Publications by authors named "Hejing Wang"

28 Publications

  • Page 1 of 1

Aldehyde dehydrogenase 1B1 is a potential marker of colorectal tumors.

Histol Histopathol 2021 Feb 13;36(2):183-194. Epub 2021 Jan 13.

Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.

Colorectal cancer (CRC) is common worldwide. Aldehyde dehydrogenase 1B1 (ALDH1B1), a member of the ALDH1 family, serves as a biomarker for cancer stem cells. We hypothesized that ALDH1B1 expression is associated with colorectal tumors. Immunohistochemistry was used to detect ALDH1B1 expression across a commercial colorectal tissue microarray. The signal intensities of the positively stained tissues were expressed using the mean integrated optical density (mean IOD). We also analyzed ALDH1B1 mRNA expression in the Oncomine database. The associations between ALDH1B1 expression and CRC stage and prognosis were then evaluated using the web-based tools, GEPIA and UALCAN. Analysis of the tissue microarray revealed that the expression of ALDH1B1 was significantly higher in colorectal adenomas and colorectal adenocarcinoma (IOD/area values=0.117±0.070 and 0.168±0.0168, respectively) compared with normal and cancer-adjacent tissues (IOD/area values=0.051±0.028 and 0.068±0.053). For samples collected in the hospital, ALDH1B1 was highly expressed in the adenoma (IOD/area=0.103±0.054) and CRC (IOD/area=0.116±0.059) tissues compared with the cancer-adjacent tissues (IOD/area=0.066±0.024, p<0.05). The expression of ALDH1B1 in tissues from two resources was not found to be significantly associated with CRC stage. In Oncomine, ALDH1B1 mRNA expression was increased in the colorectal tumor tissues compared with the normal colorectal tissues (p=0.024) and its expression was independent of CRC stage and prognosis (p<0.05). Thus, while the protein and mRNA expression of ALDH1B1 suggests that it is a potential marker of colorectal tumors, its expression is independent of CRC stage and prognosis.
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http://dx.doi.org/10.14670/HH-18-304DOI Listing
February 2021

Identification and Validation of Novel Serum Autoantibody Biomarkers for Early Detection of Colorectal Cancer and Advanced Adenoma.

Front Oncol 2020 22;10:1081. Epub 2020 Jul 22.

Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Colorectal cancer (CRC) comprises a large proportion of malignant tumors, and early detection of CRC is critical for effective treatment and optimal prognosis. We aimed to discover and validate serum autoantibodies for early detection of CRC. Combined with CRC-associated autoantibodies discovered by serological proteome and multiplex analyses, 26 predefined autoantibodies were evaluated in 315 samples (130 CRCs, 75 advanced adenomas, and 110 healthy controls) by protein microarray analysis. Autoantibodies with potential detection value were verified by enzyme-linked immunosorbent assays (ELISAs). Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the accuracy of the biomarkers. Four serum autoantibodies (ALDH1B1, UQCRC1, CTAG1, and CENPF) showed statistically different levels between patients with advanced neoplasm (CRC or advanced adenoma) and controls in microarray analysis, which were validated by ELISAs. Among the four biomarkers, the ALDH1B1 autoantibody showed the highest detection value with area under the curve (AUC) values of 0.70 and 0.74 to detect CRC and advanced adenoma with sensitivities of 75.68 and 62.31% and specificities of 63.06 and 73.87%, respectively. By combining the four biomarkers, the performance was improved with an AUC of 0.79 to detect CRC and advanced adenomas. The ALDH1B1 autoantibody has a good potential for early detection of CRC and advanced adenoma, and measuring serum autoantibodies against tumor-associated antigens may improve detection of early CRC.
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http://dx.doi.org/10.3389/fonc.2020.01081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387658PMC
July 2020

Insertion of LINE-1 Retrotransposon Inducing Exon Inversion Causes a Rotor Syndrome Phenotype.

Front Genet 2019 31;10:1399. Epub 2020 Jan 31.

Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Rotor syndrome, a rare autosomal-recessive genetic disorder characterized by conjugated hyperbilirubinemia, is caused by biallelic pathogenic variants in both and genes. Long interspersed nuclear elements (LINEs) make up about 17% of the human genome and insertion of LINE-1 in genes can result in genetic diseases. In the current study, we examined and genes in two Chinese patients diagnosed with Rotor syndrome based on laboratory tests. In one patient, a novel exon 4 inversion variant was identified. This variant may have been induced by LINE-1 retrotransposon insertion into intron 3, and was identified using genome walking. Splicing assay results indicated that the exon inversion, resulting in exon 4 (122 bp) exclusion in the mature mRNA, might generate a premature termination codon. Here, we describe an exon inversion contributing to the molecular etiology of Rotor syndrome. Our results may inform future diagnoses and guide drug prescriptions and genetic counseling.
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http://dx.doi.org/10.3389/fgene.2019.01399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005217PMC
January 2020

Autoantibodies as biomarkers for colorectal cancer: A systematic review, meta-analysis, and bioinformatics analysis.

Int J Biol Markers 2019 Dec 5;34(4):334-347. Epub 2019 Oct 5.

Department of Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China.

