial. This study aimed to identify a panel of plasma cytokines representing prognostic and predictive biomarkers of the response to anti-PD-1/PD-L1 treatment. METHODS: We prospectively studied 32 lung cancer patients who received anti-PD-1/PD-L1 antibody immunotherapy. Plasma cytokines in peripheral blood samples were evaluated and analyzed using flow cytometry at the time of diagnosis and at 2 months after the initiation of PD-1/PD-L1 inhibition. RESULTS: The baseline plasma concentrations of interleukin-18 (IL-18) and C-X-C motif chemokine ligand 10 (CXCL10) were correlated with the degree of tumor response. Moreover, the magnitude of plasma IL-18 and CXCL10 level fluctuations were correlated significantly with the objective tumor response to anti-PD-1/PD-L1 immunotherapy, and patients with high CXCL10 expression had significantly shorter PFS than those with low CXCL10 expression. A strong positive correlation between the fluctuation of IL-18 and interleukin-8 (IL-8) levels was detected, as was a negative correlation between the fluctuation of IL-18 and CXCL10 levels. The level of plasma C-C motif chemokine ligand 5 (CCL5) was significantly higher in patients with irAEs than in those without irAEs. CONCLUSIONS: Plasma cytokines are related to the clinical efficacy of PD-1/PD-L1 inhibitors. IL-18 and CXCL10 are potential predictive markers for anti-PD-1/PD-L1 therapy in lung cancer patients and may play an important role in selecting patients who would benefit from PD-1/PD-L1 inhibitors.

Interactions of Hematopoietic Stem Cells with Bone Marrow Niche.

Hematopoietic stem cells (HSCs) are ultimately responsible for the lifelong renewal of all blood cell lineages. In the bone marrow (BM), HSCs reside in specialized microenvironments referred to as the "niche." HSC niche consists of complex components including heterogeneous cell populations, growth factors, and extracellular matrix molecules. The crosstalk between HSCs and their niche is essential to regulate the survival, self-renewal, migration, quiescence, and differentiation of HSCs. The application of mice models with endogenous ablation of specific cell types, advanced imaging technologies, high-throughput single-cell RNA sequencing, and single-cell mass cytometry methods have provided deep insights into communications between HSCs and niche cells. In this chapter, we have focused on three important cell types in the BM niche: mesenchymal stem cells (MSCs), osteoblasts (OBs), and endothelial cells (ECs). In order to address the interaction between HSCs and these three cell populations in BM niche, we have described methodology for (1) collecting total BM from femur and tibia of C57BL/6 mice; (2) analyzing or sorting of MSCs, OBs, and ECs based on the selection of surface markers CD45, Ter119, CD31, Sca1, and CD51 with flow cytometry; and (3) co-culturing the sorted cells with purified HSCs for further functional assays of HSCs.

Prediction of the VeriStrat test in first-line therapy of pemetrexed-based regimens for advanced lung adenocarcinoma patients.

BACKGROUND: Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy. METHODS: This study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment. RESULTS: Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P < 0.001) than VS-P patients. In addition, the partial response (PR) rate was higher in the VS-G group than that in the VS-P group (46.7% vs. 25.0%, P = 0.212). Subgroup analysis showed that PFS was also significantly longer in the VS-G group than that in the VS-P group regardless of whether patients received chemotherapy alone or chemotherapy plus bevacizumab. CONCLUSIONS: Our study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

Nomogram model for predicting cause-specific mortality in patients with stage I small-cell lung cancer: a competing risk analysis.

BACKGROUND: The five-year cumulative incidence rate in patients diagnosed with stage I small-cell lung cancer (SCLC) who were instructed to undergo surgery was from 40 to 60%.The death competition influence the accuracy of the classical survival analyses. The aim of the study is to investigate the mortality of stage I small-cell lung cancer (SCLC) patients in the presence of competing risks according to a proportional hazards model, and to establish a competing risk nomogram to predict probabilities of both cause-specific death and death resulting from other causes. METHODS: The study subjects were patients diagnosed with stage I SCLC according to ICD-O-3. First, the cumulative incidence functions (CIFs) of cause-specific death, as well as of death resulting from other causes, were calculated. Then, a proportional hazards model for the sub-distribution of competing risks and a monogram were constructed to evaluate the probability of mortality in stage I SCLC patients. RESULTS: 1811 patients were included in this study. The five-year probabilities of death due to specific causes and other causes were 61.5 and 13.6%, respectively. Tumor size, extent of tumor, surgery, and radiotherapy were identified as the predictors of death resulting from specific causes in stage I SCLC. The results showed that surgery could effectively reduce the cancer-specific death, and the one-year cumulative incidence dropped from 34.5 to 11.2%. Like surgery, chemotherapy and radiotherapy improved the one-year survival rate. CONCLUSIONS: We constructed a predictive model for stage I SCLC using the data from the SEER database. The proportional sub-distribution models of competing risks revealed the predictors of death resulting from both specific causes and other causes. The competing risk nomogram that we built to predict the prognosis showed good reliability and could provide beneficial and individualized predictive information for stage I SCLC patients.

