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Human Epidermal Growth Factor Receptor (human + epidermal_growth_factor_receptor)
Selected AbstractsAssessment of a HER2 scoring system for gastric cancer: results from a validation studyHISTOPATHOLOGY, Issue 7 2008M Hofmann Aims:, Human epidermal growth factor receptor 2 (HER2) overexpression/amplification is implicated in the development of various solid tumour types. Validated methods and scoring systems for evaluating HER2 status exist in breast cancer, but not in gastric cancer. The aim was to establish a HER2 scoring system for gastric cancer to identify suitable patients for enrolment in a trial of trastuzumab (Herceptin®) in advanced metastatic gastric cancer. Methods and results:, Formalin-fixed paraffin-embedded gastric cancer samples were tested for HER2 status using the fluorescence in situ hybridization (FISH) pharmDxÔ kit (Dako Denmark A/S). Immunohistochemistry (IHC) was performed using the HercepTestÔ (Dako). Concordance between FISH and IHC was 93.5% in 168 evaluable samples. Eleven samples were scored as FISH+ but IHC, or equivocal. Conclusions:, IHC/FISH discrepancies were attributed to basolateral membranous immunoreactivity of glandular cells resulting in incomplete membranous reactivity and/or a higher rate of tumour heterogeneity in gastric cancer compared with breast cancer. With modifications to the IHC scoring system, the HercepTestÔ is considered valid for the identification of HER2+ gastric tumours for this clinical trial. Correlation of HER2 scores with clinical outcomes will be needed to determine which patients might benefit from trastuzumab therapy. [source] Human epidermal growth factor receptor 2 oncoprotein expression in breast cancer patients from central Anatolia, TurkeyASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 3 2009Hasan Senol COSKUN Abstract Aim: Human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis and the frequency of HER2 positivity in breast cancer patients varies among different regions of the world. We studied HER2 expression in Turkish breast cancer patients. Methods: HER 2 expression was evaluated immunohistochemically in 107 breast cancer patients. HER2 expression was reported as negative or positive (3+) according to cellular membrane staining characteristics. The frequency of HER2 overexpression, distribution according to clinical characteristics, effect on survival and effect of chemotherapy on survival in relation to HER2 overexpression was evaluated. Results: The median age of patients was 49 years (range 27,76). HER2 was 3+ in 34 patients (31.8%). There was no significant difference in age, menopausal status, histopathology, lymph node involvement, stage and estrogen and/or progesterone receptor positivity in relation to HER2 expression. Forty-three patients (40.2%) relapsed and 21 patients (19.6%) died during the follow-up period. There was no significant difference in the relapse rate, distribution of relapse sites and death rate in relation to HER2 expression. The 3- and 5-year disease free survival rates were 67.1 and 40.5%, and the overall survival rates were 87.5 and 66.1%, respectively. Survival rate and calculated survival time were relatively shorter in HER2 3+ patients than in non-HER2 3+ patients, but these differences were not statistically significant. HER2 status did not affect survival period according to chemotherapy group. Conclusion: Immunohistochemistry findings of HER2 expression in Turkish breast cancer patients were similar to those found in the published reports. A shorter survival period was observed in HER2 3+ patients, but the difference was not statistically significant. [source] 2C4, a monoclonal antibody against HER2, disrupts the HER kinase signaling pathway and inhibits ovarian carcinoma cell growthCANCER, Issue 12 2005Noriyuki Takai M.D. Abstract BACKGROUND Human epidermal growth factor receptor 2 (HER2) is overexpressed in 25,30% of ovarian carcinoma cases and a correlation between increased HER2 expression and decreased survival has been demonstrated. HER2 is a ligand-less member of the HER family that functions as the preferred coreceptor for epidermal growth factor receptor (EGFR), HER3, and HER4. METHODS An approach was developed to target HER2's role as a coreceptor using a monoclonal antibody, 2C4, which sterically hinders HER2's recruitment into a functional HER complex. RESULTS HER2 was robustly expressed in all eight ovarian carcinoma cell