Colorectal cancer is a very common cancer worldwide. Serum tumor-associated autoantibodies (TAAbs), especially the anti-p53 autoantibody, may be promising biomarkers to detect early-stage colorectal cancer. This study aimed to identify all known autoantibodies and their value in colorectal cancer diagnosis, as well as exploring the underlying connections and mechanisms through a bioinformatics analysis. Databases were used to select available articles of TAAbs in colorectal cancer. In a meta-analysis of the anti-p53 autoantibody, the diagnostic odds ratio and area under the curve (AUC) of the summary receiver-operating characteristic (SROC) curve were calculated using Stata 12.0 and Meta-Disc 1.4. We identified 73 articles including 199 single autoantibodies and 42 multiple autoantibodies. The maximum value of Youden's index was 0.76, combining c-MYC, p53, cyclin B1, p62, Koc, IMP1, and survivin. The diagnostic odds ratio for anti-p53 autoantibody at all stages was 10.86 (95% CI 8.40, 14.06) with low heterogeneity (I = 40.3%) and the AUC of the SROC curve was 0.82. For the anti-p53 autoantibody in early-stage colorectal cancer, the diagnostic odds ratio was 4.82 (95% CI 2.95, 7.87) with heterogeneity (I = 7.9%) and the AUC of the SROC curve was 0.72. Eighty-seven autoantibodies were selected for bioinformatics analyses. We found that the most enriched functional terms and protein-protein interactions may relate to the mechanism of autoantibody generation. In summary, our study summarized the diagnostic value of TAAbs in colorectal cancer, either as single molecules or in combination. Bioinformatics analyses may be a new approach to explore the mechanism of autoantibody generation.
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http://dx.doi.org/10.1177/1724600819880906DOI Listing
December 2019

Preoperative Ultrasound Assessment of Regional Lymph Nodes in Melanoma Patients Does not Provide Reliable Nodal Staging: Results From a Large Multicenter Trial.

Ann Surg 2021 04;273(4):814-820

The Angeles Clinic and Research Institute/Cedars-Sinai Medical Center.

Objective: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging.

Background: It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low.

Methods: Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen.

Results: SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive (1.2%). By basin, the sensitivity of US was 6.6% (95% confidence interval: 4.6-8.7) and the specificity 98.0% (95% CI: 97.5-98.5). Median cross-sectional area of all SN metastases was 0.13 mm2; in US true-positive nodes, it was 6.8 mm2. US sensitivity increased with increasing Breslow thickness of the primary melanoma (0% for ≤1 mm thickness, 11.9% for >4 mm thickness). US sensitivity was not significantly greater with higher trial center volume or with pre-US lymphoscintigraphy.

Conclusion: In the MSLT-II screening phase population, SN tumor volume was usually too small to be reliably detected by US. For accurate nodal staging to guide the management of melanoma patients, US is not an effective substitute for SN biopsy.
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http://dx.doi.org/10.1097/SLA.0000000000003405DOI Listing
April 2021

Beryllium inhibits apoptosis via mitochondria in beryllium-induced lung disease in the rat.

Exp Lung Res 2019 Apr - May;45(3-4):92-100. Epub 2019 Jun 1.

a School of Public Health , Health Science Center of Xi'an Jiaotong University , Xi'an , P.R. China.

We aimed to determine whether beryllium toxicity was associated with mitochondria apoptosis pathway in SD rats. Thirty-two SD rats were given an intratracheal instillation dose of 10 g/l beryllium oxide (0.5 ml per rat). Additional 32 rats were given an intratracheal instillation dose of 0.9% normal saline (0.5 ml per rat). The percentage of apoptosis, mitochondrial membrane potential, the expression level of apoptosis related genes and proteins, including bcl2, Bax and Caspase-3 were detected. The average of percentage of apoptosis, the expression of caspase-3, bax, and cytochrome c were decreased significantly in lung tissues from rats exposed to beryllium oxide compared to normal controls. The expression of bcl2 and ADP were increased significantly at 80 d after exposure. We conclude that inhibition of apoptosis by beryllium oxide involves mitochondrial apoptosis pathway in rat model of beryllium oxide-induced pulmonary disease.
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http://dx.doi.org/10.1080/01902148.2019.1621409DOI Listing
April 2020

Dust induces lung fibrosis through dysregulated DNA methylation.

Environ Toxicol 2019 Jun 28;34(6):728-741. Epub 2019 Feb 28.

Department of Occupational and Environmental Health, School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.

Pneumoconiosis is a serious occupational disease that often occurs to coal workers with no early diagnosis and effective treatment at present. Diffuse pulmonary fibrosis is the major pathological change of pneumoconiosis, and its mechanism is still unclear. Epigenetics is involved in the development of many diseases, and it is closely associated with fibrosis. In this study, we investigated whether DNA methylation contributes to the pathogenesis of pulmonary fibrosis in pneumoconiosis. By exposure to coal dust or silica dust, we established the models of coal worker's pneumoconiosis (CWP), which showed an increased expression of COL-I, COL-III. We further found that DNMT1, DNMT3a, DNMT3b, MBD2, MeCP2 protein expression changed. Pretreatment with DNMT inhibitor 5-aza-dC reduced expression of COL-I, COL-III, and reduced pulmonary fibrosis. In summary, our results showed that DNA methylation contributes to dust-induced pulmonary fibrosis and that it may serve as a theoretical basis for testing DNA methyltransferase inhibitors in the treatment of CWP.
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http://dx.doi.org/10.1002/tox.22739DOI Listing
June 2019

Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants.

Hum Mutat 2019 05 14;40(5):552-565. Epub 2019 Feb 14.

Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. In this study, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Pedigree analysis showed that besides several ATP7B homozygous variants (8/65, 12.3%), compound heterozygous variants (43/65, 66.2%) were present in the majority of WD patients. There were 20% of the patients had one (12/65, 18.5%) or multiple (1/65, 1.5%) variants in only a single allele, characterized by a high ratio of splicing or frameshift variants. Nine ATP7B variants were cloned into the pAG426GPD yeast expression vector to evaluate their functional consequences, and the results suggested different degrees of functional disruption from mild or uncertain to severe, consistent with the corresponding phenotypes. Our study revealed the complex ATP7B mutation patterns in WD patients and the applicability of a yeast model system to the evaluation of the functional consequences of ATP7B variants, which is essential for WD cases that are difficult to interpret.
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http://dx.doi.org/10.1002/humu.23714DOI Listing
May 2019

Growth of MCF-7 breast cancer cells and efficacy of anti-angiogenic agents in a hydroxyethyl chitosan/glycidyl methacrylate hydrogel.