ABCB1 polymorphism predicts the toxicity and clinical outcome of lung cancer patients with taxane-based chemotherapy.

BACKGROUND: Taxane-based chemotherapy is widely used in lung cancer. ABCB1 have a role in the prediction of treatment response and toxicity of chemotherapy in solid tumors. In this retrospective study, we investigated ABCB1 polymorphism on response and toxicity in taxane-based chemotherapy in lung cancer patients. METHODS: A total of 122 lung cancer patients who received taxane-based chemotherapy were included in this study. Fluorescence in situ hybridization (FISH) was used for ABCB1 polymorphism detection. Turbidimetric inhibition immunoassay was used for pharmacokinetic analysis. Statistical analysis was performed using SPSS 20.0. RESULTS: The frequency of the ABCB1 2677 site TT/TG/GG genotype was 32.8%, 43.4% and 23.8%, respectively and the frequency of the 3435 sites the TT/TC/CC genotype was 13.9%, 44.3% and 41.8%, respectively. The occurrence of neurotoxicity was higher in patients who had ABCB1 3435 site mutation (TT 88.2%, TC 22.2%, CC 21.6% P = 0.004). There was no significant difference between ABCB1 genotypes with regard to other chemotherapy-induced toxicity. For non-small cell lung cancer (NSCLC) patients, those harboring ABCB1 2677 and 3435 site wild-type patients had longer median progression-free survival (PFS) in the paclitaxel subgroup (3435 site: TT 3.87 vs. TC 9.50 vs. CC 14.13 months; P < 0.001; 2677 site: TT 4.37 vs. TG 9.73 vs. GG 12.1 months; P = 0.013). The area under the concentration-time curve (AUC) of 20 patients treated with docetaxel increased for ABCB1 mutation subgroups. CONCLUSION: ABCB1 mutation is associated with higher neurotoxicity of taxane-based chemotherapy. It also predicts shorter PFS for NSCLC in paclitaxel-based treatment.

Nomogram to predict cause-specific mortality in extensive-stage small cell lung cancer: A competing risk analysis.

BACKGROUND: Small-cell lung cancer (SCLC) is one of the most aggressive types of lung cancer. The prognosis for SCLC patients depends on many factors. The intent of this study was to construct a nomogram model to predict mortality for extensive-stage SCLC. METHODS: Original data was collected from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute in the United States. A nomogram prognostic model was constructed to predict death probability for extensive-stage SCLC. RESULTS: A total of 16 554 extensive-stage SCLC patients from 2004 to 2014 in the SEER database were included in this study. Gender, race, age, TNM staging (including tumor extent, nodal status, and metastasis), and treatment (surgery, chemotherapy, and radiotherapy) were identified as independent predictors for lung cancer-specific death for extensive-stage SCLC patients. A nomogram model was constructed based on multivariate models for lung cancer related death and other cause related death. Performance of the two models was validated by calibration and discrimination, with C-index values of 0.714 and 0.638, respectively. CONCLUSION: A prognostic nomogram model was established to predict death probability for extensive-stage SCLC. This validated prognostic model may be beneficial for treatment strategy choice and survival prediction.

