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author:("Li, xining")
1.  Anti-IGF-1R monoclonal antibody inhibits the carcinogenicity activity of acquired trastuzumab-resistant SKOV3 
Background
Antibody resistance, not only de novo but also acquired cases, usually exists and is related with lower survival rate and high risk of recurrence. Reversing the resistance often results in better clinical therapeutic effect. Previously, we established a trastuzumab-resistant ovarian cancer cell line, named as SKOV3-T, with lower HER2 and induced higher IGF-1R expression level to keep cell survival.
Methods
IGF-1R was identified important for SKOV3-T growth. Then, a novel anti-IGF-1R monoclonal antibody, named as LMAb1, was used to inhibit SKOV3-T in cell growth/proliferation, migration, clone formation and in vivo carcinogenicity.
Results
In both in vitro and in vivo assays, LMAb1 showed effective anti-tumor function, especially when being used in combination with trastuzumab, which was beneficial to longer survival time of mice as well as smaller tumor. It was also confirmed preliminarily that the mechanism of antibody might be to inhibit the activation of IGF-1R and downstream MAPK, AKT pathway transduction.
Conclusion
We achieved satisfactory anti-tumor activity using trastuzumab plus LMAb1 in trastuzumab-resistant ovarian cancer model. In similar cases, not only acquired but also de novo, good curative effect might be achieved using combined antibody therapy strategies.
doi:10.1186/s13048-014-0103-5
PMCID: PMC4260252  PMID: 25424625
IGF-1R; Monoclonal antibody; Acquired resistant; Trastuzumab; Ovarian cancer
2.  Potent anti-angiogenesis and anti-tumor activity of a novel human anti-VEGF antibody, MIL60 
Cellular and Molecular Immunology  2014;11(3):285-293.
Angiogenesis is crucial for tumor development, growth and metastasis. Vascular endothelial growth factor (VEGF) has been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis, and blocking the activity of VEGF can starve tumors. Avastin, which is a humanized anti-VEGF antibody, has been successfully applied in clinics since 2004. However, the price of Avastin is extremely high for Chinese people. Here, we report a novel human anti-VEGF neutralizing antibody, MIL60, which shows an affinity comparable to that of Avastin (the KD value of MIL60 was 44.5 pM, while that of Avastin was 42.7 pM). MIL60 displays favorable actions in inhibiting VEGF-triggered endothelial cell proliferation (the IC50 value of MIL60 was 31±6.4 ng/ml and that of Avastin was 47±8.1 ng/ml), migration (8 µg/ml or 0.8 µg/ml MIL60 versus the control: P<0.05) and tube formation (2 µg/ml or 0.2 µg/ml MIL60 versus the control: P<0.05) via the VEGFR2 signaling pathway. Moreover, MIL60 was shown to inhibit tumor growth and angiogenesis in vivo in xenograft models of human colon carcinoma and ovarian cancer using immunotherapy and immunohistochemistry analysis (MIL60 versus N.S.: P=0.0007; Avastin versus N.S.: P=0.00046). These data suggest that MIL60 is a potential therapeutic, anti-angiogenic agent. Our work provides a novel anti-VEGF antibody, which can be considered an anti-tumor antibody candidate and a new option for patients with various cancers.
doi:10.1038/cmi.2014.6
PMCID: PMC4085495  PMID: 24608894
angiogenesis; anti-VEGF antibody; cancer
3.  Preface 
Gland Surgery  2013;2(4):173.
doi:10.3978/j.issn.2227-684X.2013.10.07
PMCID: PMC4115754
4.  Different surgical approaches in parathyroid adenoma resections 
Gland Surgery  2013;2(4):227-229.
