AIM:To evaluate the clinical value of diffusion-weighted magnetic resonance imaging(DW-MRI)in predicting the response of rectal cancer to neoadjuvant chemoradiation.METHODS:This prospective study was approved by our i...AIM:To evaluate the clinical value of diffusion-weighted magnetic resonance imaging(DW-MRI)in predicting the response of rectal cancer to neoadjuvant chemoradiation.METHODS:This prospective study was approved by our institutional review board,and informed consent was obtained from each patient.Fifteen patients(median age 56 years)with locally advanced rectal cancer were treated in our hospital from June 2006 to December 2007.All patients were stageⅢB-C according to the results of MRI and endorectal ultrasound examinations.All patients underwent pelvic irradiation with 45 Gy/25 fx per 35 days.The concurrent chemotherapy regimen consisted of capecitabine 625mg/m2,bid(Monday-Friday),and oxaliplatin 50 mg/m2,weekly.The patients underwent surgery 5-8 wk after the completion of neoadjuvant therapy.T downstaging was defined as the downstaging of the tumor from cT3to ypT0-2 or from cT4 to ypT0-3.Good regression was defined as TRG 3-4,and poor regression was defined as TRG 0-2.Diffusion-weighted magnetic resonance images were obtained prior to and weekly during the course of neoadjuvant chemoradiation,and the apparent diffusion coefficient(ADC)values were calculated from the acquired tumor images.RESULTS:Comparison with the mean pretreatment tumor ADC revealed an increase in the mean tumor ADC during the course of neoadjuvant chemoradiation,especially at the 2ndweek(P=0.004).We found a strong negative correlation between the mean pretreatment tumor ADC and tumor regression after neoadjuvant chemoradiation(P=0.021).In the T downstage and tumor regression groups,we found a significant increase in the mean ADC at the 2ndweek of neoadjuvant therapy(P=0.011;0.004).CONCLUSION:DW-MRI might be a valuable clinical tool to help predict or assess the response of rectal cancer to neoadjuvant chemoradiation at an early timepoint.展开更多
Objective: The aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy(NAC) using oxaliplatin plus capecitabine(Cap OX) for patients with operable loc...Objective: The aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy(NAC) using oxaliplatin plus capecitabine(Cap OX) for patients with operable locally advanced colon cancer(CC).Methods: Patients with computed tomography-defined T4 or lymph node-positive CCs were enrolled. After radiological staging, patients were treated with at least 2 cycles of NAC consisting of 130 mg/m2 oxaliplatin on d 1,plus 1,000 mg/m2 capecitabine twice daily for 14 d every 3 weeks, followed by surgery, and then with the rest cycles of adjuvant chemotherapy. Radiological response was evaluated after 2 cycles of NAC. Tumor response, treatment toxicity, and surgical complications were recorded. The pathological response to therapy was evaluated according to the tumor regression grade(TRG) score. The primary endpoint was pathologic tumor response. This trial is registered in Clinical Trials.gov(No: NCT02415829).Results: Forty-seven patients were enrolled in the study. Forty-two patients completed the planned treatments.The total radiological response rate was 68%(32/47), including complete and partial response rates of 2%(1/47)and 66%(31/47), respectively. Stable disease was observed in 32%(15/47) and progressive disease was observed in none. Complete pathologic response, major regression, and at least moderate regression were achieved in 1(2%), 2(4%), and 29(62%) patients, respectively. Four patients developed grade 3 treatment toxicities. One patient with wound infection occurred after operation(1/47, 2%). There was no treatment-related death.Conclusions: Our results suggest that NAC with Cap OX is an effective and safe treatment option for patients with locally advanced CCs.展开更多
Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulat...Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (, was/+ mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.展开更多
Spinal cord injury(SCI)-induced bone loss represents the most severe osteoporosis with no effective treatment.Past animal studies have focused primarily on long bones at the acute stage using adolescent rodents. To ...Spinal cord injury(SCI)-induced bone loss represents the most severe osteoporosis with no effective treatment.Past animal studies have focused primarily on long bones at the acute stage using adolescent rodents. To mimic chronic SCI in human patients, we performed a comprehensive analysis of long-term structural and mechanical changes in axial and appendicular bones in adult rats after SCI. In this experiment, 4-month-old Fischer 344 male rats received a clinically relevant T13 contusion injury. Sixteen weeks later, sublesional femurs, tibiae,and L4 vertebrae, supralesional humeri, and blood were collected from these rats and additional non-surgery rats for micro-computed tomography(m CT), micro-finite element, histology, and serum biochemical analyses.At trabecular sites, extreme losses of bone structure and mechanical competence were detected in the metaphysis of sublesional long bones after SCI, while the subchondral part of the same bones showed much milder damage. Marked reductions in bone mass and strength were also observed in sublesional L4 vertebrae but not in supralesional humeri. At cortical sites, SCI induced structural and strength damage in both sub- and supralesional long bones. These changes were accompanied by diminished osteoblast number and activity and increased osteoclast number and activity. Taken together, our study revealed site-specific effects of SCI on bone and demonstrated sustained inhibition of bone formation and elevation of bone resorption at the chronic stage of SCI.展开更多