Cancer Cell Int 2017 16;17:55. Epub 2017 May 16.

Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shanxi People's Republic of China.

Background: Breast cancer negatively affects women's health worldwide. The tumour microenvironment plays a critical role in tumour initiation, proliferation, and metastasis. Cancer cells are traditionally grown in two-dimensional (2D) cultures as monolayers on a flat solid surface lacking cell-cell and cell-matrix interactions. These experimental conditions deviate from the clinical situation. Improved experimental systems that can mimic the in vivo situation are required to discover new therapies, particularly for anti-angiogenic agents that mainly target intercellular factors and play an essential role in treating some cancers.

Methods: Chitosan can be modified to construct three-dimensional (3D) tumour models. Here, we report an in vitro 3D tumour model using a hydroxyethyl chitosan/glycidyl methacrylate (HECS-GMA) hydrogel produced by a series of chitosan modifications. Parameters relating to cell morphology, viability, proliferation, and migration were analysed using breast cancer MCF-7 cells. In a xenograft model, secretion of angiogenesis-related growth factors and the anti-angiogenic efficacy of Endostar and Bevacizumab in cells grown in HECS-GMA hydrogels were assessed by immunohistochemistry.

Results: Hydroxyethyl chitosan/glycidyl methacrylate hydrogels had a highly porous microstructure, mechanical properties, swelling ratio, and morphology consistent with a 3D tumour model. Compared with a 2D monolayer culture, breast cancer MCF-7 cells residing in the HECS-GMA hydrogels grew as tumour-like clusters in a 3D formation. In a xenograft model, MCF-7 cells cultured in the HECS-GMA hydrogels had increased secretion of angiogenesis-related growth factors. Recombinant human endostatin (Endostar), but not Bevacizumab (Avastin), was an effective anti-angiogenic agent in HECS-GMA hydrogels.

Conclusions: The HECS-GMA hydrogel provided a 3D tumour model that mimicked the in vivo cancer microenvironment and supported the growth of MCF7 cells better than traditional tissue culture plates. The HECS-GMA hydrogel may offer an improved platform to minimize the gap between traditional tissue culture plates and clinical applicability. In addition, the anti-angiogenic efficacy of drugs such as Endostar and Bevacizumab can be more comprehensively studied and assessed in HECS-GMA hydrogels.
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http://dx.doi.org/10.1186/s12935-017-0424-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434523PMC
May 2017

Why use sex hormones in relapsing-remitting multiple sclerosis? - Authors' reply.

Lancet Neurol 2016 07;15(8):790-791

David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA.

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http://dx.doi.org/10.1016/S1474-4422(16)00129-0DOI Listing
July 2016

A photo-polymerized poly(N-acryloyl l-lysine) hydrogel for 3D culture of MCF-7 breast cancer cells.

J Mater Chem B 2016 May 27;4(19):3339-3350. Epub 2016 Apr 27.

State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.

The most common in vitro cell culture platform, standard two-dimensional (2D) monolayer cell culture, often fails to mimic the tumor microenvironment, while animal models complicate research on the effect of individual factors on cell behaviors. Both are unsatisfactory in the research of molecular mechanisms of tumor development and progression and the discovery and development of anticancer drugs. In vitro three-dimensional (3D) cell culture can partially simulate in vivo conditions and 3D-cultured cancer cells can recapture many essential features of native tumor tissues. In this study, to mimic the in vivo breast tumor microenvironment, novel reduction-responsive poly(N-acryloyl l-lysine) (pLysAAm) hydrogels were synthesized by rapid photo-polymerization of N-acryloyl l-lysine and using N,N'-bis(acryloyl)-(l)-cystine as a crosslinker, and their physicochemical properties were characterized systemically. The results showed that the pLysAAm hydrogels were formed within 93 s under UV irradiation and exhibited almost total elastic recovery from compressions as high as 75%. The lyophilized hydrogel samples displayed a highly porous structure with interconnected pores, had an equilibrium swelling ratio of about 20, and were degraded faster in a glutathione-containing solution than in PBS solution. The biological versatility of the pLysAAm hydrogels was demonstrated by both in vitro MCF-7 cell culture and in vivo tumor formation. Compared to cells cultured as 2D monolayers, the 3D-cultured cells presented 3D cell morphology, exhibited better cell viability, expressed higher levels of pro-angiogenic factors, and showed significantly greater migration and invasion abilities. The results from assay of tumorigenicity in nude mice and histologic analysis demonstrated the enhanced tumorigenic and angiogenic capabilities of the MCF-7 cells pre-cultured in pLysAAm hydrogels. These findings suggest that pLysAAm hydrogels may be used to bridge the gap between standard in vitro cell cultures and living tissues, aid breast cancer research, and help researchers to develop novel anticancer therapeutics.
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http://dx.doi.org/10.1039/c6tb00511jDOI Listing
May 2016

Comb-like amphiphilic polypeptide-based copolymer nanomicelles for co-delivery of doxorubicin and P-gp siRNA into MCF-7 cells.

Mater Sci Eng C Mater Biol Appl 2016 May 5;62:564-73. Epub 2016 Feb 5.

Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

A comb-like amphiphilic copolymer methoxypolyethylene glycol-graft-poly(L-lysine)-block-poly(L-phenylalanine) (mPEG-g-PLL-b-Phe) was successfully synthesized. To synthesize mPEG-g-PLL-b-Phe, diblock copolymer PLL-b-Phe was first synthesized by successive ring-opening polymerization of α-amino acid N-carboxyanhydrides followed by the removal of benzyloxycarbonyl protecting groups, and then mPEG was grafted onto PLL-b-Phe by reductive amination via Schiff's base formation. The chemical structures of the copolymers were identified by (1)H NMR. mPEG-g-PLL-b-Phe copolymer had a critical micelle concentration of 6.0mg/L and could self-assemble in an aqueous solution into multicompartment nanomicelles with a mean diameter of approximately 78 nm. The nanomicelles could encapsulate doxorubicin (DOX) through hydrophobic and π-π stacking interactions between DOX molecules and Phe blocks and simultaneously complex P-gp siRNA with cationic PLL blocks via electrostatic interactions. The DOX/P-gp siRNA-loaded nanomicelles showed spherical morphology, possessed narrow particle size distribution and had a mean particle size of 120 nm. The DOX/P-gp siRNA-loaded nanomicelles exhibited pH-responsive release behaviors and displayed accelerated release under acidic conditions. The DOX/P-gp siRNA-loaded nanomicelles were efficiently internalized into MCF-7 cells, and DOX released could successfully reach nuclei. In vitro cytotoxicity assay demonstrated that the DOX/P-gp siRNA-loaded nanomicelles showed a much higher cytotoxicity in MCF-7 cells than DOX-loaded nanomicelles due to their synergistic killing effect and that the blank nanomicelles had good biocompatibility. Thus, the novel comb-like mPEG-g-PLL-b-Phe nanomicelles could be a promising vehicle for co-delivery of chemotherapeutic drug and genetic material.
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http://dx.doi.org/10.1016/j.msec.2016.02.007DOI Listing
May 2016

A double-network poly(Nɛ-acryloyl L-lysine)/hyaluronic acid hydrogel as a mimic of the breast tumor microenvironment.

Acta Biomater 2016 Mar 21;33:131-41. Epub 2016 Jan 21.

Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an 710061, China.

Unlabelled: To mimic the structure of breast tumor microenvironment, novel double-network poly(Nɛ-acryloyl L-lysine)/hyaluronic acid (pLysAAm/HA) hydrogels were fabricated by a two-step photo-polymerization process for in vitro three-dimensional (3D) cell culture. The morphology, mechanical properties, swelling and degradation behaviors of pLysAAm/HA hydrogels were investigated. The growth behavior and function of MCF-7 cells cultured on the hydrogels and standard 2D culture plates were compared. The results showed that pLysAAm/HA hydrogels had a highly porous microstructure with a double network and that their mechanical properties, swelling ratio and degradation rate depended on the degree of methacrylation of HA. The results of in vitro studies revealed that the pLysAAm/HA hydrogels could support MCF-7 cell adhesion, promote cell proliferation, and induce the diversification of cell morphologies and overexpression of VEGF, IL-8 and bFGF. The MCF-7 cells cultured on 3D hydrogels showed significantly increased migration and invasion abilities as compared to 2D-cultured cells. Preliminary in vivo results confirmed that the 3D culture of MCF-7 cells resulted in greater tumorigenesis than their 2D culture. These results indicate that the pLysAAm/HA hydrogels can provide a 3D microenvironment for MCF-7 cells that is more representative of the in vivo breast cancer.

Statement Of Significance: Traditional 2D cell cultures cannot ideally represent their in vivo physiological conditions. In this work, we reported a method for preparing double-network poly(Nɛ-acryloyl L-lysine)/hyaluronic acid hydrogel, and demonstrated its suitability for use in mimicing breast tumor microenvironment. Results showed the prepared hydrogels had controllable mechanical properties, swelling ratio and degradation rate. The MCF-7 cells cultured in hydrogels expressed much higher levels of pro-angiogenic growth factors and displayed significantly enhanced migration and invasion abilities. The tumorigenic capability of MCF-7 cells pre-cultured in 3D hydrogels was enhanced significantly. Therefore, the novel hydrogel may provide a more physiologically relevant 3D in vitro model for breast cancer research. To our knowledge, this is the first report assessing a HA-based double-network hydrogel used as a tumor model.
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http://dx.doi.org/10.1016/j.actbio.2016.01.027DOI Listing
March 2016

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial.

Lancet Neurol 2016 Jan 29;15(1):35-46. Epub 2015 Nov 29.

David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.

Background: Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women.

Methods: We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204.

Findings: We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy.

Interpretation: Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial.

Funding: National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.
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http://dx.doi.org/10.1016/S1474-4422(15)00322-1DOI Listing
January 2016

Lack of FGF23 response to acute changes in serum calcium and PTH in humans.

J Clin Endocrinol Metab 2014 Oct 25;99(10):E1951-6. Epub 2014 Jul 25.

Department of Pediatrics (K.W.-P., H.W., R.E., B.G., I.B.S.), David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095; and Endocrine Unit and Division of Pediatric Nephrology (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.

Context: 1,25-Dihydroxyvitamin D (1,25D) administration and long-term increases in phosphate, PTH, and calcium concentrations are associated with increases in circulating fibroblast growth factor 23 (FGF23); however, whether or not acute changes in serum calcium modulate short-term FGF23 release is unknown.

Objective/design: To assess the direct effect of acute changes in calcium and PTH on circulating FGF23 levels.

Setting: A university clinical and translational research center.

Patients/participants: Twelve healthy volunteers and 10 dialysis patients.

Interventions: Calcium gluconate and sodium citrate were infused for 120 minutes on 2 consecutive days.

Main Outcome Measures: Serum levels of ionized calcium, phosphorus, PTH, 1,25D, and plasma C-terminal FGF23 levels were obtained at 0, 13, 30, 60, 90, and 120 minutes during the infusions.

