A nomogram based on clinical characteristics and nutritional indicators for relative and absolute weight loss during radiotherapy in initially inoperable patients with locally advanced esophageal squamous cell carcinoma.

OBJECTIVE: Radiation for locally advanced esophageal squamous cell carcinoma often is accompanied by radiation esophagitis, which interferes with oral intake. We aimed to develop a nomogram model to identify initially inoperable patients with relative and absolute weight loss who need prophylactic nutritional supplementation. METHODS: A total of 365 initially inoperable patients with locally advanced esophageal squamous cell carcinoma receiving radiotherapy between January 2018 and December 2022 were included in the study, which was divided into discovery and validation cohorts. Receiver operating characteristic and Kaplan-Meier curve analyses were performed to compare the areas under the curve and survival benefits. RESULTS: A total of 42.2% (154 of 365) of the patients had been diagnosed with cancer cachexia. The malnourished group had a higher interruption rate of radiotherapy and number of complication diseases (P < 0.05). Meanwhile, patients with malnutrition had lower lymphocytes and prognostic nutritional index (P < 0.05). The combined index showed a higher area under the curve value (0.67; P < 0.001) than number of complication diseases (area under the curve = 0.52) and prognostic nutritional index (area under the curve = 0.49) for relative weight loss (≥ 5%). Similarly, the combined index had a higher area under the curve value (0.79; P < 0.001) than number of complication diseases (area under the curve = 0.56), treatment regimens (area under the curve = 0.56), subcutaneous fat thickness (area under the curve = 0.60), pretreatment body weight (area under the curve = 0.61), neutrophils (area under the curve = 0.56), and prognostic nutritional index (area under the curve = 0.50) for absolute weight loss (≥ 5 kg). Absolute and relative weight loss remained independent prognostic factors, with short overall survival rates compared with the normal group (P < 0.05). Patients with high nomogram scores supported by nutritional intervention had less weight loss, better nutrition scores, and increased plasma CD8+ T cells, and interferon gamma. CONCLUSIONS: We developed a nomogram model that was intended to estimate relative and absolute weight loss in initially inoperable patients with locally advanced esophageal squamous cell carcinoma during radiotherapy, which might help facilitate an objective decision on prophylactic nutritional supplementation.

Facile synthesis, crystal structure, quantum calculation, and biological evaluations of novel selenenyl sulfide compounds as potential agrochemicals.

BACKGROUND: In order to design compounds with fresh molecular skeleton to break through the limitation of available agrochemicals, a series of 36 novel selenenyl sulfide compounds were chemically synthesized, and their biological activities were fully evaluated against tobacco mosaic virus (TMV), 14 plant pathogenic fungi, three insect species and plant acetohydroxyacid synthase (AHAS). RESULTS: All the target compounds were characterized by proton nuclear magnetic resonance (1 H-NMR), carbon-13 (13 C)-NMR, selenium-77 (77 Se)-NMR, and high-resolution mass spectrometry (HRMS). The crystal structure of 10j indicated that the Se-S bond was successfully constructed. Compounds 10d, 10h, 10s, 10u, 10aa, 10ac, 10ae, 10ag, and 10ai exhibited 40%, 43%, 39%, 41%, 47%, 46%, 47%, 42%, and 39% anti-TMV activities at 500 mg L-1 , better than that of ribavirin. The median effective concentration (EC50 ) against Sclerotinia sclerotiorum of 10ac was 6.69 mg L-1 and EC50 values against Physalospora piricola and Pyricularia grisea of 10z were 12.25 mg L-1 and 15.27 mg L-1 , respectively, superior to the corresponding values of chlorothalonil. Compounds 10c and 10v demonstrated 100% larvicidal activity against Culex pipiens pallens at 5 mg L-1 , while 10a displayed 100% insecticidal activity against Mythimna separata at 200 mg L-1 . Compounds 10c, 10j, and 10o showed > 60% inhibitions against plant AHAS at 10 µmol L-1 . From the quantum calculation, highest occupied molecular orbital (HOMO) was considered as a factor that affects the anti-TMV activity. CONCLUSION: The preliminary results suggested that more efforts should be devoted to exploring the selenenyl sulfides for the discovery of new leads of antiviral agent, fungicide, insecticide or AHAS inhibitors as potential agrochemicals for crop protection. © 2023 Society of Chemical Industry.