Non-smallcell lung cancer(NSCLC)cells intake and consume glucose at high efficiency by aerobic glycolysis to maintain robust cell growth and resist cell death.MicroRNAs(miRNAs)have been known to play pivotal roles in ...Non-smallcell lung cancer(NSCLC)cells intake and consume glucose at high efficiency by aerobic glycolysis to maintain robust cell growth and resist cell death.MicroRNAs(miRNAs)have been known to play pivotal roles in NSCLC development partly through mediating glycolysis.However,only a few miRNAs have been experimentally confirmed as critical regulators of glycolysis in NSCLC.TCGA datasets were analyzed to screen for differentially expressed miRNAs between NSCLC and normal tissues.The function of miR-1294-5p was determined in NSCLC cells by cell proliferation,glucose uptake,lactate release,and Extracellular Acidification Rate(ECAR)assays.The target of miR-1294-5p was predicted by TargetScan and miRDB,which was further validated by flow cytometry analysis,RT-qPCR,western blotting,a dual-luciferase reporter assay,and RNA immunoprecipitation(RIP)assay.In the present study,it was found that miR-1294-5p was a significantly downregulated miRNA in lung adenocarcinoma(LUAD)and lung squamous cell carcinoma(LUSC).The overexpression of miR-1294-5p inhibited glycolysis,lactate export,ECAR,and cell proliferation in NSCLC cells.Analysis with bioinformatic tools,Western Blotting,RT-qPCR,flow cytometry analysis,dual-luciferase reporter assay,and RIP assay showed that miR-1294-5p directly bound to complementary sites in the 3’-Untranslated Region(UTR)of TMPRSS11B resulted in downregulation of TMPRSS11B expression.In addition,transfection of recombinant TMPRSS11B rescued the functions of miR-1294-5p on glycolysis and proliferation of NSCLC cells.The findings provided novel insights for understanding the regulation of glycolytic metabolism in NSCLC.展开更多
Objective The aim of this study was to evaluate the impact of serum carcinoembryonic antigen(CEA)in the prediction of pathological complete response(pCR)in locally advanced rectal cancer(LARC)patients treated with neo...Objective The aim of this study was to evaluate the impact of serum carcinoembryonic antigen(CEA)in the prediction of pathological complete response(pCR)in locally advanced rectal cancer(LARC)patients treated with neoadjuvant chemoradiotherapy(nCRT).Methods A total of 925 LARC patients who underwent nCRT followed by TME between March 2006 and February 2018 were enrolled at Fudan University Shanghai Cancer Center.Using logistic regression models,we investigated the associations between serum CEA levels and pathological complete remission(pCR).Further stratified analyses were performed according to different CEA thresholds.Results We found that pre-nCRT CEA and post-nCRT CEA were negatively correlated with pCR(P<0.001).Stratified analyses revealed that when the CEA cutoff value was set to 5 ng/mL,10.6%of patients with post-nCRT CEA levels>5 ng/mL achieved pCR.Meanwhile,when the CEA cutoff value was set to 10 ng/mL,only 6.8%of the patients with post-nCRT CEA levels>10 ng/mL achieved pCR.Conclusion In summary,pre and post-nCRT CEA levels≤5 ng/mL were favorable predictors of pCR in LACR patients,and the“watch and wait”strategy is not recommended for patients with post-nCRT CEA levels>10 ng/mL.展开更多
This study evaluated the effects of flavonoids from mulberry leaves(FML)on plasma biochemical indices,serum activities of lipid metabolism-related enzymes,fat morphology,fatty acid composition,and lipid metabolism in ...This study evaluated the effects of flavonoids from mulberry leaves(FML)on plasma biochemical indices,serum activities of lipid metabolism-related enzymes,fat morphology,fatty acid composition,and lipid metabolism in different adipose tissues of finishing pigs.We used 120 Chinese hybrid barrows of Berkshire and Bama mini-pigs with an average initial body weight of 45.11±4.23 kg.The pigs were randomly assigned to five treatment groups and fed a control diet based on corn,soybean meal,and wheat bran or a control diet supplemented with 0.02%,0.04%,0.08%,or 0.16%FML.Each experimental group had six replicates(pens),with four pigs per pen.After a 7-d adaptation period,the feeding trial was conducted for 58 d.Blood and adipose tissue samples were collected from 30 pigs(one pig per pen)at the end of the test.The results showed that FML supplementation significantly decreased the feed intake to body gain ratio,the plasma concentrations of total cholesterol and free fatty acids,and the serum activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase(linear or quadratic effects,P<0.05),and decreased the plasma triglyceride concentration(quadratic,P=0.07).Increasing FML supplementation increased the average daily gain and serum activities of lipoprotein lipase(linear and quadratic effects,P<0.05)and adipose triglyceride lipase(linear,P<0.05).Dietary FML supplementation decreased the adipocyte area in the dorsal subcutaneous adipose(DSA)tissue of finishing pigs(linear,P=0.05)and increased the adipocyte area in the visceral adipose tissue(quadratic,P<0.01).Increasing FML supplementation decreased the C20:1 content in DSA,abdominal subcutaneous adipose,and visceral adipose tissues of finishing pigs(P<0.05)and increased the C18:3n3 and n-3 PUFA contents(P<0.05).The lipid metabolism genes were regulated by the PPARγ-LXRa-ABCA1 signaling pathway,and their expressions differed in different adipose tissues.These findings suggest that FML improved growth performance,regulated lipid metabolism,inhibited fat production,and improved fatty acid distribution in the adipose tissue of finishing pigs,thereby improving pig fat's nutritional quality and health value.展开更多