Three patients were referred to our clinic for the management of a persistent symptomatic primary hyperparathyroidism. Pre-operative imageological localization revealed evidence of an adenoma. Here we are presenting three videos demonstrating the different surgical approaches of parathyroid adenoma resection, with the use of an intraoperative gamma probe and nerve monitoring.
doi:10.3978/j.issn.2227-684X.2013.10.03
PMCID: PMC4115755  PMID: 25083487
Video-assisted thoracoscopic approach parathyroidectomy; robotic trans-axillary parathyroidectomy; remote access parathyroidectomy; scarless parathyroidectomy
5.  Negative developing of parathyroid using carbon nanoparticles during thyroid surgery 
Gland Surgery  2013;2(2):100-101.
doi:10.3978/j.issn.2227-684X.2013.04.05
PMCID: PMC4115730  PMID: 25083465
6.  The role of noncoding RNA in hepatocellular carcinoma 
Gland Surgery  2013;2(1):25-29.
Increasing noncoding RNAs (ncRNAs) were found to show abnormal expression patterns in various human cancers. Based on their length, ncRNAs are briefly divided into two categories. Transcripts that are shorter than 200 nucleotides are recognized as short/small noncoding RNAs and greater than 200 nucleotides as long noncoding RNAs (lncRNAs). Short/small noncoding RNAs include microRNAs, piRNAs, snoRNAs, and endogenous siRNAs. Numerous studies have revealed that these short/small ncRNA play important roles in multiple biological processes and tumorigenesis. In contrast to small ncRNAs, long noncoding RNAs are much less known concerning their functions in human cancers especially in hepatocellular carcinoma (HCC). In this review, we highlight recent progress regarding HCC development, tumorigenesis, metastasis, clinical implication, as well as the role in the risk of HBV infection.
doi:10.3978/j.issn.2227-684X.2013.02.07
PMCID: PMC4115723  PMID: 25083452
MicroRNA; long noncoding RNA; hepatitis B virus; hepatocellular carcinoma
7.  A long non-coding RNA, PTCSC3, as a tumor suppressor and a target of miRNAs in thyroid cancer cells 
Papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) is a newly identified non-coding RNA, which is highly thyroid-specific. Dramatic downregulation in thyroid cancers suggests its potential roles in the occurrence and development of thyroid tumors. The present study aimed to investigate the effects of PTCSC3 on the biological features of thyroid cancer cells and to explore its possible function as a competing endogenous RNA to bind with miRNAs. Constructs containing the long non-coding RNA, PTCSC3, were transfected into various thyroid cancer cell lines (BCPAP, FTC133 and 8505C). Cell growth, cell cycle transition and apoptosis were measured by MTT assay and flow cytometry. In silico analysis was performed to identify the binding site of PTCSC3 for target miRNAs. Additionally, detection of putative miRNA by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in thyroid cancer cells transfected with PTCSC3 was determined to confirm the interaction. Following transfection with PTCSC3, all three thyroid cancer cells originating from various pathological types of thyroid cancers demonstrated significant growth inhibition, cell cycle arrest and increased apoptosis. The top 20 miRNAs to have a potential interaction with PTCSC3 were identified, out of which miR-574-5p was selected to further confirm the inverse correlation with PTCSC3 in thyroid cancer cells in vitro. In the present study, PTCSC3 as a tumor suppressor was investigated as a competing endogenous RNA for miR-574-5p.
doi:10.3892/etm.2013.933
PMCID: PMC3628718  PMID: 23599737
thyroid cancer; papillary thryoid susceptibility candidate 3; miR-574-5p
8.  Opposite Role of Tumor Necrosis Factor Receptors in Dextran Sulfate Sodium-Induced Colitis in Mice 
PLoS ONE  2012;7(12):e52924.