Results: During the calcium infusion, serum calcium concentrations increased from 1.33 ± 0.01 to 1.57 ± 0.04 mmol/L (P < .05 from baseline) and from 1.20 ± 0.05 to 1.50 ± 0.03 mmol/L (P < .05 from baseline) in healthy subjects and in dialysis patients, respectively, whereas serum calcium values decreased from 1.33 ± 0.01 to 1.03 ± 0.02 mmol/L (P < .05 from baseline) and from 1.26 ± 0.04 to 1.07 ± 0.03 mmol/L (P < .05 from baseline) in the two groups, respectively during the sodium citrate infusion. PTH levels decreased from 35 (29, 57) to 8 (2,10) pg/mL (healthy subjects) (P < .05 from baseline) and from 292 (109, 423) to 44 (28, 86) pg/mL (dialysis patients) (P < .05 from baseline) during the calcium infusion and rose from 31 (25, 56) to 122 (95, 157) pg/mL and from 281 (117, 607) to 468 (169, 928) pg/mL (P < .05 from baseline) during sodium citrate infusion. Serum 1,25D levels and plasma FGF23 values remained unchanged during both infusions in both groups.

Conclusions: Short-term changes in calcium and PTH levels do not affect FGF23 concentrations in either healthy volunteers or dialysis patients.
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http://dx.doi.org/10.1210/jc.2014-2125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393489PMC
October 2014

A multicenter retrospective study on clinical characteristics, treatment patterns, and outcome in elderly patients with hepatocellular carcinoma.

Oncologist 2011 24;16(3):310-8. Epub 2011 Feb 24.

Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

Background: There is a paucity of information on the clinical presentation and outcome of elderly hepatocellular carcinoma (HCC) patients. We performed a multicenter retrospective comparative study to assess the impact of age on potential differences in clinical characteristics, treatment patterns, and outcome in HCC patients.

Methods: We retrospectively analyzed HCC patients treated at two U.S. tertiary institutions from 1998 to 2008. Demographics, tumor parameters, etiology and severity of cirrhosis, treatment, and survival from diagnosis were collected and analyzed. After exclusion of transplanted patients, survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models.

Results: Three hundred thirty-five HCC patients were divided into two groups: "elderly" (95 patients, age ≥ 70 years) and "younger" (240 patients, aged <70 years). The male/female (M/F) ratio was 5.8:1 and 1.7:1 in the younger and elderly groups, respectively (p < .0001). Hepatitis C virus (HCV) infection rate was 48.3% in younger and 21.1% in elderly patients (p < .0001); Child class B and C cirrhosis accounted for 35.8% in younger and 25.3% in elderly patients (p = .063). Compared with younger patients, the elderly received transplant less frequently (19.6% versus 5.3%, p = .0002) and were more likely to receive supportive care only (22.9% versus 36.8%, p = .01). No significant differences between the two age groups were seen in tumor parameters or other treatments received. Overall (p = .47) and HCC-specific survival rates (p = .38) were similar in both age groups.

Conclusions: Characteristics that distinguish elderly from younger HCC patients include lower M/F ratio, worse performance status, lower rate of HCV infection, and less advanced underlying cirrhosis. Elderly patients were less likely to have a liver transplant and more likely to receive supportive care only. However, overall and HCC-specific survival were similar between the two groups.
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http://dx.doi.org/10.1634/theoncologist.2010-0223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228108PMC
August 2011

A phase II trial of docetaxel with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (TORI B01).

Clin Breast Cancer 2010 Aug;10(4):307-12

David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Introduction: Addition of the antiangiogenic agent bevacizumab to paclitaxel significantly improves response rates and progression-free survival for metastatic breast cancer (MBC). To assess the activity of docetaxel plus bevacizumab, a multicenter phase II trial was conducted.

Patients And Methods: Patients with measurable first-line HER2/neu-negative MBC were eligible. This trial began as a 2-arm study with a docetaxel-alone arm. When bevacizumab became widely available, it was converted to a 1-arm open-label trial of docetaxel/bevacizumab. Patients enrolled in the docetaxel-alone arm were permitted to cross over to docetaxel/bevacizumab. Patients received bevacizumab 15 mg/kg and docetaxel 75 mg/m2 intravenously (I.V.) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal.

Results: From March 2005 to September 2006, 76 patients were enrolled. Of the 7 patients who were randomized to docetaxel alone, 6 crossed over to docetaxel/bevacizumab (included in the safety analysis only). Two patients were found to be ineligible before receiving drug. Efficacy data are based on the 67 patients who were originally enrolled in the docetaxel/bevacizumab arm and received at least 1 dose of study medication. The confirmed objective response rate is 51% (34 of 67) with 9% complete responses (6 of 67) and 42% partial responses (28 of 67). Nine additional patients (13%) had stable disease lasting >or= 6 months. With a median follow-up of 21.7 months, the median time to progression is 9.3 months, and median overall survival is 26.3 months. Common grade 3/4 adverse events included neutropenia (33%), leukopenia/lymphopenia (25%), fatigue (22%), infection (17%), pain (16%), and hypertension (9%).

Conclusion: Docetaxel/bevacizumab was generally well tolerated with manageable toxicity and promising efficacy results.
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http://dx.doi.org/10.3816/CBC.2010.n.040DOI Listing
August 2010

Relationship between plasma fibroblast growth factor-23 concentration and bone mineralization in children with renal failure on peritoneal dialysis.

J Clin Endocrinol Metab 2009 Feb 2;94(2):511-7. Epub 2008 Dec 2.

Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, A2-383 MDCC, 10833 LeConte Boulevard, Los Angeles, California 90095, USA.

Context: Fibroblast growth factor (FGF)-23 is produced in bone, and circulating levels are markedly elevated in patients with end-stage kidney disease, but the relationship between plasma levels of FGF-23 and bone histology in dialysis patients with secondary hyperparathyroidism is unknown.