Purpose Colorectal cancer is a common malignant tumor worldwide.In China,the ratio of rectal cancer to coloncancer in terms of incidence is close to 1:1.Low rectal cancer accounts for more than half of all cases of re...Purpose Colorectal cancer is a common malignant tumor worldwide.In China,the ratio of rectal cancer to coloncancer in terms of incidence is close to 1:1.Low rectal cancer accounts for more than half of all cases of rectal cancer.In recent years,the proportion of rectal cancer has trended downward,however the incidence of rectal cancer inyounger adults is increasing.The CACA Guidelines for Holistic Integrative Management of Rectal Cancer were editedto help improve the diagnosis and comprehensive treatment in China.Methods This guideline has been prepared by consensuses reached by the CACA Committee of Colorectal CancerSociety,based on a careful review of the latest evidence including China’s studies,and referred to domestic and internationalrelative guidelines,also considered China’s specific national conditions and clinical practice.Results The CACA Guidelines for Holistic Integrative Management of Rectal Cancer include the epidemiology of rectalcancer,prevention and screening,diagnosis,treatment of nonmetastatic and metastatic rectal cancer,follow-up,and whole-course rehabilitation management.Conclusion Committee of Colorectal Cancer Society,Chinese Anti-Cancer Association,standardizes the diagnosisand treatment of rectal cancer in China through the formulation of the CACA Guidelines.展开更多
Inflammation and lung function decline are the main pathophysiological features of chronic obstructive pulmonary disease (COPD). Acupuncture can improve lung function in patients with COPD, but the underlying mechan...Inflammation and lung function decline are the main pathophysiological features of chronic obstructive pulmonary disease (COPD). Acupuncture can improve lung function in patients with COPD, but the underlying mechanisms are not well understood. Orexins (OXs), which are found in peripheral plasma, are neuropeptides that regulate respiration and their levels are related to COPD. Therefore, we hypothesized that acupuncture might alter OXs, reduce lung inflammation and improve lung function in COPD. METHODS: COPD was induced in rats by exposure to cigarette smoke for 8 weeks and injecting with lipopolysaccharide twice. Electroacupuncture (EA) was performed at Feishu (BL13) and Zusanli (ST36) for 30 min/d for 2 weeks. Rat lung function and morphology were assessed after EA. The levels of tumor necrosis factor-α (TNF-a) and intedeukin-1β (IL-16) in bronchoalveolar lavage fluid (BALF) and orexin A and B levels in the lung tissue were detected by enzyme-linked immunosorbent assay. OX receptor mRNA levels and immunopositive cells were assessed with real-time polymerase chain reaction and immunohistochemical methods, respectively. The relationships among lung function, cell factors, and OX levels were analyzed by Pearson correlation analyses. RESULTS: Compared with the control group, lung function was significantly decreased in the rats with COPD (P〈0.05). There were obvious increases in TNF-α and IL-1β levels in BALF (P〈0.05 and P〈0.01, respectively), orexin A level in lung tissue (P〈0.01; but not orexin B) and mRNA expressions of OX 1 type receptor (OXR1) and OX 2 type receptor (OXR2) in lung tissue (P〈0.05 and P〈0.01, respectively); the integrative optical densities (IODs) of both receptors were greater in the COPD group (P〈0.05). For rats with COPD subjected to EA, lung function was improved (P〈0.05). There were notable decreases in TNF-a and IL-1β levels (P〈0.05 and 〈0.01, respectively) in BALF. Orexin A, but not orexin B, levels in lung tissue also decreased (P〈0.01), as did mRNA expression of OXlR and OX2R in lung tissue (P〈0.05 and P〈0.01, respectively). Receptor IODs were also reduced after EA treatment (P〈0.05). Furthermore, orexin A levels and ratio of forced expiratory volume in 0.3 s to forced vital capacity were strongly negatively correlated (P〈0.01), and orexin A was positively correlated with TNF-α and IL-1β (P〈0.001 and P〈0.05, respectively).CONCLUSION: EA at Zusanli and Feishu improved lung function of rats with COPD and had an anti-inflammatory effect, which may be related to down-regulation of OXA and its receptors.展开更多
A series of fluorescent siloxane-polyurethanes(HPMS-PUs) containing an amino-functionalized,1 8-naphthalimide,fluorescent monomer(AABD) as a chain extender were synthesized.The properties of the HPMS-PUs were inve...A series of fluorescent siloxane-polyurethanes(HPMS-PUs) containing an amino-functionalized,1 8-naphthalimide,fluorescent monomer(AABD) as a chain extender were synthesized.The properties of the HPMS-PUs were investigated by UV–vis and fluorescence spectroscopies,thermogravimetric analysis and thermal migration behavior.The maximum absorption and emission wavelengths of HPMS-PUs showed a red shift of about 4 nm and a blue shift of about 9 nm,respectively,compared to those of AABD.The Stokes shifts of AABD and HPMS-PU2 were 3514 and 2931 cm 1,respectively.The quantum yield of HPMS-PU2 was 0.79,which was six times higher than that of AABD.Concentration self-quenching was observed in both AABD and HPMS-PUs.The fluorescence of HPMS-PUs was quite stable with respect to both temperature and fluorescence quencher effects.The thermal stability of HPMS-PUs increased with AABD content.The fluorophore units in the HPMS-PUs did not readily migrate.展开更多