lines; expression of EGFR and HER3 was variable. Even though four of the eight cell lines responded to EGF, 2C4 antibody moderately inhibited in vitro proliferation of only two cell lines (OVCA433 and SK-OV-3). Furthermore, ligand-stimulated p-MAPK expression was inhibited by 2C4 only in these two cell lines after exposure to EGF. Immunoprecipitation and eTag analysis revealed that OVCA433 expressed heterodimers of EGFR/HER2, and these heterodimers were disrupted after treatment with 2C4, whereas OVCA432 cells did not have these heterodimers. In murine xenograft experiments, the in vivo growth of OVCA433, but not of OVCA432, ovarian carcinoma cells was significantly inhibited by 2C4 treatment of the mice. CONCLUSION 2C4 is able to disrupt the HER signaling pathway and inhibit the in vitro and in vivo growth of ovarian carcinoma cell lines. The response appears limited to lines in which HER2 heterodimers were able to transduce proliferative signals. Our findings suggest a strong rationale to conduct clinical trials of 2C4 in a subset of patients with ovarian tumors. Cancer 2005. © 2005 American Cancer Society. [source] Understanding the HER family in breast cancer: interaction with ligands, dimerization and treatmentsHISTOPATHOLOGY, Issue 5 2010Fabrício F T Barros Barros F F T, Powe D G, Ellis I O & Green A R (2010) Histopathology56, 560,572 Understanding the HER family in breast cancer: interaction with ligands, dimerization and treatments Breast carcinoma is the most frequent type of cancer affecting women. Among the recently described molecular and phenotypic classes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive tumours are associated with a poor prognosis. HER2 plays an important role in cancer progression being targeted to provide predictive and prognostic information. Moreover, HER2 is related to cancer resistance against a variety of therapies; however, trastuzumab (herceptin) has proved successful in treatment of this subgroup. Nevertheless, resistance to this drug may be acquired by patients after a period of treatment, which indicates that other molecular mechanisms might influence success of this therapy. Dimerization between members of the HER family may contribute to resistance against treatments due to different combinations that trigger different downstream pathways. This is promoted by ligands, which are expressed as transmembrane precursor protein molecules and have a conserved epidermal growth factor-like domain. Through resistance to trastuzumab, other drugs are being developed to interact in different domains of HER2 protein. It might be a good strategy to apply new drugs simultaneously to trastuzumab due to act in different domains of HER2. The study of interaction between receptors/ligands will characterize specifically their signalling pathway and understand which strategy to acquire. [source] Anti-cancer activity of anti-p185HER-2 ricin A chain immunotoxin on gastric cancer cellsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2010Xin-Xin Zhou Abstract Background and Aim:, Overexpression of the human epidermal growth factor receptor 2 (HER-2) protein has been detected in gastric cancer and has been associated with an unfavorable prognosis. We investigated the anti-cancer effects of anti-p185HER-2 ricin A chain (RTA) immunotoxin, alone or in combination with 5-flurouracil on SGC7901-HER-2+ cells. Methods:, SGC7901-HER-2+ cells were obtained by transfecting SGC7901 cells with HER-2-pcDNA3.1. Anti-p185HER-2 -RTA was prepared by chemical conjugation of anti-HER-2 monoclonal antibody (mAb) and RTA. The SGC7901-HER-2+ cells were incubated with RTA, anti-p185HER-2 -RTA, and/or 5-flurouracil. The effects of drugs on cells were evaluated by MTT assay and Annexin V-fluorescein isothiocyanate and propidium iodide double staining flow cytometry. The expression of caspase-3, caspase-9, cyclooxygenase-2, and nuclear factor-,B/p65 were assayed by western blot. SGC7901-HER-2+ cells were transplanted into BALB/c nude mice to produce solid tumors in an attempt to study the immunotoxin activity in vivo. Results:,In vitro, anti-p185HER-2 -RTA inhibited cell growth and induced apoptosis in SGC7901-HER-2+ cells. Anti-p185HER-2 -RTA enhanced caspase-3 and caspase-9 activity, while downregulating the expression of cyclooxygenase-2 and nuclear factor-,B/p65. Its combination with 5-flurouracil further inhibited the growth of SGC7901-HER-2+ cells. In vivo, our data showed that anti-p185HER-2 -RTA significantly