Tumor necrosis factor-α (TNF-α) is a key factor for the pathogenesis of inflammatory bowel diseases (IBD), whose function is known to be mediated by TNF receptor 1 (TNFR1) or 2. However, the precise role of the two receptors in IBD remains poorly understood. Herein, acute colitis was induced by dextran sulfate sodium (DSS) instillation in TNFR1 or 2−/− mice. TNFR1 ablation led to exacerbation of signs of colitis, including more weight loss, increased mortality, colon shortening and oedema, severe intestinal damage, and higher levels of myeloperoxidase compared to wild-type counterparts. While, TNFR2 deficiency had opposite effects. This discrepancy was reflected by alteration of proinflammatory cytokine and chemokine production in the colons. Importantly, TNFR1 ablation rendered enhanced apoptosis of colonic epithelial cells and TNFR2 deficiency conferred pro-apoptotic effects of lamina propria (LP)-immune cells, as shown by the decreased ratio of Bcl-2/Bax and enhanced nuclear factor (NF)-κB activity.
doi:10.1371/journal.pone.0052924
PMCID: PMC3532169  PMID: 23285227
9.  MicroRNA expression profiles in differentiated thyroid cancer, a review 
MicroRNAs (miRNAs) are a class of short endogenous non-coding RNAs regulating gene expression in many biological processes, including proliferation, apoptosis and differentiation. The deregulation of miRNA expression is believed to be an important regulator of tumor development and progression of thyroid cancer. In this review, we discussed important roles and expression profiles of miRNA in differentiated thyroid cancer (DTC) as well as the promising implication in clinical practice.
PMCID: PMC3515973  PMID: 23236561
Differentiated thyroid cancer; microRNA; mutations; fine needle aspiration biopsy
10.  Single incision robotic transaxillary approach to perform parathyroidectomy 
Gland Surgery  2012;1(3):169-170.
doi:10.3978/j.issn.2227-684X.2012.09.02
PMCID: PMC4115694  PMID: 25083444
11.  The role of noncoding RNA in thyroid cancer 
Gland Surgery  2012;1(3):146-150.
Increasing noncoding RNAs (ncRNAs) were found to show abnormal expression patterns in various human cancers. Based on size, ncRNAs are generally grouped into two categories, short noncoding RNAs and long noncoding RNAs (lncRNAs) of greater than 200 nt. Small noncoding RNAs include microRNAs, piRNAs, snoRNAs, and endogenous siRNAs, out of the role of miRNAs in development and cancer biology has been extensively studied. In contrast to small noncoding RNAs like miRNAs, long noncoding RNAs are much less known concerning their functions in human cancers especially in thyroid cancer. The present review highlighted the roles of miRNAs and newly discovered lncRNAs in thyroid development, tumorigenesis, metastasis, and their clinical implication.
doi:10.3978/j.issn.2227-684X.2012.10.07
PMCID: PMC4115695  PMID: 25083438
MicroRNA; long noncoding RNA; thyroid cancer
12.  Robotic clipless transperitoneal adrenalectomy 
Gland Surgery  2012;1(3):171-172.
doi:10.3978/j.issn.2227-684X.2012.10.08
PMCID: PMC4115705  PMID: 25083445
13.  Early-onset breast cancer in a woman with Graves’ disease 
The relationship between thyroid and breast diseases has been documented, but the clinical significance of Graves’ disease and breast cancer is unclear. We present a young patient with a history of Graves’ disease who developed a multicentric infiltrating ductal carcinoma of the breast several months after discontinuing her treatment with propylthiouracil. Early-onset breast cancer in women without a family history of early breast cancer may be related to hyperthyroidism. The relationship between thyroid hormone and estrogen is discussed.
PMCID: PMC3443885  PMID: 22993658
Graves’ disease; thyroid hormone; estrogen; breast cancer
14.  Concurrent occurrence of primary hepatocellular and cholangiocellular carcinoma in the different part of the liver: a case report 
Combined hepatocellular-cholangiocarcinoma which shows features of both hepatocellular and biliary epithelial differentiation is a rare form of primary liver cancer. The rarer is that the two types of cancer occur in the different lobe of the same liver concurrently.