Super-enhancers(SEs) are regulatory elements with enriched accumulation of key transcription factors.Few studies were done investigating SEs in lung cancers.Here we analyzed epigenetic profiling data to identify SEs i...Super-enhancers(SEs) are regulatory elements with enriched accumulation of key transcription factors.Few studies were done investigating SEs in lung cancers.Here we analyzed epigenetic profiling data to identify SEs in lung cancer cell lines.Enhancers were classified as SEs and typical enhancers(TEs).Most of the TEs were overlapped between normal cell and cancer cells.A great portion of SEs were differentiated comparing these cells.Analysis of GO terms associated with SEs revealed SE remodeling(lost on some sites while gain on others) between normal and lung cancer cells.By comparing the average number of SEs in each GO term in cancer cells with the number in control cells,surprisingly,no GO terms with significantly increased SE number in cancer condition were observed.On the contrary,in aspects such as "cell-cell adhesion","receptor activity" and"negative regulation of canonical Wnt signaling pathway",the related SEs were significantly reduced in cancer cells.These findings suggest that in lung cancer,cells may not gain decisive gene expression in the related aspect,instead,they may have lost control of the fateful genes.Taken together,our work with the usability of omics data identified SEs in lung cancer cells and further showed cancer-specific features of SE-related terms.展开更多
The problem of estimating high-dimensional Gaussian graphical models has gained much attention in recent years. Most existing methods can be considered as one-step approaches, being either regression-based or likeliho...The problem of estimating high-dimensional Gaussian graphical models has gained much attention in recent years. Most existing methods can be considered as one-step approaches, being either regression-based or likelihood-based. In this paper, we propose a two-step method for estimating the high-dimensional Gaussian graphical model. Specifically, the first step serves as a screening step, in which many entries of the concentration matrix are identified as zeros and thus removed from further consideration. Then in the second step, we focus on the remaining entries of the concentration matrix and perform selection and estimation for nonzero entries of the concentration matrix. Since the dimension of the parameter space is effectively reduced by the screening step,the estimation accuracy of the estimated concentration matrix can be potentially improved. We show that the proposed method enjoys desirable asymptotic properties. Numerical comparisons of the proposed method with several existing methods indicate that the proposed method works well. We also apply the proposed method to a breast cancer microarray data set and obtain some biologically meaningful results.展开更多
Exposure to fine ambient particulate matter(PM_(2.5)) is known to be associated with cardiovascular disease. To uncover the molecular mechanisms involved in cardiovascular toxicity of PM_(2.5), we investigated alterat...Exposure to fine ambient particulate matter(PM_(2.5)) is known to be associated with cardiovascular disease. To uncover the molecular mechanisms involved in cardiovascular toxicity of PM_(2.5), we investigated alterations in the protein profile of human umbilical vein endothelial cells(HUVECs) treated with PM_(2.5) using two-dimensional electrophoresis in conjunction with mass spectrometry(MS). A total of 31 protein spots were selected as differentially expressed proteins and identified by matrix-assisted laser desorption/ionization-time of flight(MALDI-TOF) MS. The results demonstrated that DNA damage and cell apoptosis are important factors contributing to PM_(2.5)-mediated toxicity in HUVECs. It is further proposed that PM_(2.5) can inhibit superoxide dismutase(SOD) activity and increase reactive oxygen species(ROS) and malonaldehyde(MDA) production in a concentration-dependent manner. Induction of apoptosis and DNA damage through oxidative stress pathways may be one of the key toxicological events occurring in HUVECs under PM_(2.5) stress. These results indicated that the toxic mechanisms of PM_(2.5) on cardiovascular disease are related to endothelial dysfunction.展开更多
The chromate industry in China has de-veloped rapidly since 2000.China pro-duced 150 000 tons of chromates (based on sodium bichromate) in 2000 and be-came the biggest chromate producing country worldwide.The output i...The chromate industry in China has de-veloped rapidly since 2000.China pro-duced 150 000 tons of chromates (based on sodium bichromate) in 2000 and be-came the biggest chromate producing country worldwide.The output increased to 270 000 tons in 2005 and went further up to approximately 300 000 tons in 2006 and 2007,accounting for around one third of the world total.展开更多