inhibited the growth of SGC7901-HER-2+ cells-transplanted tumors. Conclusions:, Anti-p185HER-2 -RTA inhibits the growth of SGC7901-HER-2+ cells. The effect may be related to the activation of caspase-3 and caspase-9 and inhibition of cyclooxygenase-2 and nuclear factor-,B/p65. Anti-p185HER-2 -RTA plus 5-FU enhance anti-cancer activity, suggesting useful clues for further study for the treatment of HER-2 positive gastric cancers. [source] Degradation of HER2 Receptor Through Hypericin-mediated Photodynamic TherapyPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2010Ján Kova Current treatment of breast cancer is often affected by resistance to therapeutics, for which the human epidermal growth factor receptor 2 (HER2) may be responsible. Here, we report for the first time the use of hypericin-mediated photodynamic therapy (HY-PDT) in combination with a selective HER2 inhibitor (AG 825) on SKBR-3, a HER2 overexpressing human breast adenocarcinoma cell line. The results demonstrate that HY-PDT is able to degrade HER2 with an impact on its signaling cascade. Combination with AG 825 resulted in increased apoptosis induction, total degradation of HER2 and inhibition of colony formation. Downregulation of HSP90, Mcl-1, Bcl-xL and upregulation of Bax was also observed. This knowledge provides the basis for the possible application of HY-PDT in preclinical and clinical models of breast cancer treatment. [source] Annular erythema as a sign of recurrent breast cancerAUSTRALASIAN JOURNAL OF DERMATOLOGY, Issue 2 2010Eugene Tan ABSTRACT Three women with known breast cancer presented with very similar annular erythemas of their chest walls. All women were in remission from their breast cancer for at least 6 months. Their breast cancers had initially responded well to multi-modality treatment with no clinical or radiologic evidence of recurrence, until the development of the annular erythema. In the first case, the annular erythema was treated unsuccessfully as a dermatitis and then as tinea corporis. In the second case, subacute cutaneous lupus was considered but lupus antibodies were negative. In the third case, the annular erythema was promptly recognized and biopsied. Histology in all three cases revealed identical findings of invasive ductal carcinoma involving the lymphatics of the skin. Immunohistochemical staining of the carcinoma was positive for human epidermal growth factor receptor 2 but negative for oestrogen and progesterone receptors. Annular erythema can pose a wide differential but rarely has it been described as a sign of locally recurrent cancer. These cases highlight the importance of recognizing this entity in the oncologic patient, where prompt skin biopsies can confirm the diagnosis and allow early initiation of therapy. [source] Invasive neuroendocrine carcinoma of the breastCANCER, Issue 19 2010A distinctive subtype of aggressive mammary carcinoma Abstract BACKGROUND: Neuroendocrine carcinoma (NEC) of the breast, a pathologic entity newly defined in the 2003 World Health Organization classification of tumors, is a rare type of tumor that is not well recognized or studied. The purpose of this first case-controlled study is to reveal the clinicopathologic features, therapeutic response, and outcomes of patients with NEC of the breast. METHODS: Seventy-four patients with NEC of the breast who were treated at The University of Texas M. D. Anderson Cancer Center were analyzed; 68 of them had complete clinical follow-up. Two cohorts of invasive mammary carcinoma cases were selected to pair with NEC to reveal demographic, pathologic, and clinical features at presentation, along with therapeutic response to treatment and patient outcomes. RESULTS: NEC was more likely to be estrogen receptor/progesterone receptor positive and human epidermal growth factor receptor 2 negative. Despite similar age and disease stages at presentation, NEC showed a more aggressive course than invasive ductal carcinoma, with a higher propensity for local and distant recurrence and poorer overall survival. High nuclear grade, large tumor size, and regional lymph node metastasis were significant negative prognostic factors for distant recurrence-free survival; high nuclear grade and regional lymph node metastasis were also significant negative prognostic factors for overall survival. Although endocrine therapy and radiation therapy showed a trend toward improved survival, the small number of cases in this study limited the