Deubiquitinating enzyme Josephin-2 stabilizes PHGDH to promote a cancer stem cell phenotype in hepatocellular carcinoma.

BACKGROUND: Deubiquitinating enzymes (DUBs) have been shown to be possible targets for hepatocellular carcinoma (HCC) treatment. OBJECTIVE: This study was designed to reveal the effect and underlying mechanism of Josephin-2, a relatively newly defined DUB, in HCC progression. METHODS: SNU-387 and PLC/PRF/5 cells were used for in vitro functional assays. The levels of Josephin-2 and phosphoglycerate dehydrogenase (PHGDH) were determined using RT-qPCR and western blotting. Cell proliferation, migration and invasion were assessed by CCK-8, colony formation and Transwell. Spheroid-forming assay was performed to assess the cancer stem cell (CSC)-phenotype of HCC cells. A xenograft mice model was applied to verify the effect of Josephin-2 on HCC cell growth in vivo. RESULTS: Herein, we showed that Josephin-2 expression was negatively correlated with HCC patient survival in data from the online database. Cell experiments indicated that knockdown of Josephin-2 attenuated HCC cell malignant biological behaviors. Besides, Josephin-2 silencing also decreased the spheroid-formation while inhibited the expression of CSC biomarkers (CD133, OCT4, SOX2 and EpCAM) in HCC cells. Mechanistically, Josephin-2 had a deubiquitinating activity towards the regulation of PHGDH protein, the rate-limiting enzyme in the first step of serine biosynthesis pathway. Depletion of Josephin-2 enhanced the ubiquitination degradation of PHGDH and ultimately inhibited the proliferation and CSC-phenotype of HCC in vitro and in vivo. CONCLUSION: Our work uncovered the regulatory effects of Josephin-2 on PHGDH protein stability and profiled its contribution in HCC malignant progression, which might provide a potential therapeutic target for HCC.

A mixed blessing for liver transplantation patients - Rapamycin.

BACKGROUND: Liver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT. DATA SOURCES: In this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder. RESULTS: Rapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders. CONCLUSIONS: Rapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.

TCF21 rs2327429 and TCF21 rs12190287 are associated with colorectal cancer in a Chinese population.

Aims: TCF21 is considered a tumor suppressor gene. This work was designed to explore the associations between TCF21 polymorphisms and colorectal cancer (CRC) susceptibility. Methods: A case-control study was designed with 421 patients with CRC and 469 non-CRC controls. Six tagging single-nucleotide polymorphisms (rs2327429 T>C, rs2327430 T>C, rs2327433 A>G, rs12190287 C>G, rs7766238 G>A and rs4896011 T>A) were genotyped by ligase detection reaction of PCR. Results: TCF21 rs2327429 and rs12190287 polymorphisms were associated with CRC susceptibility in a Chinese Han population. Conclusion: rs2327429 and rs12190287 polymorphisms may be predictive of CRC susceptibility in Chinese Han populations.

Stochastic radiative transfer in random media. II. Coupling of radiation to material.

We study the mechanism of the impact of random media on the stochastic radiation transport based on a one-dimensional (1D) planar model. To this end, we use a random sampling of mixtures combined with a deterministic solution of the time-dependent radiation transport equation coupled to a material temperature equation. Compared to purely absorbing cases [C.-Z. Gao et al., Phys. Rev. E 102, 022111 (2020)10.1103/PhysRevE.102.022111], we find that material temperatures can significantly suppress the impact of mixing distribution and size, which is understood from the analysis of energy transport channels. By developing a steady-state stochastic transport model, it is found that the mechanism of transmission of radiation is distance dependent, which is closely related to the mean free path of photons l_{p}. Furthermore, we suggest that it is the relationship between l_{p} and L (the width of random medium) that determines the impact of random media on the stochastic radiation transport, which is further corroborated by additional simulations. Most importantly, combining the proposed simple relationship and 1D simulations, we resolve the existing disputable issue of the impact of random media in previous multidimensional works, showing that multidimensional results are essentially consistent and the observed weak or remarkable impact of random media is mainly due to the distinctly different relationship between l_{p} and L. Our results may have practical implications in relevant experiments of stochastic radiative transfer.