文摘AIM:To evaluate the clinical value of diffusion-weighted magnetic resonance imaging(DW-MRI)in predicting the response of rectal cancer to neoadjuvant chemoradiation.METHODS:This prospective study was approved by our institutional review board,and informed consent was obtained from each patient.Fifteen patients(median age 56 years)with locally advanced rectal cancer were treated in our hospital from June 2006 to December 2007.All patients were stageⅢB-C according to the results of MRI and endorectal ultrasound examinations.All patients underwent pelvic irradiation with 45 Gy/25 fx per 35 days.The concurrent chemotherapy regimen consisted of capecitabine 625mg/m2,bid(Monday-Friday),and oxaliplatin 50 mg/m2,weekly.The patients underwent surgery 5-8 wk after the completion of neoadjuvant therapy.T downstaging was defined as the downstaging of the tumor from cT3to ypT0-2 or from cT4 to ypT0-3.Good regression was defined as TRG 3-4,and poor regression was defined as TRG 0-2.Diffusion-weighted magnetic resonance images were obtained prior to and weekly during the course of neoadjuvant chemoradiation,and the apparent diffusion coefficient(ADC)values were calculated from the acquired tumor images.RESULTS:Comparison with the mean pretreatment tumor ADC revealed an increase in the mean tumor ADC during the course of neoadjuvant chemoradiation,especially at the 2ndweek(P=0.004).We found a strong negative correlation between the mean pretreatment tumor ADC and tumor regression after neoadjuvant chemoradiation(P=0.021).In the T downstage and tumor regression groups,we found a significant increase in the mean ADC at the 2ndweek of neoadjuvant therapy(P=0.011;0.004).CONCLUSION:DW-MRI might be a valuable clinical tool to help predict or assess the response of rectal cancer to neoadjuvant chemoradiation at an early timepoint.
基金supported by grants from the National Natural Science Foundation of China (Grant No. 81472620)Shanghai Science and Technology Planning Fund (No. 13140902100)+1 种基金Shanghai Combination Study Project for Major Diseases (No. 2014ZYJB0101)Shanghai Health and Family Planning Commission (No. JGY1404)
文摘Objective: The aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy(NAC) using oxaliplatin plus capecitabine(Cap OX) for patients with operable locally advanced colon cancer(CC).Methods: Patients with computed tomography-defined T4 or lymph node-positive CCs were enrolled. After radiological staging, patients were treated with at least 2 cycles of NAC consisting of 130 mg/m2 oxaliplatin on d 1,plus 1,000 mg/m2 capecitabine twice daily for 14 d every 3 weeks, followed by surgery, and then with the rest cycles of adjuvant chemotherapy. Radiological response was evaluated after 2 cycles of NAC. Tumor response, treatment toxicity, and surgical complications were recorded. The pathological response to therapy was evaluated according to the tumor regression grade(TRG) score. The primary endpoint was pathologic tumor response. This trial is registered in Clinical Trials.gov(No: NCT02415829).Results: Forty-seven patients were enrolled in the study. Forty-two patients completed the planned treatments.The total radiological response rate was 68%(32/47), including complete and partial response rates of 2%(1/47)and 66%(31/47), respectively. Stable disease was observed in 32%(15/47) and progressive disease was observed in none. Complete pathologic response, major regression, and at least moderate regression were achieved in 1(2%), 2(4%), and 29(62%) patients, respectively. Four patients developed grade 3 treatment toxicities. One patient with wound infection occurred after operation(1/47, 2%). There was no treatment-related death.Conclusions: Our results suggest that NAC with Cap OX is an effective and safe treatment option for patients with locally advanced CCs.
基金supported by ASBMR Research Career Enhancement Award (to LQ)NIH grants AR060991 (to LQ)AR062908 (to ME-I)
文摘Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (, was/+ mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.
基金supported by the National Institutes of Health(R01DK095803 to LQ, 1K08HD049598 to YZ)Penn Center for Musculoskeletal Disorders P30AR050950(NIAMS/NIH)+1 种基金ASBMR Junior Faculty Osteoporosis Basic Research Award(to LQ)NIH/NIAMS R03-AR065145(to XSL)
文摘Spinal cord injury(SCI)-induced bone loss represents the most severe osteoporosis with no effective treatment.Past animal studies have focused primarily on long bones at the acute stage using adolescent rodents. To mimic chronic SCI in human patients, we performed a comprehensive analysis of long-term structural and mechanical changes in axial and appendicular bones in adult rats after SCI. In this experiment, 4-month-old Fischer 344 male rats received a clinically relevant T13 contusion injury. Sixteen weeks later, sublesional femurs, tibiae,and L4 vertebrae, supralesional humeri, and blood were collected from these rats and additional non-surgery rats for micro-computed tomography(m CT), micro-finite element, histology, and serum biochemical analyses.At trabecular sites, extreme losses of bone structure and mechanical competence were detected in the metaphysis of sublesional long bones after SCI, while the subchondral part of the same bones showed much milder damage. Marked reductions in bone mass and strength were also observed in sublesional L4 vertebrae but not in supralesional humeri. At cortical sites, SCI induced structural and strength damage in both sub- and supralesional long bones. These changes were accompanied by diminished osteoblast number and activity and increased osteoclast number and activity. Taken together, our study revealed site-specific effects of SCI on bone and demonstrated sustained inhibition of bone formation and elevation of bone resorption at the chronic stage of SCI.