Objective: The aim of the study was to evaluate the correlation between plasma levels of FGF-23 and bone histology in pediatric patients with end-stage kidney disease who display biochemical evidence of secondary hyperparathyroidism.

Design: We performed a cross-sectional analysis of the relationship between plasma FGF-23 levels and bone histomorphometry.

Setting: The study was conducted in a referral center.

Study Participants: Participants consisted of forty-nine pediatric patients who were treated with maintenance peritoneal dialysis and who had serum PTH levels (1st generation Nichols assay) greater than 400 pg/ml.

Intervention: There were no interventions.

Main Outcome Measure: Plasma FGF-23 levels and bone histomorphometry were measured.

Results: No correlation existed between values of PTH and FGF-23. Bone formation rates correlated with PTH (r = 0.44; P < 0.01), but not with FGF-23. Higher FGF-23 concentrations were associated with decreased osteoid thickness (r = -0.49; P < 0.01) and shorter osteoid maturation time (r = -0.48; P < 0.01).

Conclusions: High levels of FGF-23 are associated with improved indices of skeletal mineralization in dialyzed pediatric patients with high turnover renal osteodystrophy. Together with other biomarkers, FGF-23 measurements may indicate skeletal mineralization status in this patient population.
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http://dx.doi.org/10.1210/jc.2008-0326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646517PMC
February 2009

An inverse relation between COX-2 and E-cadherin expression correlates with aggressive histologic features in prostate cancer.

Appl Immunohistochem Mol Morphol 2006 Dec;14(4):375-83

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, CA 90095,

The identification of biomarkers in prostatic carcinoma has yielded important data regarding prognosis and has aided in increasing diagnostic accuracy. Additionally, this approach has yielded important insights into the biology of prostatic carcinoma. In this study, we report that the expression of the cyclooxygenase isoenzyme, COX-2, is significantly increased in prostatic carcinoma, whereas that of the cell adhesion molecule, E-cadherin, is decreased. The expression of COX-2 was positively correlated with higher tumor stage, and the presence of carcinoma in surgical margins at prostatectomy. Conversely, the expression of E-cadherin was inversely related to these prognostic indicators. Lastly, the expressions of COX-2 and E-cadherin were very strongly and inversely correlated. These results provide important insights into the biologic underpinnings of prostate carcinoma; and further studies into COX-2 expression in prostate core biopsies may show utility in preprostatectomy prognostication. Furthermore, these results may provide a rational basis for therapeutic intervention and chemoprevention with COX-2 inhibitor therapy in prostate carcinoma.
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http://dx.doi.org/10.1097/01.pai.0000210417.61117.6cDOI Listing
December 2006

Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer.

Clin Cancer Res 2006 Jul;12(13):4018-26

Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1738, USA.

Purpose: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy.

Experimental Design: A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA > 0.2 and < 5 ng/mL and Gleason score < or = 7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels.

Results: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption.

Conclusions: We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-2290DOI Listing
July 2006

Tea polyphenols and theaflavins are present in prostate tissue of humans and mice after green and black tea consumption.

J Nutr 2006 Jul;136(7):1839-43

Department of Pathology, VA West Los Angeles, CA 90073, USA.

Green and black tea have shown promise in the chemoprevention of prostate cancer. The objective of this study was to determine the bioavailability and bioactivity of tea polyphenols (PP) and theaflavins in human serum and human and mouse tissues. A decaffeinated black tea diet was administered to C57BL/6 mice. PPs and theaflavins were found in the small and large intestine, liver, and prostate in conjugated and free forms. The relative prostate bioavailability of theaflavin was 70% higher than that of epigallocatechin gallate (EGCG). In the second mouse study, a green tea (GT) diet was administered followed by the control diet for 1-5 d. Epicatechin (EC), EGCG, and epicatechin gallate (ECG) concentrations in prostate tissue were significantly decreased after 1 d of consuming the control diet. Epigallocatechin gallate (EGC), however, did not decrease significantly. For the human study, 20 men scheduled for surgical prostatectomy were randomly assigned to consume 1.42 L daily of GT, BT, or a caffeine-matched soda control (SC) for 5 d before radical prostatectomy. Tea PPs were greater in prostate samples from men consuming BT and GT than in men consuming SC (P = 0.0025). Although tea PP were not detectable in serum, ex vivo LNCaP prostate cancer cell proliferation was less when cells were grown in media containing patient serum collected after BT (P < 0.001) and GT (P = 0.025) consumption relative to baseline serum This is the first human study to show that tea polyphenols and theaflavins are bioavailable in the prostate where they may be active in the prevention of prostate cancer.
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http://dx.doi.org/10.1093/jn/136.7.1839DOI Listing
July 2006

Bioavailability and antioxidant effect of epigallocatechin gallate administered in purified form versus as green tea extract in healthy individuals.

J Nutr Biochem 2005 Oct;16(10):610-6

Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

Tea polyphenols have strong in vitro antioxidant activity. Due to their limited bioavailability, however, their contribution to in vivo antioxidant activity may depend on the form of administration. A human intervention study was performed to evaluate the bioavailability and antioxidant capacity of (-)-epigallocatechin-3-gallate (EGCG) administered as a single large dose in the form of either purified EGCG or as green tea extract (Polyphenon E). Plasma concentrations of tea polyphenols were determined by high-performance liquid chromatography (HPLC) analysis combined with coulometric array electrochemical detection (ECD). We found no differences in plasma EGCG concentrations and trolox equivalents determined by the trolox equivalent antioxidant capacity assay after administration of either form of EGCG. However, we found that the plasma antioxidant activity was significantly affected by changes in the plasma urate concentration, which may have interfered with the effect of tea polyphenols on the antioxidant activity. In addition, lymphocyte 8-hydroxydeoxyguanosine to deoxyguanosine (8-OHdG/10(6)dG) ratios were determined by HPLC with ECD. The 8-OHdG/10(6)dG ratios did not change significantly during the 24 h following both EGCG interventions but correlated significantly within individuals determined during the two interventions separated by 1 week. In summary, changes in plasma uric acid due to dietary intake were significantly correlated to the plasma antioxidant activity and exerted a stronger influence on the plasma antioxidant activity compared with the EGCG intervention. In future studies of dietary effects on the plasma antioxidant capacity, changes in plasma uric acid will need to be closely monitored.
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http://dx.doi.org/10.1016/j.jnutbio.2005.03.003DOI Listing
October 2005

Bioavailability and antioxidant activity of tea flavanols after consumption of green tea, black tea, or a green tea extract supplement.