Context-enriched interactome powered by proteomics helps the identification of novel regulators of macrophage activation.

The role of pro-inflammatory macrophage activation in cardiovascular disease (CVD) is a complex one amenable to network approaches. While an indispensible tool for elucidating the molecular underpinnings of complex diseases including CVD, the interactome is limited in its utility as it is not specific to any cell type, experimental condition or disease state. We introduced context-specificity to the interactome by combining it with co-abundance networks derived from unbiased proteomics measurements from activated macrophage-like cells. Each macrophage phenotype contributed to certain regions of the interactome. Using a network proximity-based prioritization method on the combined network, we predicted potential regulators of macrophage activation. Prediction performance significantly increased with the addition of co-abundance edges, and the prioritized candidates captured inflammation, immunity and CVD signatures. Integrating the novel network topology with transcriptomics and proteomics revealed top candidate drivers of inflammation. In vitro loss-of-function experiments demonstrated the regulatory role of these proteins in pro-inflammatory signaling.

When human cells or tissues are injured, the body triggers a response known as inflammation to repair the damage and protect itself from further harm. However, if the same issue keeps recurring, the tissues become inflamed for longer periods of time, which may ultimately lead to health problems. This is what could be happening in cardiovascular diseases, where long-term inflammation could damage the heart and blood vessels. Many different proteins interact with each other to control inflammation; gaining an insight into the nature of these interactions could help to pinpoint the role of each molecular actor. Researchers have used a combination of unbiased, large-scale experimental and computational approaches to develop the interactome, a map of the known interactions between all proteins in humans. However, interactions between proteins can change between cell types, or during disease. Here, Halu et al. aimed to refine the human interactome and identify new proteins involved in inflammation, especially in the context of cardiovascular disease. Cells called macrophages produce signals that trigger inflammation whey they detect damage in other cells or tissues. The experiments used a technique called proteomics to measure the amounts of all the proteins in human macrophages. Combining these data with the human interactome made it possible to predict new links between proteins known to have a role in inflammation and other proteins in the interactome. Further analysis using other sets of data from macrophages helped identify two new candidate proteins ­ GBP1 and WARS ­ that may promote inflammation. Halu et al. then used a genetic approach to deactivate the genes and decrease the levels of these two proteins in macrophages, which caused the signals that encourage inflammation to drop. These findings suggest that GBP1 and WARS regulate the activity of macrophages to promote inflammation. The two proteins could therefore be used as drug targets to treat cardiovascular diseases and other disorders linked to inflammation, but further studies will be needed to precisely dissect how GBP1 and WARS work in humans.

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response.

The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two-stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT-PCR analysis (qRT-PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10-19 ). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC.

The clinical value of exhaled nitric oxide in patients with lung cancer.

INTRODUCTION AND OBJECTIVES: To investigate the clinical value of fractional exhaled nitric oxide (FeNO) in lung cancer patients. METHODS: A total of 172 healthy control subjects and 164 patients with histopathologically confirmed lung cancer were enrolled in this study. The FeNO measurements and pulmonary function tests were conducted in the Chinese PLA General Hospital. The recorded data included FeNO, the forced expiratory volume in one second (FEV1 ), the forced vital capacity (FVC), FEV1 /FVC, the FEV1 (% predicted), the demographic characteristics, the presence of complications and the smoking status. RESULTS: The patients with lung cancer had a significantly higher level of eNO than the healthy control subjects (33.85 ± 15.63 ppb, n = 163; 16.83 ± 4.17 ppb, n = 172; P < 0.01). The areas under receiver operating characteristic curves for eNO predicting airway inflammation in lung cancer subjects and healthy control subjects was 0.932 (95% confidence interval: 0.904-0.961). In the lung cancer group, the eNO levels in the squamous cell carcinoma, adenocarcinoma, small-cell lung cancer and lung carcinoid tumor groups were significantly different (P < 0.01). Lung cancer patients with a predicted FEV1 % value <80% had a higher level of eNO than the patients with a predicted FEV1 % value ≥80%. CONCLUSIONS: The eNO levels in patients with lung cancer were higher than the normal level, especially in the patients with squamous cell carcinoma and small-cell lung cancer. The differences in eNO among the lung cancer subtypes were statistically significant. Measuring eNO will be helpful in diagnosing airway inflammation in lung cancer and in the classification of lung cancer.

Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study.

The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (Mpro) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV Mpro significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV Mpro. These novel compounds displayed excellent IC50 data in the range of 0.516-5.954 µM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures.

[HIF-2α/Notch3 pathway mediates CoCl2-induced migration and invasion in human breast cancer MCF-7 cells].

The aim of this study is to investigate the effects of hypoxia inducible factor-2α (HIF-2α) and Notch3 on CoCl2-induced migration and invasion of human breast cancer cell line MCF-7. MCF-7 cells were exposed to normoxia (21% O2) or chemical hypoxia (21% O2 plus CoCl2). Short hairpin RNA (shRNA) was used to knock down HIF-2α and Notch3 in MCF-7 cells. The mRNA expression levels of HIF-2α, Notch3 and Hey1 were measured by RT-PCR. Western blot was performed to determine the protein expression levels of HIF-2α, Notch3, Hey1, Snail and E-cadherin. CoCl2 treatment resulted in higher protein expression levels of HIF-2α, Notch3, Hey1, Snail (P < 0.05) and lower levels of E-cadherin (P < 0.05), and promoted migration and invasion of MCF-7 cells (P < 0.05). shRNA-HIF-2α suppressed CoCl2-induced mRNA expression of Notch3 and Hey1. Notch3 knockdown down-regulated Snail and up-regulated E-cadherin at protein level under simulated hypoxia (P < 0.05), and inhibited CoCl2-induced migration and invasion of MCF-7 cells (P < 0.05). In conclusion, our data provide evidence that HIF-2α may promote the migration and invasion of MCF-7 cells under chemical hypoxic conditions by potentiating Notch3 pathway.

Short term effects of small incision lenticule extraction surgery on corneal endothelium.

AIM: To assess the effects of small incision lenticule extraction (SMILE) surgery on the corneal endothelium at 1d to 1mo postoperatively. METHODS: A retrospective, observational study was conducted on 47 patients (47 eyes) who received SMILE surgery. Patients were grouped according to contact lens wear condition. The corneal endothelium was examined preoperatively and at 1d, 1wk and 1mo postoperatively. The corneal endothelium was analyzed for endothelial cell density (ECD), percentage of hexagonal cells, and coefficient of variation (CV) of cell size. RESULTS: There were no significant decrease in the ECD, percentage of hexagonal cells or increase in CV at 1d, 1wk and 1mo postoperatively (P>0.05). However, there was a small increase of ECD by 2.88% in contact lens wearers (78.26±113.62 cell/mm(2), P<0.05). CONCLUSION: SMILE has no significant adverse effects on the corneal ECD and morphology during 1mo follow-up time.

[Reversal of adriamycin resistance by digoxin in human breast cancer cell line MCF-7/adriamycin and its mechanism].