文摘Non-smallcell lung cancer(NSCLC)cells intake and consume glucose at high efficiency by aerobic glycolysis to maintain robust cell growth and resist cell death.MicroRNAs(miRNAs)have been known to play pivotal roles in NSCLC development partly through mediating glycolysis.However,only a few miRNAs have been experimentally confirmed as critical regulators of glycolysis in NSCLC.TCGA datasets were analyzed to screen for differentially expressed miRNAs between NSCLC and normal tissues.The function of miR-1294-5p was determined in NSCLC cells by cell proliferation,glucose uptake,lactate release,and Extracellular Acidification Rate(ECAR)assays.The target of miR-1294-5p was predicted by TargetScan and miRDB,which was further validated by flow cytometry analysis,RT-qPCR,western blotting,a dual-luciferase reporter assay,and RNA immunoprecipitation(RIP)assay.In the present study,it was found that miR-1294-5p was a significantly downregulated miRNA in lung adenocarcinoma(LUAD)and lung squamous cell carcinoma(LUSC).The overexpression of miR-1294-5p inhibited glycolysis,lactate export,ECAR,and cell proliferation in NSCLC cells.Analysis with bioinformatic tools,Western Blotting,RT-qPCR,flow cytometry analysis,dual-luciferase reporter assay,and RIP assay showed that miR-1294-5p directly bound to complementary sites in the 3’-Untranslated Region(UTR)of TMPRSS11B resulted in downregulation of TMPRSS11B expression.In addition,transfection of recombinant TMPRSS11B rescued the functions of miR-1294-5p on glycolysis and proliferation of NSCLC cells.The findings provided novel insights for understanding the regulation of glycolytic metabolism in NSCLC.
基金Supported by a grant from the Scientific research project of Nantong Municipal Health Commission(No.QA2019049)。
文摘Objective The aim of this study was to evaluate the impact of serum carcinoembryonic antigen(CEA)in the prediction of pathological complete response(pCR)in locally advanced rectal cancer(LARC)patients treated with neoadjuvant chemoradiotherapy(nCRT).Methods A total of 925 LARC patients who underwent nCRT followed by TME between March 2006 and February 2018 were enrolled at Fudan University Shanghai Cancer Center.Using logistic regression models,we investigated the associations between serum CEA levels and pathological complete remission(pCR).Further stratified analyses were performed according to different CEA thresholds.Results We found that pre-nCRT CEA and post-nCRT CEA were negatively correlated with pCR(P<0.001).Stratified analyses revealed that when the CEA cutoff value was set to 5 ng/mL,10.6%of patients with post-nCRT CEA levels>5 ng/mL achieved pCR.Meanwhile,when the CEA cutoff value was set to 10 ng/mL,only 6.8%of the patients with post-nCRT CEA levels>10 ng/mL achieved pCR.Conclusion In summary,pre and post-nCRT CEA levels≤5 ng/mL were favorable predictors of pCR in LACR patients,and the“watch and wait”strategy is not recommended for patients with post-nCRT CEA levels>10 ng/mL.
基金supported by the Hunan Province Key R&D Program Project(2020NK2033)Natural Science Foundation of Hunan Province(2022JJ30317)+1 种基金Innovation Platform and Talent Plan Program of Hunan Province(2022NK4145)National Natural Science Foundation of China(31972600)
文摘This study evaluated the effects of flavonoids from mulberry leaves(FML)on plasma biochemical indices,serum activities of lipid metabolism-related enzymes,fat morphology,fatty acid composition,and lipid metabolism in different adipose tissues of finishing pigs.We used 120 Chinese hybrid barrows of Berkshire and Bama mini-pigs with an average initial body weight of 45.11±4.23 kg.The pigs were randomly assigned to five treatment groups and fed a control diet based on corn,soybean meal,and wheat bran or a control diet supplemented with 0.02%,0.04%,0.08%,or 0.16%FML.Each experimental group had six replicates(pens),with four pigs per pen.After a 7-d adaptation period,the feeding trial was conducted for 58 d.Blood and adipose tissue samples were collected from 30 pigs(one pig per pen)at the end of the test.The results showed that FML supplementation significantly decreased the feed intake to body gain ratio,the plasma concentrations of total cholesterol and free fatty acids,and the serum activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase(linear or quadratic effects,P<0.05),and decreased the plasma triglyceride concentration(quadratic,P=0.07).Increasing FML supplementation increased the average daily gain and serum activities of lipoprotein lipase(linear and quadratic effects,P<0.05)and adipose triglyceride lipase(linear,P<0.05).Dietary FML supplementation decreased the adipocyte area in the dorsal subcutaneous adipose(DSA)tissue of finishing pigs(linear,P=0.05)and increased the adipocyte area in the visceral adipose tissue(quadratic,P<0.01).Increasing FML supplementation decreased the C20:1 content in DSA,abdominal subcutaneous adipose,and visceral adipose tissues of finishing pigs(P<0.05)and increased the C18:3n3 and n-3 PUFA contents(P<0.05).The lipid metabolism genes were regulated by the PPARγ-LXRa-ABCA1 signaling pathway,and their expressions differed in different adipose tissues.These findings suggest that FML improved growth performance,regulated lipid metabolism,inhibited fat production,and improved fatty acid distribution in the adipose tissue of finishing pigs,thereby improving pig fat's nutritional quality and health value.