Am J Clin Nutr 2004 Dec;80(6):1558-64

Center for Human Nutrition, David Geffen School of Medicine and the Department of Biostatistics, School of Public Health, University of California, Los Angeles, 90095, USA.

Background: Green and black tea polyphenols have been extensively studied as cancer chemopreventive agents. Many in vitro experiments have supported their strong antioxidant activity. Additional in vivo studies are needed to examine the pharmacokinetic relation of absorption and antioxidant activity of tea polyphenols administered in the form of green or black tea or tea extract supplements.

Objective: The purpose of this study was to compare the pharmacokinetic disposition of tea polyphenols and their effect on the antioxidant capacity in plasma 8 h after a bolus consumption of either green tea, black tea, or a green tea extract supplement.

Design: Thirty healthy subjects were randomly assigned to 3 different sequences of green tea, black tea, or a green tea extract supplement in a 3 x 3 crossover design with a 1-wk washout period in between treatments.

Results: Flavanol absorption was enhanced when tea polyphenols were administered as a green tea supplement in capsule form and led to a small but significant increase in plasma antioxidant activity compared with when tea polyphenols were consumed as black tea or green tea. All 3 interventions provided similar amounts of (-)-epigallocatechin-3-gallate.

Conclusions: Our observations suggest that green tea extract supplements retain the beneficial effects of green and black tea and may be used in future chemoprevention studies to provide a large dose of tea polyphenols without the side effects of caffeine associated with green and black tea beverages.
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http://dx.doi.org/10.1093/ajcn/80.6.1558DOI Listing
December 2004

A pilot clinical study of short-term isoflavone supplements in breast cancer patients.

Nutr Cancer 2004 ;49(1):59-65

University of California, Los Angeles, Department of Surgery, Division of Oncology, 90095, USA.

Many laboratory-based studies have shown that soy can suppress breast cancer proliferation. However, given the recent controversy generated by animal experiments that soy may under certain conditions stimulate breast cancer growth, we decided to carry out a pilot clinical trial in order to elucidate any interaction(s) between short-term isoflavone supplement administration and breast cancer growth. After a core-needle biopsy established the diagnosis of breast cancer, 17 patients were administered soy isoflavone tablets for two weeks. This surgically based study provided the unique opportunity to make objective observations based on human breast cancer tissues and blood obtained prior to and after isoflavone supplement treatment in the same patient. Twenty-six historical control cases with similar characteristics to the experimental patients were selected for comparison. We observed that the apoptosis/mitosis ratios in isoflavone-treated cancer specimens were not significantly different from those of control untreated cancer specimens. Furthermore, there appeared to be a statistically nonsignificant trend towards cancer growth inhibition in the isoflavone treatment group, as manifested by higher apoptosis/mitosis ratios compared with those from the control untreated group. Ex vivo/in vitro assays using serum from breast cancer patients prior to and at the conclusion of soy treatment reveal no significant proliferative changes on both breast cancer cells and endothelial cells. We concluded that the effect of soy on breast cancer deserves further studies in larger clinical trials.
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http://dx.doi.org/10.1207/s15327914nc4901_8DOI Listing
April 2005

Factors predictive of tumor-positive nonsentinel lymph nodes after tumor-positive sentinel lymph node dissection for melanoma.

J Clin Oncol 2004 Sep;22(18):3677-84

John Wayne Cancer Institute, Santa Monica, CA 90404, USA.

Purpose: Approximately 20% of sentinel node (SN) positive melanoma patients have additional non-SN (NSN) metastasis. The rationale for this study was to identify the factors associated with additional nodal disease, as a method to determine which patients may most benefit from completion lymph node dissection (CLND).

Patients And Methods: During 1990 to 2002, 1,599 patients have undergone SN biopsy at our institute. 19.5% underwent CLND for tumor-positive SN. One hundred ninety-one of these patients had clinicopathologic information available for review. Univariate analyses used chi2 test, Wilcoxson rank sum test, and chi2 test for trend. Multivariate analyses used logistic regression and Wald test.

Results: Forty-six (24%) patients had tumor-positive NSN. Univariate analyses showed that primary thickness (Breslow and Clark), primary site, SN tumor size, and number of tumor-positive SNs were significantly associated with tumor-positive NSN. Multivariate analysis (167 patients), confirmed that Breslow and SN tumor size were independently predictive. Sex, histology, ulceration, mitotic index, and SN basin location were not predictive. Risk stratification by the number of prognostic factors present (Breslow > or = 3 mm and SN tumor size > or = 2 mm) showed that probability of finding tumor-positive NSN was 12.3% in the low-risk group (0 factors), 30.9% in the intermediate-risk group (1 factor), and 41.9% in the high-risk group (2 factors).

Conclusion: Thicker primary and larger SN tumor size are factors that correlate best with tumor-positive NSN. Although none of these factors are absolutely predictive of residual nodal disease, these factors must be strongly considered if the SN contains metastasis, as they provide enhanced risk assessment for NSN tumor-positivity.
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http://dx.doi.org/10.1200/JCO.2004.01.012DOI Listing
September 2004

COX-2-dependent stabilization of survivin in non-small cell lung cancer.

