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M Derenzini

Publications and source records attributed to M Derenzini.

At least 19 recordsLinked to original sources
PubMed2006

A statistical model predicting high hepatocyte proliferation index and the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis.

BACKGROUND: Incidence of hepatocellular carcinoma in hepatitis C virus-related cirrhosis is 4% per year. Although cost-effective, current screening could be improved. AIM: To develop a statistical model including non-invasive parameters able to identify patients at high risk of developing hepatocellular carcinoma. METHODS: One hundred and fifty-eight patients (73F:85M) with compensated chronic hepatitis C virus liver disease underwent evaluation, including argyrophilic nucleolar organizer regions proliferation index, and were followed up for 56.18 +/- 1.44 months. RESULTS: Fifty-six patients had chronic hepatitis without cirrhosis and low argyrophilic nucleolar organizer regions proliferation index (< or =25%), 65 had hepatitis C virus-related cirrhosis and low argyrophilic nucleolar organizer regions proliferation index and 37 had hepatitis C virus-related cirrhosis and high argyrophilic nucleolar organizer regions proliferation index (>25%). Groups were similar for gender and viral genotype distribution. None of the patients with chronic hepatitis without cirrhosis developed hepatocellular carcinoma, compared with 6.1% of low argyrophilic nucleolar organizer regions proliferation index and 30.6% of high argyrophilic nucleolar organizer regions proliferation index (P = 0.002). By multivariable logistic regression analysis, the following parameters were independently associated with hepatocellular carcinoma development and used for the development of the statistical model: platelets (OR 0.98), gamma-globulins (OR 0.111), alanine aminotransferase/aspartate aminotransferase ratio (OR 0.07), serum ferritin (OR 1.0) and ultrasonographic pattern (coarse OR 2.9, coarse nodular OR 10.12). The statistical model properly allocated 95.9% of patients with low argyrophilic nucleolar organizer regions proliferation index and 72.2% of patients with high argyrophilic nucleolar organizer regions proliferation index. CONCLUSIONS: The model, to be validated in large prospective studies, may help tailoring screening according to the risk of hepatocellular carcinoma development.

Adult↗
PubMed2006

Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer.

Dyskerin is a nucleolar protein, altered in dyskeratosis congenita, which carries out two separate functions, both fundamental for proliferating cells. One function is the pseudo-uridylation of ribosomal RNA (rRNA) molecules, necessary for their processing, and the other is the stabilization of the telomerase RNA component, necessary for telomerase activity. A significant feature of dyskeratosis congenita is an increased susceptibility to cancer; so far, however, no data have been reported on dyskerin changes in human tumours. Therefore, in this study, the distribution of dyskerin in a large series of human tumours from the lung, breast, and colon, as well as from B-cell lymphomas, was analysed by immunohistochemistry. Dyskerin proved never to be lost or delocalized outside the nucleolus. A quantitative analysis of dyskerin mRNA expression was then performed in 70 breast carcinomas together with the evaluation of telomerase RNA component levels and rRNA pseudo-uridylation. Dyskerin mRNA levels were highly variable and directly associated with both telomerase RNA component levels and rRNA pseudo-uridylation. Dyskerin gene silencing in the MCF-7 human breast carcinoma cell line reduced telomerase activity and rRNA pseudo-uridylation. Significantly, patients with low dyskerin expression were characterized by a better clinical outcome than those with a high dyskerin level. These data indicate that dyskerin is not lost in human cancers and that the levels of its expression and function are associated with tumour progression.

Breast Neoplasms↗
PubMed2004

The prognostic value of the AgNOR parameter in human breast cancer depends on the pRb and p53 status.

BACKGROUND: The amount of argyrophilic nucleolar organiser regions (AgNORs) represents a cell kinetics parameter used in tumour pathology for prognostic purposes. AgNOR expression is directly related to the rate of ribosome biogenesis, which has been recently shown to be controlled also by the tumour suppressor proteins pRb and p53. AIMS: To ascertain the relative prognostic value of AgNORs and of pRb and p53 expression in breast carcinoma. METHODS: This study was carried out on 335 human primary breast carcinomas with a median follow up time of 108 months. AgNORs were measured by morphometric analysis on sections that had been selectively silver stained; expression of p53 and phosphorylated and non-phosphorylated pRb forms was assessed by immunohistochemistry. RESULTS: Patients were divided into groups with low (249) and high (86) AgNOR values; with normal (267) and mutated p53 (68); and with normal (256) and hyperphosphorylated or deleted pRb (79). Univariate analysis of disease free survival showed that AgNORs and the status of pRb and p53 were significantly related to the patients' clinical outcome. However, among the four groups characterised by different pRb and p53 status, the AgNOR parameter was not capable of distinguishing subgroups of patients with different clinical outcomes. CONCLUSIONS: These findings indicate that the prognostic value of the AgNOR parameter depends on the status of the tumour suppressor proteins pRb and p53, and it cannot be ascribed to the relation between AgNORs and the cell proliferation rate.