文摘Purpose Colorectal cancer is a common malignant tumor worldwide.In China,the ratio of rectal cancer to coloncancer in terms of incidence is close to 1:1.Low rectal cancer accounts for more than half of all cases of rectal cancer.In recent years,the proportion of rectal cancer has trended downward,however the incidence of rectal cancer inyounger adults is increasing.The CACA Guidelines for Holistic Integrative Management of Rectal Cancer were editedto help improve the diagnosis and comprehensive treatment in China.Methods This guideline has been prepared by consensuses reached by the CACA Committee of Colorectal CancerSociety,based on a careful review of the latest evidence including China’s studies,and referred to domestic and internationalrelative guidelines,also considered China’s specific national conditions and clinical practice.Results The CACA Guidelines for Holistic Integrative Management of Rectal Cancer include the epidemiology of rectalcancer,prevention and screening,diagnosis,treatment of nonmetastatic and metastatic rectal cancer,follow-up,and whole-course rehabilitation management.Conclusion Committee of Colorectal Cancer Society,Chinese Anti-Cancer Association,standardizes the diagnosisand treatment of rectal cancer in China through the formulation of the CACA Guidelines.
基金supported by grants from the National Natural Science Foundation of China(No.81072870No.81102660+1 种基金No.81373743)Open Research Fund of Zhejiang First-foremost Key Subject-Acupuncture&Moxibustion(No.ZTK2010B06)
文摘Inflammation and lung function decline are the main pathophysiological features of chronic obstructive pulmonary disease (COPD). Acupuncture can improve lung function in patients with COPD, but the underlying mechanisms are not well understood. Orexins (OXs), which are found in peripheral plasma, are neuropeptides that regulate respiration and their levels are related to COPD. Therefore, we hypothesized that acupuncture might alter OXs, reduce lung inflammation and improve lung function in COPD. METHODS: COPD was induced in rats by exposure to cigarette smoke for 8 weeks and injecting with lipopolysaccharide twice. Electroacupuncture (EA) was performed at Feishu (BL13) and Zusanli (ST36) for 30 min/d for 2 weeks. Rat lung function and morphology were assessed after EA. The levels of tumor necrosis factor-α (TNF-a) and intedeukin-1β (IL-16) in bronchoalveolar lavage fluid (BALF) and orexin A and B levels in the lung tissue were detected by enzyme-linked immunosorbent assay. OX receptor mRNA levels and immunopositive cells were assessed with real-time polymerase chain reaction and immunohistochemical methods, respectively. The relationships among lung function, cell factors, and OX levels were analyzed by Pearson correlation analyses. RESULTS: Compared with the control group, lung function was significantly decreased in the rats with COPD (P〈0.05). There were obvious increases in TNF-α and IL-1β levels in BALF (P〈0.05 and P〈0.01, respectively), orexin A level in lung tissue (P〈0.01; but not orexin B) and mRNA expressions of OX 1 type receptor (OXR1) and OX 2 type receptor (OXR2) in lung tissue (P〈0.05 and P〈0.01, respectively); the integrative optical densities (IODs) of both receptors were greater in the COPD group (P〈0.05). For rats with COPD subjected to EA, lung function was improved (P〈0.05). There were notable decreases in TNF-a and IL-1β levels (P〈0.05 and 〈0.01, respectively) in BALF. Orexin A, but not orexin B, levels in lung tissue also decreased (P〈0.01), as did mRNA expression of OXlR and OX2R in lung tissue (P〈0.05 and P〈0.01, respectively). Receptor IODs were also reduced after EA treatment (P〈0.05). Furthermore, orexin A levels and ratio of forced expiratory volume in 0.3 s to forced vital capacity were strongly negatively correlated (P〈0.01), and orexin A was positively correlated with TNF-α and IL-1β (P〈0.001 and P〈0.05, respectively).CONCLUSION: EA at Zusanli and Feishu improved lung function of rats with COPD and had an anti-inflammatory effect, which may be related to down-regulation of OXA and its receptors.