PMCID: PMC3443894  PMID: 22993657
Hepatocellular carcinoma; cholangiocellular carcinoma; liver; diagnosis; treatment
15.  BRAF mutation in papillary thyroid carcinoma 
BRAF mutation is the most common genetic alternation in thyroid cancer, particularly in papillary thyroid cancer (PTC). Excessive activation of BRAF/MAPK signaling pathway due to BRAF mutation plays a central role in the tumorigenesis and development of PTC. The association of BRAF mutation with poor clinicopathological characteristics of PTC further demonstrated the importance of the BRAF mutation alternation in PTC. Detection of BRAF mutation on FNA specimen before surgery is recommended as a useful diagnostic marker and prognostic indicator for PTC, and thus influences surgeon’s decision on management of PTC. Recent studies have focused on inhibition of BRAF activation and several small molecules have been developed as targeting therapy.
PMCID: PMC3443896  PMID: 22993650
BRAF mutation; papillary thyroid carcinoma; BRAF/MAPK signaling pathway; targeting therapy
16.  Structural basis of LaDR5, a novel agonistic anti-death receptor 5 (DR5) monoclonal antibody, to inhibit DR5/TRAIL complex formation 
BMC Immunology  2012;13:40.
Background
As a member of the TNF superfamily, TRAIL could induce human tumor cell apoptosis through its cognate death receptors DR4 or DR5, which can induce formation of the death inducing signaling complex (DISC) and activation of the membrane proximal caspases (caspase-8 or caspase-10) and mitochondrial pathway. Some monoclonal antibodies against DR4 or DR5 have been reported to have anti-tumor activity.
Results
In this study, we reported a novel mouse anti-human DR5 monoclonal antibody, named as LaDR5, which could compete with TRAIL to bind DR5 and induce the apoptosis of Jurkat cells in the absence of second cross-linking in vitro. Using computer-guided molecular modeling method, the 3-D structure of LaDR5 Fv fragment was constructed. According to the crystal structure of DR5, the 3-D complex structure of DR5 and LaDR5 was modeled using molecular docking method. Based on distance geometry method and intermolecular hydrogen bonding analysis, the key functional domain in DR5 was predicted and the DR5 mutants were designed. And then, three mutants of DR5 was expressed in prokaryotic system and purified by affinity chromatograph to determine the epitope of DR5 identified by LaDR5, which was consistent with the theoretical results of computer-aided analysis.
Conclusions
Our results demonstrated the specific epitope located in DR5 that plays a crucial role in antibody binding and even antineoplastic bioactivity. Meanwhile, revealed structural features of DR5 may be important to design or screen novel drugs agonist DR5.
doi:10.1186/1471-2172-13-40
PMCID: PMC3436762  PMID: 22788777
TRAIL; Death receptor 5; Monoclonal antibody; Apoptosis; Breast cancer
17.  Identification of JAK2 as a Mediator of FIP1L1-PDGFRA-Induced Eosinophil Growth and Function in CEL 
PLoS ONE  2012;7(4):e34912.
The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha fusion gene (F/P) arising in the pluripotent hematopoietic stem cell (HSC),causes 14% to 60% of patients with hypereosinophilia syndrome (HES). These patients, classified as having F/P (+) chronic eosinophilic leukemia (CEL), present with clonal eosinophilia and display a more aggressive disease phenotype than patients with F/P (–) HES patients. The mechanisms underlying predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. Given that the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (Stat) signaling pathway is key to cytokine receptor-mediated eosinophil development and activated Stat3 and Stat5 regulate the expression of genes involved in F/P malignant transformation, we investigated whether and how JAK proteins were involved in the pathogenesis of F/P-induced CEL. F/P activation of JAK2, Stat3 and Stat5, were confirmed in all the 11 F/P (+) CEL patients examined. In vitro inhibition of JAK2 in EOL-1, primary F/P(+) CEL cells (PC) and T674I F/P Imatinib resistant cells(IR) by either JAK2-specific short interfering RNA (siRNA) or the tryphostin derivative AG490(AG490), significantly reduced cellular proliferation and induced cellular apoptosis. The F/P can enhance the IL-5-induced JAK2 activation, and further results indicated that JAK2 inhibition blocked IL-5-induced cellular migration and activation of the EOL-1 and PC cells in vitro. F/P-stimulation of the JAK2 suppressed cells led to a significantly reduction in Stat3 activation, but relatively normal induction of Stat5 activation. Interestingly, JAK2 inhibition also reduced PI3K, Akt and NF-κB activity in a dose-dependent manner, and suppressed expression levels of c-Myc and Survivin. These results strongly suggest that JAK2 is activated by F/P and is required for F/P stimulation of cellular proliferation and infiltration, possibly through induction of c-Myc and Survivin expression via activation of multiple signaling pathways, including NF-κB, Stat3, and PI3K/Akt.