statistical power to reveal therapeutic benefits in NEC of the breast. CONCLUSIONS: NEC is a distinct type of aggressive mammary carcinoma. Novel therapeutic approaches should be explored for this uniquely different clinical entity. Cancer 2010. © 2010 American Cancer Society. [source] Breast cancer subtypes and response to systemic treatment after whole-brain radiotherapy in patients with brain metastasesCANCER, Issue 18 2010Anna Niwi, ska MD Abstract BACKGROUND: The aim of this study was to assess the role of systemic treatment after whole-brain radiotherapy (WBRT) in immunohistochemically defined biological subsets of breast cancer patients with brain metastases. METHODS: The group of 420 consecutive breast cancer patients with brain metastases treated at the same institution between the years of 2003 to 2009 was analyzed. Patients were divided into 4 immunohistochemically biological subsets, based on the levels of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptors, and labeled as luminal A, luminal B, HER2, and triple-negative. Survival from brain metastases with and without systemic treatment after WBRT was calculated in 4 subsets. RESULTS: In the entire group, the median survival from brain metastases in patients without and with systemic treatment after WBRT was 3 and 10 months, respectively (P < .0001). In the triple-negative subset, the median survival from brain metastases with and without systemic treatment was 4 and 3 months (P = .16), and in the luminal A subset, it was 12 and 3 months, respectively (P = .003). In the luminal B subset, the median survival without further treatment, after chemotherapy and/or hormonal therapy, and after chemotherapy and/or hormonal therapy with targeted therapy was 2 months, 9 months, and 15 months, respectively (P < .0001). In the HER2 subset, the median survival was 4 months, 6 months, and 13 months, respectively (P < .0001). No significant response to systemic treatment was noted in the triple-negative breast cancer population. CONCLUSIONS: Systemic therapy, ordered after WBRT, appears to improve survival in patients with the luminal A, luminal B, and HER2 breast cancer subtypes. Targeted therapy was found to have an additional positive impact on survival. In patients with triple-negative breast cancer, the role of systemic treatment after WBRT appears to be less clear, and therefore this issue requires further investigation. Cancer 2010. © 2010 American Cancer Society. [source] Radiofrequency field-induced thermal cytotoxicity in cancer cells treated with fluorescent nanoparticles,CANCER, Issue 13 2010Evan S. Glazer MD Abstract BACKGROUND: Nonionizing radiation, such as radiofrequency field and near infrared laser, induces thermal cytotoxicity in cancer cells treated with gold nanoparticles. Quantum dots are fluorescent semiconducting nanoparticles that were hypothesized to induce similar injury after radiofrequency field irradiation. METHODS: Gold nanoparticles and 2 types of quantum dot (cadmium-selenide and indium-gallium-phosphide) conjugated to cetuximab (C225), a monoclonal antibody against human epidermal growth factor receptor (EGFR)-1, demonstrated concentration-dependent heating in a radiofrequency field. The authors investigated the effect of radiofrequency field exposure after targeted nanoparticle treatment in a coculture of 2 human cancer cell lines that have differential EGFR-1 expression (a high-expressing pancreatic carcinoma, Panc-1, and a low-expressing breast carcinoma, Cama-1). RESULTS: Radiofrequency revealed that Panc-1 or Cama-1 cells not containing gold nanoparticles or quantum dots had a viability of >92%. The viability of Panc-1 cells exposed to the radiofrequency field after treatment with 50 nM Au-C225 was 39.4% ± 8.3% without injury to bystander Cama-1 cells (viability was 93.7% ± 1.0%; P , .0006). Panc-1 cells treated with targeted cadmium-selenide quantum dots were only 47.5% viable after radiofrequency field exposure (P<.0001 compared with radiofrequency only Panc-1 control cells). Targeted indium-gallium-phosphide quantum dots decreased Panc-1 viability to 58.2% ± 3.4% after radiofrequency field exposure (P = ,.0004 compared with Cama-1 and Panc-1 controls). CONCLUSIONS: The authors selectively induced radiofrequency field cytotoxicity in Panc-1 cells without injury to bystander Cama-1 cells using EGFR-1,targeted nanoparticles, and demonstrated an interesting bifunctionality of fluorescent nanoparticles as agents for both