Survival analysis via nomogram of surgical patients with malignant pleural mesothelioma in the Surveillance, Epidemiology, and End Results database.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that originates from the pleura and has a poor prognosis. Eligible patients can benefit from surgery, but their survival is affected by many factors. Therefore, we created a graphic model that could predict the prognosis of surgically treated patients. METHODS: We retrospectively analyzed data from the Surveillance, Epidemiology, and End Results database from 2004 to 2014 to identify the key factors affecting the prognosis of surgically treated MPM patients. On this basis we built a nomogram to predict survival. We then evaluated the performance of the nomogram in a validation cohort. RESULTS: In a training cohort of 828 cases, independent prognostic factors, including age, gender, histological type, differentiation, N stage, chemotherapy, type of surgery, and lymph node dissection, were identified. We then developed a nomogram to evaluate individual patient survival. In Kaplan-Meier analysis, a higher score in the nomogram was associated with a worse prognosis. We also used a validation cohort consisting of 312 patients to evaluate the performance of the nomogram, which was well calibrated and had good discrimination ability, with concordance indices of 0.715 and 0.656 for the training and validation cohorts, respectively. CONCLUSION: This study has improved our understanding of resected MPM and shown that key factors, including age and histological type, are associated with overall survival. The nomogram is a reliable tool that can help clinicians turn individualized prediction into reality and maximize patient benefit by identifying the most beneficial treatment approach.

SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints.

SETD2, an epigenetic tumor suppressor, is frequently mutated in MLL-rearranged (MLLr) leukemia and relapsed acute leukemia (AL). To clarify the impact of SETD2 mutations on chemotherapy sensitivity in MLLr leukemia, two loss-of-function (LOF) Setd2-mutant alleles (Setd2F2478L/WT or Setd2Ex6-KO/WT) were generated and introduced, respectively, to the Mll-Af9 knock-in leukemia mouse model. Both alleles cooperated with Mll-Af9 to accelerate leukemia development that resulted in resistance to standard Cytarabine-based chemotherapy. Mechanistically, Setd2-mutant leukemic cells showed downregulated signaling related to cell cycle progression, S, and G2/M checkpoint regulation. Thus, after Cytarabine treatment, Setd2-mutant leukemic cells exit from the S phase and progress to the G2/M phase. Importantly, S and G2/M cell cycle checkpoint inhibition could resensitize the Mll-Af9/Setd2 double-mutant cells to standard chemotherapy by causing DNA replication collapse, mitotic catastrophe, and increased cell death. These findings demonstrate that LOF SETD2 mutations confer chemoresistance on AL to DNA-damaging treatment by S and G2/M checkpoint defects. The combination of S and G2/M checkpoint inhibition with chemotherapy can be explored as a promising therapeutic strategy by exploiting their unique vulnerability and resensitizing chemoresistant AL with SETD2 or SETD2-like epigenetic mutations.

Survival comparison of right and left side non-small cell lung cancer in stage I-IIIA patients: A Surveillance Epidemiology and End Results (SEER) analysis.

BACKGROUND: Primary tumors located in the right and left side have distinctive prognoses, but the details have not been fully identified in non-small cell lung cancer (NSCLC). This study investigated the impact of primary tumor side on long-term survival in NSCLC patients. METHODS: Data of 90 407 patients from the Surveillance, Epidemiology, and End Results (SEER) Program were analyzed. To avoid bias between groups, we used innovative propensity score matching (PSM) analysis. RESULTS: There was no significant distinction in overall survival (OS) between right (n = 53 496) and left (n = 36 911) side tumors (hazard ratio [HR] 0.993, 95% confidence interval [CI] 0.9756-1.011; P = 0.432). Left side was associated with superior five-year cancer-specific survival (CSS) compared to right side NSCLC (HR 0.977, 95% CI 0.9574-0.9969; P = 0.024). No significant difference was observed in OS (P = 0.689) or CSS (P = 0.288) after PSM analysis. In the 51 319 patients who underwent surgery, left side (n = 21 245) was associated with poor OS compared to right side (n = 30 074) NSCLC (HR 1.039, 95% CI 1.011-1.067; P = 0.006), while CSS was similar (HR 1.031, 95% CI 0.997-1.065; P = 0.069). In patients who underwent surgery, there was also no significant difference in OS (P = 0.986) or CSS (P = 0.979) after PSM analysis. CONCLUSION: The prognosis between right and left side NSCLC in stage I-IIIA was similar regardless of whether patients underwent surgery. Primary tumor side cannot be considered a prognostic factor when choosing appropriate treatment.

Ketotifen fumarate attenuates feline gingivitis related with gingival microenvironment modulation.