The aim of this study was to investigate the effects of digoxin on the chemoresistance of human breast cancer cell line MCF-7/adriamycin (ADR) and its underlying mechanism. MCF-7 and MCF-7/ADR cells were designated as control and ADR groups, respectively. MCF-7/ADR cells in ADR + digoxin group received 48 h of digoxin (10 nmol/L) treatment; MCF-7/ADR cells transfected with pLKO.1-shHIF-1α and pLKO.1-shcontrol plasmids were named shHIF-1α and shcontrol groups, respectively. CCK-8 assay was employed to detect the cytotoxic effect of ADR on MCF-7/ADR cells, and IC50 value and resistance index were calculated according to CCK-8. RT-PCR was used to measure the mRNA levels of hypoxia inducible factor-1α (HIF-1α) and multidrug resistance-1 (MDR1). Western blot was used to analyze the protein levels of HIF-1α and MDR1. Flow cytometry was used to determine the apoptosis. The result showed that the resistance index of MCF-7/ADR cells was 115.6, and it was reduced to 47.2 under the action of digoxin (P < 0.05). In comparison with control group, ADR groups showed increased protein and mRNA levels of HIF-1α and MDR1 (P < 0.05). Digoxin reduced the protein levels of HIF-1α and MDR1, as well as the mRNA level of MDR1, but did not affect the mRNA level of HIF-1α. After HIF-1α gene was silenced, the protein levels of HIF-1α and MDR1 were down-regulated (P < 0.05), and the pro-apoptotic effect of ADR on MCF-7/ADR cells was enhanced. Although it was also observed that digoxin promoted cell apoptosis in both shcontrol and shHIF-1α groups, the difference between the two groups was not significant. In conclusion, the results suggest that digoxin may partially reverse the ADR resistance in human breast cancer cell line MCF-7/ADR by means of down-regulating the expression levels of HIF-1α and MDR1 and promoting apoptosis via HIF-1α-independent pathway.

Evaluation of the mandibular split patterns in sagittal split ramus osteotomy.

PURPOSE: To evaluate the split patterns of the mandibular ramus in sagittal split ramus osteotomy (SSRO) using cone-beam computed tomography (CBCT) and examine the related anatomic features that may be associated with these split patterns. PATIENTS AND METHODS: The authors designed and implemented a retrospective cohort study and enrolled a sample composed of consecutive patients with different maxillofacial deformities who underwent an SSRO from July 2011 through October 2012 at the Department of Orthognathic Surgery at the Tianjin Stomatological Hospital of Nankai University. The split patterns, which were selected at random at 1 side per patient, were evaluated by CBCT as the outcome variable 1 month after the operation. The predictor variable was composed of a set of heterogeneous anatomic variables that could be associated with the split patterns. Type I split was defined as a split at the lingual side near the mylohyoid sulcus. Type II split was defined as a split at the posterior border of the mandibular ramus. Appropriate bivariate and regression statistics were computed, and the level of statistical significance was set at a P value less than .05. RESULTS: One hundred thirty patients with different maxillofacial deformities (62 male and 68 female; mean age, 23 yr) underwent an SSRO. Two types of split patterns of the mandibular ramus were observed in SSRO: a split at the lingual side near the mylohyoid sulcus, which occurred in 75.38% of patients, and split at the posterior border region of the mandibular ramus, which occurred in 24.62% of patients. No fracture lines were observed through the mandibular canal. The thickness of the lingual cortical bone between the mandibular canal and the posterior border of the ramus was significantly associated with the split patterns (P < .05). The thickness of the cortical bone in the posterior border of the ramus, the degree of the mandibular angle, and the shapes of the mandibular ramus in the axial plane also were found to influence these split patterns. There was no meaningful association between the split patterns and a patient's age and gender. CONCLUSION: The split patterns of the mandibular ramus during SSRO were influenced by some anatomic features of the mandibular ramus. Therefore, examining the anatomy of the mandible with CBCT before surgery may play an important role in predicting the split patterns of the mandibular ramus during SSRO.

SP600125 reduces lipopolysaccharide-induced apoptosis and restores the early-stage differentiation of osteoblasts inhibited by LPS through the MAPK pathway in MC3T3-E1 cells.