doi:10.1371/journal.pone.0034912
PMCID: PMC3327703  PMID: 22523564
18.  Defective anchoring of JNK1 in the cytoplasm by MKK7 in Jurkat cells is associated with resistance to Fas-mediated apoptosis 
Molecular Biology of the Cell  2011;22(1):117-127.
MKK7 works as a cytoplasmic anchoring protein for JNK1 in various cell lines but exhibits aberrant nuclear entry in Jurkat cells, which leads to resistance to Fas-mediated apoptosis.
The c-Jun N-terminal protein kinase (JNK) plays a context-dependent role in tumorigenesis. Stress-induced redistribution of JNK from the cytoplasm to the nucleus has been demonstrated as essential for stress-induced cell death. However, accumulation of basal JNK activity in the nucleus has frequently been seen in tumor cells. Our previous report revealed aberrant nuclear entry of JNK protein in Jurkat human leukemic T-cells even without JNK hyperactivation. Because inhibition of JNK activity, especially JNK1 activity, in Jurkat cells results in augmented Fas-mediated apoptosis, it is possible that aberrant subcellular localization of JNK, especially the JNK1 isoform, contributes to the resistance to Fas-mediated apoptosis. Here we report that MKK7 works as a cytoplasmic anchoring protein for JNK1 in various types of cells, including human peripheral blood mononuclear cell (PBMC) T-cells, but exhibits aberrant nuclear entry in Jurkat cells. Ectopic expression of a JNK1 mutant defective of nuclear entry or a nuclear JNK inhibitor leads to impaired UV-induced apoptosis in both PBMC T- and Jurkat cells. The same treatment shows no effect on Fas-mediated apoptosis of PBMC T-cells but sensitizes Jurkat cells to Fas-mediated apoptosis. Taken together, our work suggests that aberrant subcellular organization of the JNK pathway might render certain tumor cells resistant to Fas-mediated apoptosis.
doi:10.1091/mbc.E10-06-0492
PMCID: PMC3016969  PMID: 21148294
19.  Lethal Action of Quinolones against a Temperature-Sensitive dnaB Replication Mutant of Escherichia coli 
Inhibition of DNA replication in an Escherichia coli dnaB-22 mutant failed to block quinolone-mediated lethality. Inhibition of protein synthesis by chloramphenicol inhibited nalidixic acid lethality and, to a lesser extent, ciprofloxacin lethality in both dnaB-22 and wild-type cells. Thus, major features of quinolone-mediated lethality do not depend on ongoing replication.
doi:10.1128/AAC.50.1.362-364.2006
PMCID: PMC1346826  PMID: 16377712
20.  Fluoroquinolone-Resistant Streptococcus agalactiae: Epidemiology and Mechanism of Resistance 
Quinolone-resistant Streptococcus agalactiae bacteria were recovered from single-patient isolates and found to contain mutations in the gyrase and topoisomerase IV genes. Pulsed-field gel electrophoresis demonstrated that four isolates from the same long-term care facility were closely related; in seven cases, quinolone-resistant Haemophilus influenzae and S. agalactiae bacteria were isolated from the same patient.
doi:10.1128/AAC.49.6.2495-2497.2005
PMCID: PMC1140524  PMID: 15917553
21.  Quinolone-Resistant Haemophilus influenzae: Determination of Mutant Selection Window for Ciprofloxacin, Garenoxacin, Levofloxacin, and Moxifloxacin 
Antimicrobial Agents and Chemotherapy  2004;48(11):4460-4462.