cancer cell imaging and treatment. Cancer 2010. © 2010 American Cancer Society. [source] Targeted therapy in inflammatory breast cancer,CANCER, Issue S11 2010Hideko Yamauchi MD Abstract Despite the introduction of multimodality treatment approaches, the prognosis of inflammatory breast cancer (IBC) is poor. Recent developments in molecular targeted therapy may be effective against IBC. The authors report the results of a literature review. Trastuzumab and lapatinib, which target human epidermal growth factor receptor 2 (HER-2), have demonstrated benefit in clinical trials for HER-2,positive breast cancers. WNT1-inducible signaling pathway protein 3, Ras homolog gene family member C guanosine triphosphatase, epidermal growth factor receptor (EGFR), and p27kip1 also have been studied as potential targets in IBC. Molecular targets in vasculolymphatic processes (angiogenesis, lymphangiogenesis, and vasculogenesis) have demonstrated greater potential in IBC than in non-IBC. Although loss of E-cadherin is a hallmark of epithelial-to-mesenchymal transition and may correlate with the promotion of metastasis, paradoxically, E-cadherin is overexpressed in IBC through an unknown mechanism. On the basis of dissecting the molecular mechanism of the aggressiveness of IBC, the authors currently are investigating whether EGFR may aid in developing innovative targeted therapies. Cancer 2010;116(11 suppl):2758,9. © 2010 American Cancer Society. [source] Time to disease recurrence in basal-type breast cancers,CANCER, Issue 21 2009Effects of tumor size, lymph node status Abstract BACKGROUND: Basal-like breast cancers are a subgroup of breast cancers defined by the absence of staining for estrogen-receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2/neu) and by positive staining for the cytokeratins (CKs) expressed in the myoepithelial cells of the ducts and lobules (CK5/CK6, CK14) and for epidermal growth factor receptor (EGFR). This class of tumors has an unusually aggressive course, and it is not clear whether conventional prognostic factors for breast cancers also predict outcome for patients who have the basal phenotype. METHODS: A panel of 962 breast cancers was stained for 5 markers (ER, PR, HER-2/neu, CK5/CK6, and EGFR). The patients were followed for clinical outcomes for up to 15 years from diagnosis, and the rates of distant disease recurrence and death were compared by tumor size (,2 cm or >2 cm) and by lymph node status within the subgroups of women with basal and nonbasal cancers. RESULTS: Of the 962 women with breast cancer, 116 cancers were basal (12%), 845 were nonbasal (88%), and 1 could not be classified as either basal or nonbasal and was excluded. In total, 426 tumors measured ,2 cm (45%), and 530 tumors measured >2 cm (55%). Among women with nonbasal cancers, large tumor size was an adverse prognostic factor. Among women with basal cancers, a transient adverse effect of size on disease recurrence was observed; however, after 10 years, mortality rates were equal for women with small tumors and women with large tumors. CONCLUSIONS: Among women with basal breast cancers, the long-term prognosis was similar for women with large tumors and women with small tumors. However, women with large basal tumors appeared to develop recurrent disease sooner. Cancer 2009. © 2009 American Cancer Society. [source] Fragile histidine triad protein, WW domain-containing oxidoreductase protein Wwox, and activator protein 2, expression levels correlate with basal phenotype in breast cancerCANCER, Issue 4 2009Gulnur Guler MD Abstract BACKGROUND: The expression of fragile histidine triad protein (Fhit) and WW domain-containing oxidoreductase protein (Wwox), tumor suppressors that are encoded by fragile (FRA) loci FRA3B and FRA16D, are lost concordantly in breast cancers. In the current study, the authors examined correlations among Fhit, Wwox, the activator protein 2 transcription factors AP2, and AP2,, cytokeratins 5 and 6 (CK5/6), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) and their associations with breast cancer phenotypes. METHODS: Tissue microarrays constructed from 837 breast cancer blocks were immunostained. Expression in >10% of tumor cells was considered positive for cytoplasmic CK5/6, membranous EGFR, and nuclear AP2, and AP2,. Cytoplasmic Fhit and Wwox staining was scored according to staining intensity. ER, PR, and HER-2 status of tumors was derived from records. Correlations among immunohistochemical markers