Bone degradation is a serious complication of chronic inflammatory diseases such as septic arthritis, osteomyelitis, and infected orthopedic implant failure. Effective therapeutic treatments for bacteria-caused bone destruction are limited. In a previous study, we found that lipopolysaccharide (LPS) induced osteoblast apoptosis and inhibited early and late-stage differentiation of osteoblasts via activation of the C-Jun N-terminal kinase (JNK) pathway. This study aimed to investigate the effect of JNK inhibition by SP600125 on the apoptosis and differentiation of MC3T3-E1 osteoblasts suppressed by LPS. Following pretreatment with SP600125 for 2 h, MC3T3-E1 cells were treated LPS. Following this treatment, cell viability, activity of alkaline phosphatase (ALP) and caspase-3 were measured. mRNA and protein expression of osteoblast-specific genes, mitogen-activated protein kinases (MAPKs), Bax, Bcl-2 and caspase-3 were determined by quantitative polymerase chain reaction (qPCR) and western blot analysis. The results showed that SP600125 significantly restored LPS-inhibited cell metabolism and ALP activity and reduced the upregulated caspase-3 activity of MC3T3-E1 cells induced by LPS. SP600125 also significantly restored the LPS-suppressed mRNA and protein expression levels of early-stage osteoblast-associated genes in a dose-dependent manner. SP600125 significantly downregulated expression of Bax and caspase-3 but upregulated Bcl-2 expression in MC3T3-E1 cells stimulated by LPS. Furthermore, SP600125 selectively triggered the MAPK pathway by reducing the expression of JNK1, while enhancing the expression of extracellular signal-regulated kinase 1 (ERK1). Our results suggested that SP600125 reduced LPS-induced osteoblast apoptosis and restored early-stage differentiation of osteoblasts inhibited by LPS through MAPK signaling. These findings suggest that the therapeutic agent that inhibited JNK1 is of potential use for the restoration of osteoblast function in bacteria-induced bone diseases.

RTN4 3'-UTR insertion/deletion polymorphism and susceptibility to non-small cell lung cancer in Chinese Han population.

Nogo protein, encoded by gene reticulon-4 (RTN4), includes three major isoforms by different splicing, named Nogo-A Nogo-B and Nogo-C. Nogo proteins play an important role in the apoptosis of cells, especially in tumor cells. RTN4 single nucleotide polymorphisms (SNPs) can influence the efficiency of transcription and translation thus being related with an individual's predisposition to cancer. The CAA insertion/deletion polymorphism (rs34917480) within RTN4 3'-UTR has been reported to be associated with many cancer types. In order to investigate the relationship between this polymorphism and susceptibility to non-small cell lung cancer (NSCLC) in the Chinese population, we conducted the present case-control study including 411 NSCLC patients and 471 unrelated healthy controls. The genotype distributions were significantly different between cases and controls (p=0.014). We found that the del allele could significantly increase NSCLC risk (ins/ins vs ins/del: p=0.007, OR 1.46, 95%CI=1.11-1.93; dominant model: p=0.004, OR 1.47, 95%CI=1.13-1.92 and allele model: p=0.008, OR 1.35, 95%CI=1.08-1.67). This association was stronger in participants over 60 years old, males and smokers. We therefore conclude that the CAA insertion/deletion polymorphism (rs34917480) contributes to non-small cell lung cancer risk in Chinese population. Age, sex and environmental exposure are also related to carcinogenic effects of rs34917480.

Antiviral activity of an isatin derivative via induction of PERK-Nrf2-mediated suppression of cap-independent translation.

We report here an isatin derivative 45 (ID45) against coxsackievirus B3 (CVB3) replication, which was synthesized based on a high-throughput screen of a unique natural product library. ID45 showed the most potent anti-CVB3 activity among the four synthesized compounds. Treatment of cells with ID45 before or after infection significantly reduced viral particle formation, resulting in protection of cells from virus-induced apoptosis. In addition, ID45 treatment caused remarkable up-regulation of glucose-regulated protein 78 (GRP78), a hallmark of endoplasmic reticulum (ER) stress and an indicator of enhanced cell viability. In identifying the ER stress response pathway induced by ID45, we found that ID45 activated PKR-like ER protein kinase (PERK) but failed to up-regulate eIF2α phosphorylation. Instead ID45 activated transcription factor Nrf2 (NF-E2-related factor-2), which is evidenced by its nuclear translocation and upregulation of its downstream target genes NQO1 (NAD(P)H quinone-oxidoreductase 1) and GCLM (glutamate-cysteine ligase, modifier subunit). This observation was further verified by using siRNAs of GRP78 or Nrf2, which blocked both the translocation of Nrf2 and up-regulation of its target genes, leading to aggressive viral replication and enhanced cell apoptosis. Finally, we found that ID45-induced up-regulation of NQO1 protected eIF4GI, a eukaryotic cap-dependent translation initiation factor, from cleavage by CVB3 protease and degradation by proteasomes. Taken together, our findings established that a novel antiviral mechanism of isatin derivative ID45 inhibits CVB3 replication by promoting cell survival through a PERK/Nrf2-dependent ER stress pathway, which benefits host cap-dependent translation but suppresses CVB3 cap-independent translation.