Stepwise selection of ciprofloxacin-resistant Haemophilus influenzae mutants produced first-, second-, third-, and fourth-step substitutions in GyrA (S84Y), ParC (S84R), GyrA (D88N), and ParC (E88K), respectively. Successive mutations raised the mutant selection window. The wild-type selection window for garenoxacin, levofloxacin, and moxifloxacin was also measured.
doi:10.1128/AAC.48.11.4460-4462.2004
PMCID: PMC525419  PMID: 15504883
22.  Quinolone-Resistant Haemophilus influenzae in a Long-Term-Care Facility: Nucleotide Sequence Characterization of Alterations in the Genes Encoding DNA Gyrase and DNA Topoisomerase IV 
Fluoroquinolone-resistant isolates of Haemophilus influenzae, obtained from a long-term care facility, were examined for nucleotide sequence differences in the quinolone-resistance-determining regions of gyrA, gyrB, parC, and parE. Similarities among the resistant isolates, plus multiple differences with susceptible isolates, suggest clonal dissemination involving two resistant subclones.
doi:10.1128/AAC.48.9.3570-3572.2004
PMCID: PMC514738  PMID: 15328129
23.  Selection of Streptococcus pneumoniae Mutants Having Reduced Susceptibility to Moxifloxacin and Levofloxacin 
With Streptococcus pneumoniae, moxifloxacin was 4- and 10-fold more effective than levofloxacin at restricting selection of resistant mutants and at killing resistant mutants, respectively. The selection frequency for first-step topoisomerase mutants was 1,000 times lower for moxifloxacin than for levofloxacin; this difference was lost when second-step mutants were selected.
doi:10.1128/AAC.46.2.522-524.2002
PMCID: PMC127057  PMID: 11796368
24.  Enhancement of Fluoroquinolone Activity by C-8 Halogen and Methoxy Moieties: Action against a Gyrase Resistance Mutant of Mycobacterium smegmatis and a Gyrase-Topoisomerase IV Double Mutant of Staphylococcus aureus 
Antimicrobial Agents and Chemotherapy  2001;45(10):2703-2709.
The increasing prevalence of antibiotic resistance among bacterial pathogens prompted a microbiological study of fluoroquinolone structure-activity relationships with resistant mutants. Bacteriostatic and bactericidal activities for 12 fluoroquinolones were examined with a gyrase mutant of Mycobacterium smegmatis and a gyrase-topoisomerase IV double mutant of Staphylococcus aureus. For both organisms C-8 halogen and C-8 methoxy groups enhanced activity. The MIC at which 99% of the isolates tested were inhibited (MIC99) was reduced three- to fivefold for the M. smegmatis mutant and seven- to eightfold for the S. aureus mutant by C-8 bromine, chlorine, and methoxy groups. With both organisms a smaller reduction in the MIC99 (two- to threefold) was associated with a C-8 fluorine moiety. In most comparisons with M. smegmatis the response to a C-8 substituent was similar (within twofold) for wild-type and mutant cells. In contrast, mutant S. aureus was affected more than the wild type by the addition of a C-8 substituent. C-8 halogen and methoxy groups also improved the ability to kill the two mutants and the respective wild-type cells when measured with various fluoroquinolone concentrations during an incubation period equivalent to four to five doubling times. Collectively these data help define a group of fluoroquinolones that can serve (i) as a base for structure refinement and (ii) as test compounds for slowing the development of fluoroquinolone resistance during infection of vertebrate hosts.
doi:10.1128/AAC.45.10.2703-2709.2001
PMCID: PMC90720  PMID: 11557458

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