FASEB J 2004 Jan 3;18(1):206-8. Epub 2003 Nov 3.

UCLA Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, Los Angeles, California, USA.

Elevated tumor cyclooxygenase 2 (COX-2) expression is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. The mechanism(s) by which COX-2 exerts its cytoprotective effects are not completely understood but may be due to an imbalance of pro- and anti-apoptotic gene expression. To analyze COX-2-dependent gene expression and apoptosis, we created cell lines constitutively expressing COX-2 cDNA in sense and antisense orientations. Whereas COX-2 sense cells have significantly heightened resistance to radiation and drug-induced apoptosis, COX-2 antisense cells are highly sensitive to apoptosis induction. We found that the expression of the anti-apoptotic protein survivin correlated positively with COX-2 expression. A COX-2-dependent modulation of survivin ubiquitination led to its stabilization in COX-2 overexpressing cells, and this effect was replicated by exogenous PGE2 treatment of parental tumor cells. In contrast to previous studies in other cell types, in nonsmall cell lung cancer cells survivin was expressed in a cell cycle-independent manner. When established in SCID mice in vivo, COX-2 antisense-derived tumors had significantly decreased survivin levels while COX-2 sense-derived tumors demonstrated elevated levels compared with controls. In accord with these findings, survivin and COX-2 were frequently upregulated and co-expressed in human lung cancers in situ.
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http://dx.doi.org/10.1096/fj.03-0369fjeDOI Listing
January 2004

Body weight loss with phentermine alone versus phentermine and fenfluramine with very-low-calorie diet in an outpatient obesity management program: a retrospective study.

Curr Ther Res Clin Exp 2003 Jul;64(7):447-60

Division of Clinical Nutrition, Department of Medicine, University of California at Los Angeles (UCLA) Center for Human Nutrition, and.

Background: Obesity, which is epidemic in the United States, is associated with increased morbidity and mortality. The combination of diet, exercise, and a behavior-modification program often does not result in ideal body weight.

Objective: The aim of this study was to determine the efficacy of phentermine (Phen) alone compared with phentermine plus fenfluramine (Phen-Fen), when used in combination with a very-low-calorie diet (VLCD) for weight loss in an outpatient obesity center.

Methods: We analyzed data collected at the UCLA outpatient University Obesity Center between 1993 and 1999. Data for patients who attended the center for at least 12 weeks and at least 4 visits, who were taking Phen or Phen-Fen, and whose body mass index (BMI) was ≥30 kg/m(2) were included in this retrospective study.

Results: During the study period, 3200 visits were recorded. Of 1133 potential participants, 446 patients were included in the analysis (309 women, 137 men; mean [SD] age, 46.7 [11.4] years; mean [SEM] body weight, 109.6 [26.7] kg; mean [SEM] BMI, 38.0 [7.6] kg/m(2)). Of these, 128 women and 60 men (mean [SEM] body weight at baseline, 103.4 [24.0] kg and 124.9 [28.2] kg, respectively) received Phen alone; 181 women and 77 men (mean [SEM] body weight at baseline, 102.5 [21.4] kg and 124.9 [30.2] kg, respectively) received Phen-Fen. No statistically significant differences were found between the Phen and Phen-Fen groups in mean age, body weight, or BMI for women or men at baseline. No significant differences in the time of weight loss were found when a VLCD was used with Phen alone compared with the Phen-Fen combination for either sex even at 12 weeks. For women, the mean total body weight loss was 7.4% in the Phen group and 8.7% in the Phen-Fen group, but these differences were not significant. For men, the mean total body weight loss was 7.8% in the Phen group and 8.2% in the Phen-Fen group, but these differences were not significant. No significant differences in BMI, severe adverse events, or dropout rate were found between the 2 treatment groups for men or women.

Conclusions: This outpatient study did not detect any significant difference between adjunctive uses of Phen compared with Phen-Fen pharmacotherapy when used with VLCD over 12 weeks. Phen can be used to achieve significant weight loss when combined with VLCD. The tolerability and positive physical response further suggest that Phen is a valuable medication for obesity management in the outpatient setting.
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http://dx.doi.org/10.1016/S0011-393X(03)00126-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053043PMC
July 2003

Biochemotherapy for metastatic melanoma with limited central nervous system involvement.

Oncology 2003 ;64(4):328-35

Division of Medical Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA 90404, USA.

Objectives: Biochemotherapy outcomes were examined in stage IV melanoma patients with previously treated or active central nervous system (CNS) metastases prior to systemic therapy.

Patients And Methods: Patients who received biochemotherapy for metastatic melanoma with active or pretreated CNS metastases were compared to patients without evidence of CNS metastases in terms of response, time to progression (TTP), overall survival (OS), and treatment toxicity.

Results: Twenty-six (16%) of 159 total patients began biochemotherapy with previously treated or active CNS metastases (group I), compared to 133 (84%) who were radiographically free of CNS involvement (group II). A partial or complete response to biochemotherapy was seen in 13 (50%) group I patients, compared to 56 (42%) group II patients (p = 0.243). The median TTP and median survival were 5.5 and 7.0 months, respectively, for group I patients and 6.0 and 9.9 months, respectively, for group II patients (p = 0.222 and 0.434 for TTP and OS, respectively). Five (19%) group I patients survived longer than 24 months. Gamma Knife radiosurgery or surgical resection of CNS disease prior to biochemotherapy improved survival versus delayed treatment (p = 0.017 and 0.005, respectively).

Conclusion: Patients with limited CNS metastases and widespread systemic disease can achieve prolonged survival with targeted treatment of CNS lesions and aggressive systemic therapy.
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http://dx.doi.org/10.1159/000070289DOI Listing
June 2003