Lipopolysaccharide (LPS) induces the apoptosis and inhibits osteoblast differentiation through JNK pathway in MC3T3-E1 cells.

Bone degradation is a serious complication of chronic inflammatory diseases such as septic arthritis, osteomyelitis, and infected orthopedic implant failure. Up to date, effective therapeutic treatments for bacteria-caused bone destruction are limited. In our previous study, we found that LPS promoted osteoclast differentiation and activity through activation of mitogen-activated protein kinases (MAPKs) pathway such as c-Jun N-terminal kinases (JNK) and extracellular signal regulated kinase (ERK1/2). The current study was to evaluate the mechanism of LPS on the apoptosis and osteoblast differentiation in MC3T3-E1 cells. MC3T3-E1 osteoblasts were non-treated, treated with LPS. After treatment, the cell viability, the activity of alkaline phosphatase (ALP) and caspase-3 were measured. The expressions of osteoblast-specific genes and Bax, Bcl-2, and caspase-3 were determined by real-time quantitative polymerase chain reaction (qPCR). Protein levels of Bax, Bcl-2, caspase-3, and phosphorylation of MAPKs were measured using Western blotting assays. The MAPK signaling pathway was blocked by pretreatment with JNK inhibitor SP600125. LPS treatment induced a significant decrease in cell metabolism, viability, and ALP activity in MC3T3-E1 cells. LPS also significantly decreased mRNA expressions of osteoblast-related genes in MC3T3-E1 cells. On the other hand, LPS significantly upregulated mRNA expressions and protein levels of Bax and caspase-3 as well as activation of caspase-3, whereas decreased Bcl-2 expression in MC3T3-E1 cells. Furthermore, LPS significantly promoted MAPK pathway including the phosphorylation of JNK and the phosphorylation of ERK1/2; moreover, pretreatment with JNK inhibitor not only attenuated both of phosphorylation-JNK and ERK1/2 enhanced by LPS in MC3T3-E1 cells, but also reversed the downregulated expressions of osteoblast-specific genes including ALP and BSP induced by LPS. In conclusion, LPS could induce osteoblast apoptosis and inhibit osteoblast differentiation via activation of JNK pathway.

Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers.

BACKGROUND: Tissue factor (TF), the physiologic initiator of coagulation, is over-expressed in pancreatic cancer, and is associated with a pro-coagulant and pro-angiogenic state. We hypothesized that in patients with pancreaticobiliary cancers (PBC), elevated circulating microparticle-associated TF (MP-TF) activity would be associated with thrombosis and worsened survival. PATIENTS AND METHODS: Clinical data and plasma were obtained for consecutive patients with PBC seen at Roswell Park Cancer Institute from 2005-08. MP-TF activity levels were measured using a TF-dependent FXa generation assay. RESULTS: The study population comprised 117 patients, including pancreatic (n=80), biliary (n=34) or unknown primary histologically consistent with PBC (n=3). Of these, 52 patients (44.5%) experienced thromboembolism, including pulmonary embolism (n=15), deep venous thrombosis (n=21) and other arterial or venous events (n=32). Mean TF was 2.15 (range 0.17- 31.01) pg/mL. Median survival was 98.5 days for MP-TF activity ≥ 2.5 pg/mL versus 231 days for MP-TF activity<2.5 pg/mL (p<0.0001). In multivariate analysis, elevated MP-TF activity was associated with both VTE (OR 1.4, 95% CI 1.1-1.6) and mortality (HR 2.5, 95% CI 1.4-4.5). CONCLUSIONS: Elevated circulating MP-TF activity is associated with thrombosis and worsened survival in patients with PBC. MP-TF activity as a prognostic biomarker warrants further prospective evaluation.