基金Financial support from the 863 program (No. 2011AA02A204)
文摘A series of fluorescent siloxane-polyurethanes(HPMS-PUs) containing an amino-functionalized,1 8-naphthalimide,fluorescent monomer(AABD) as a chain extender were synthesized.The properties of the HPMS-PUs were investigated by UV–vis and fluorescence spectroscopies,thermogravimetric analysis and thermal migration behavior.The maximum absorption and emission wavelengths of HPMS-PUs showed a red shift of about 4 nm and a blue shift of about 9 nm,respectively,compared to those of AABD.The Stokes shifts of AABD and HPMS-PU2 were 3514 and 2931 cm 1,respectively.The quantum yield of HPMS-PU2 was 0.79,which was six times higher than that of AABD.Concentration self-quenching was observed in both AABD and HPMS-PUs.The fluorescence of HPMS-PUs was quite stable with respect to both temperature and fluorescence quencher effects.The thermal stability of HPMS-PUs increased with AABD content.The fluorophore units in the HPMS-PUs did not readily migrate.
基金supported by National Natural Science Foundation of China (81600307) to Xin LiNational Key Investigation Program (2016YFC1100900)
文摘Super-enhancers(SEs) are regulatory elements with enriched accumulation of key transcription factors.Few studies were done investigating SEs in lung cancers.Here we analyzed epigenetic profiling data to identify SEs in lung cancer cell lines.Enhancers were classified as SEs and typical enhancers(TEs).Most of the TEs were overlapped between normal cell and cancer cells.A great portion of SEs were differentiated comparing these cells.Analysis of GO terms associated with SEs revealed SE remodeling(lost on some sites while gain on others) between normal and lung cancer cells.By comparing the average number of SEs in each GO term in cancer cells with the number in control cells,surprisingly,no GO terms with significantly increased SE number in cancer condition were observed.On the contrary,in aspects such as "cell-cell adhesion","receptor activity" and"negative regulation of canonical Wnt signaling pathway",the related SEs were significantly reduced in cancer cells.These findings suggest that in lung cancer,cells may not gain decisive gene expression in the related aspect,instead,they may have lost control of the fateful genes.Taken together,our work with the usability of omics data identified SEs in lung cancer cells and further showed cancer-specific features of SE-related terms.
基金National Natural Science Foundation of China (Grant No. 11671059)。
文摘The problem of estimating high-dimensional Gaussian graphical models has gained much attention in recent years. Most existing methods can be considered as one-step approaches, being either regression-based or likelihood-based. In this paper, we propose a two-step method for estimating the high-dimensional Gaussian graphical model. Specifically, the first step serves as a screening step, in which many entries of the concentration matrix are identified as zeros and thus removed from further consideration. Then in the second step, we focus on the remaining entries of the concentration matrix and perform selection and estimation for nonzero entries of the concentration matrix. Since the dimension of the parameter space is effectively reduced by the screening step,the estimation accuracy of the estimated concentration matrix can be potentially improved. We show that the proposed method enjoys desirable asymptotic properties. Numerical comparisons of the proposed method with several existing methods indicate that the proposed method works well. We also apply the proposed method to a breast cancer microarray data set and obtain some biologically meaningful results.
基金Project supported by the Medical and Health Science and Technology Fund of Zhejiang Province(No.2016KYB224)the Scientific Research Fund of Zhejiang Chinese Medicine University(No.2015ZG17),China
文摘Exposure to fine ambient particulate matter(PM_(2.5)) is known to be associated with cardiovascular disease. To uncover the molecular mechanisms involved in cardiovascular toxicity of PM_(2.5), we investigated alterations in the protein profile of human umbilical vein endothelial cells(HUVECs) treated with PM_(2.5) using two-dimensional electrophoresis in conjunction with mass spectrometry(MS). A total of 31 protein spots were selected as differentially expressed proteins and identified by matrix-assisted laser desorption/ionization-time of flight(MALDI-TOF) MS. The results demonstrated that DNA damage and cell apoptosis are important factors contributing to PM_(2.5)-mediated toxicity in HUVECs. It is further proposed that PM_(2.5) can inhibit superoxide dismutase(SOD) activity and increase reactive oxygen species(ROS) and malonaldehyde(MDA) production in a concentration-dependent manner. Induction of apoptosis and DNA damage through oxidative stress pathways may be one of the key toxicological events occurring in HUVECs under PM_(2.5) stress. These results indicated that the toxic mechanisms of PM_(2.5) on cardiovascular disease are related to endothelial dysfunction.
文摘The chromate industry in China has de-veloped rapidly since 2000.China pro-duced 150 000 tons of chromates (based on sodium bichromate) in 2000 and be-came the biggest chromate producing country worldwide.The output increased to 270 000 tons in 2005 and went further up to approximately 300 000 tons in 2006 and 2007,accounting for around one third of the world total.