and tumor subtypes were assessed by univariate and multivariate statistical methods. RESULTS: Triple-negative tumors had more frequent expression of EGFR, CK5/6 (P < .001), and AP2, (P = .003) and more frequent loss of Fhit and Wwox (P < .001), and an inverse correlation was observed between Fhit, Wwox expression and EGFR, ER, and PR expression (P < .001). Reduced Fhit expression was more common in HER-2-positive and AP2,-positive cases (P < .001 and P = .002, respectively). There was a direct correlation noted between Fhit and Wwox (P < .001) and a borderline positive relation between AP2, and AP2, (P = .054). CONCLUSIONS: The results from this investigation suggested that reduced expression levels of Fhit, Wwox, and nuclear AP2, have roles in the pathogenesis of basal-like differentiation in breast cancer. Alteration in the expression of fragile site genes occurs in most of these cancers and may contribute to defects in DNA repair, as observed in breast cancer 1 (BRCA1)-deficient cancers. Thus, DNA damage response checkpoint proteins may be targets for treatment. Cancer 2009. © 2009 American Cancer Society. [source] Relationship between cyclooxygenase-2 and human epidermal growth factor receptor 2 in vascular endothelial growth factor C up-regulation and lymphangiogenesis in human breast cancerCANCER SCIENCE, Issue 9 2010Rabindra N. Bhattacharjee No abstract is available for this article. [source] Improving the efficacy of trastuzumab in breast cancerCANCER SCIENCE, Issue 6 2007Eiji Suzuki Although overexpression of human epidermal growth factor receptor 2 (HER2) protein, amplification of the gene or both are associated with poor prognosis in breast cancer, trastuzumab has clearly provided clinical benefits in metastatic breast cancer, adjuvant treatment settings and primary systemic therapy. However, even in those HER2 overexpressors, the majority of patients who achieve an initial response generally acquire resistance within 1 year. Therefore, it is critical to elucidate the mechanism of resistance and to search for better combination treatments with chemotherapeutic agents or other novel modalities. Here, we discuss both clinical and preclinical data regarding these issues. (Cancer Sci 2007; 98: 767,771) [source] HER-2-Targeted Nanoparticle,Affibody Bioconjugates for Cancer TherapyCHEMMEDCHEM, Issue 12 2008Frank Alexis Dr. Affibodies are a class of polypeptide ligand that are potential candidates for tissue-specific targeting of drug-encapsulated controlled release polymeric nanoparticles (NPs). We developed drug delivery vehicles composed of polymeric NPs surface modified with affibody ligands that bind the extracellular domain of the human epidermal growth factor receptor,2 (HER-2) for targeted delivery to cells that overexpress the HER-2 antigen. [source] Extramammary Paget's disease of the groin with underlying carcinoma and fatal outcomeCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 5 2008J. C. Pascual Summary Extramammary Paget's disease (EMPD) is considered to be an intraepithelial adenocarcinoma. Typically involved anatomical sites are the vulvar, perianal, perineal, scrotal and penile regions. Clinically, the lesions present as well-defined, moist, erythematous plaques usually accompanied by pruritus. An unusual feature of EMPD is its association with cutaneous, adnexal-structure adenocarcinomas and its association with internal malignancies. Histopathological examination shows epidermal acanthosis and elongated rete ridges. Paget's cells are large intraepidermal cells with a large nucleous and abundant pale cytoplasm. Recent studies of perianal and vulvar EMPD have described distinct immunohistochemical subtypes termed cutaneous and endodermal. Cutaneous EMPD is characteristically positive for cytokeratin (CK)7, negative for CK20, and positive for gross cystic disease fluid protein (GCDFP)15+, whereas endodermal EMPD shows a CK7+ CK20+ GCDFP15, phenotype. Surgery remains the treatment of choice, with either wide surgical excision or Mohs' micrographic surgery. We present a case of EMPD with an underlying carcinoma, which combined immunohistochemical findings suggestive of the cutaneous subtype (positive for CK7, GCDFP15, mucin (MUC)1, human epidermal growth factor receptor (HER)2/neu positive) and the endodermal subtype, frequently associated with internal malignancy (CK20, MUC2, CDX-2 positve); however, our patient had no associated internal malignancy. [source] | ||||||||||||||||||||||