Gingivitis is evidenced by inflammation of the free gingiva, and still reversible. If left untreated, it may then progress to periodontitis. In the present study, the therapeutical effect of ketotifen fumarate on gingivitis was explored. Domestic cats with varying degrees of gingivitis naturally were enrolled in this study. Subgroups of animals were treated twice daily for one week with or without ketotifen fumarate (5 mg/kg). Effects of ketotifen fumarate were measured on gingival index, cells accumulation, mediators release, receptor-ligand interaction, oxidative stress, MAPK and NF-κB pathways, epithelial barrier and apoptosis. Ketotifen fumarate attenuated the initiation and progression of gingivitis, inhibited the infiltrations of mast cells, B lymphocytes, T lymphocytes, macrophages, neutrophils and eosinophils as well as the release of IgE, ß-hexosaminidase, tryptase, chymase, TNF-α, IL-4, and IL-13, influenced endothelial cells, fibroblasts and epithelial cells proliferation and apoptosis, and induced Th2 cells polarization, where ketotifen fumarate also might affect their interactions. Ketotifen fumarate reduced the oxidative stress, and inhibited NF-κB and p38 MAPK related with mast cells and macrophages accumulation. Ketotifen fumarate improved the aberrant expression of ZO-1 and inhibits the following apoptosis. On the other hand, these cells and mediators augmented functional attributes of them involving SCF/c-Kit, α4ß7/VCAM-1 and IL-8/IL-8RB interactions, thus creating a positive feedback loop to perpetuate gingivitis, where an inflammation microenvironment was modeled. Our results showed a previously unexplored therapeutic potential of ketotifen fumarate for gingivitis and further suggest that, in addition to biofilms, targeting inflammation microenvironment could be new strategy for the treatment of gingivitis/periodontitis.

Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. Their incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in patients with MDS, their clinical features are quite similar. Here, we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS patient bone marrow stem/progenitors. Major MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) activate the HIF1A signature. Although inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS and as an effective therapeutic target for a broad spectrum of patients with MDS.Significance: We showed that dysregulation of HIF1A signaling could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver mutations. This could resolve the disconnection between genotypes and phenotypes and provide a new clue as to how a variety of driver mutations cause common MDS phenotypes. Cancer Discov; 8(11); 1438-57. ©2018 AACR. See related commentary by Chen and Steidl, p. 1355 This article is highlighted in the In This Issue feature, p. 1333.

Effects of anti-CD44 monoclonal antibody IM7 carried with chitosan polylactic acid-coated nano-particles on the treatment of ovarian cancer.

Failure in early diagnosis and ineffective treatment are the major causes of ovarian cancer mortality. Hyaluronan and its receptor, cluster of differentiation (CD)44, have been considered to be valid targets for treating cancer. The anti-CD44 monoclonal antibody IM7 is effective in treating ovarian cancer; however, its toxicity should not be ignored. The present study has developed a new drug carrier system composed of chitosan nano-particles coated with polylactic acid (PLA) to improve the treatment efficacy and reduce toxicity. An ionic crosslinking method and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide were used to prepare the IM7 antibody, which was loaded with chitosan nano-particles. The surfaces of the nano-particles were coated with PLA to generate PLA-chitosan-IM7. Subsequently, transmission electron microscopy (TEM) was used to observe the size and zeta potential of the nano-particles. In addition, a spectrophotometer was used to calculate the loading rate and release rate of the nano-particles in acidic and neutral environments. MTT assay was used to evaluate the anti-proliferative effect of PLA-chitosan-IM7 on the human ovarian cancer cell line HO-8910PM. In addition, an in vivo imaging system was used to further investigate the effect of PLA-chitosan-IM7 on the treatment of mice with ovarian cancer. A total of 35 days subsequent to PLA-chitosan-IM7 treatment, all animals were sacrificed by CO2, and the tumors were removed and weighted. The PLA-chitosan-IM7 nano-particles were successfully prepared, since TEM revealed that their size was 300-400 nm and their zeta potential was +25 mV. According to the spectrophotometry results, the loading rate was 52%, and PLA-chitosan-IM7 exhibited good resistance to acids. MTT assay demonstrated that PLA-chitosan-IM7 could suppress the proliferation of HO-8910PM cells in vitro. The in vivo imaging system revealed that PLA-chitosan-IM7 was effective in controlling the development of human ovarian cancer cells and the tumor weight. These results suggest that PLA-chitosan-IM7 could be effective in treating cancers in vitro and in vivo, which may provide a novel approach to enhance the effectiveness of anti-CD44 treatment while reducing its toxicity.