Biomarkers, Tumor↗
PubMed2003

Enhanced telomere shortening in transformed lymphoblasts from patients with X linked dyskeratosis.

AIM: Dyskeratosis congenita (DC) is characterised by the failure of those tissues that are rapidly dividing in the adult, particularly the skin, mucosae, and haemopoietic system. The X linked form of the disease is caused by mutations of the DKC1 gene, which encodes dyskerin, a protein that is necessary for the function of telomerase. Cultured DC lymphoblastoid cells are characterised by a reduced expansion of the cell population because of the progressive increase in apoptosis compared with the number of cell divisions. This report aimed to verify whether this is caused by a defect in telomerase function. METHODS: Variations in telomere length over time were evaluated in two cultured lymphoblastoid cell lines derived from patients with X linked DC and control cells derived from a non-affected individual. In addition, the effect of inhibiting poly (ADP-ribose) polymerase (PARP), which is involved in the cellular response to excessive telomere shortening, was assessed. One DC cell line and the control cells were treated with the specific PARP inhibitor 1,5-dihydroxyquinoline (IQ). RESULTS: In DC cells the increase in cell death was associated with progressive telomere shortening, and this was not seen in the control cells. Treatment with IQ delayed the increase of apoptosis in DC cells. CONCLUSIONS: These observations indicate that the reduced expansion that characterises cultured cells obtained from patients with X linked DC is caused by premature telomere shortening.

Apoptosis↗
PubMed2002

Thymidylate synthase protein expression and activity are related to the cell proliferation rate in human cancer cell lines.

AIMS: To ascertain whether the expression and enzyme activity of thymidylate synthase (TS) are related to the rapidity of cell proliferation in human cancer cell lines. METHODS: Ten asynchronously growing human cancer cell lines of different origin were used, characterised by various doubling times. TS expression was evaluated by western blot analysis using the TS 106 monoclonal antibody. TS activity was determined by the enzyme catalytic assay. The quantitative variation of TS in different phases of the cell cycle was investigated using two parameter flow cytometry for the TS protein and DNA analysis. The number of proliferating cells was evaluated by Ki67 immunostaining. RESULTS: TS expression and activity were significantly related to each other (r = 0.765; p = 0.01) and to the cell doubling time (r = -0.899; p < 0.001 and r = -0.919; p < 0.001, respectively). Ki67 immunolabelling showed no association between the number of cycling cells and TS protein expression and activity. Two parameter flow cytometry indicated that differences of TS expression in the cell lines were not related to the cell cycle phases or to the proportion of S phase cells. CONCLUSIONS: These results show that the expression and activity of the TS protein in asynchronously growing cancer cells are significantly related to the cell doubling time; the faster the cell proliferation, the greater the expression and activity of TS. These findings could explain why TS values are of prognostic value per se and why tumours with high TS expression benefit more from chemotherapy.

Biomarkers, Tumor↗
PubMed2001

Coupling of 5-fluoro 2'-deoxyuridine to lactosaminated poly-l-lysine: an approach to a regional, non-invasive chemotherapy of liver micrometastases.

Nucleoside analogs conjugated with galactosyl-terminating peptides selectively enter liver cells and after intracellular release from the carrier partly exit into bloodstream, resulting in higher concentrations in liver blood than in systemic circulation. The aim of the present experiments was to ascertain whether, in mice injected with non-toxic doses of a 5-fluoro 2'-deoxyuridine (FUdR) conjugate with lactosaminated poly-L-lysine (L-poly(LYS)), the drug was released by hepatic cells in high enough amounts to be pharmacologically active on neoplastic cells infiltrating the liver. We observed that L-poly(LYS)-FUdR inhibited the growth of hepatic metastases induced by intrasplenic administration of murine colon carcinoma C-26 cells. L-poly(LYS)-FUdR was not toxic for C-26 cells in vitro, was selectively taken up by mouse liver, and was stable in mouse blood, indicating that the effect on the metastases was due to FUdR (and/or its active metabolites) released in liver blood after the conjugate was taken up by the hepatic cells. These results suggest that L-poly(LYS)-FUdR might be useful in adjuvant chemotherapy of tumors giving liver metastases. The drug released from hepatic cells into liver blood following conjugate administration via the peripheral venous route might accomplish a locoregional, non-invasive treatment of micrometastases nourished by liver sinusoids.

Amino Sugars↗
PubMed2001

[Silver-stained Nucleolar Organizer Regions (AgNOR)].

The present paper discusses the relevance of silver-stained Nucleolar Organizer Regions (AgNOR) to tumour pathology. First, the structural and functional aspects of AgNORs and the biological meaning of their quantitative variations have been reviewed to clearly define which indications can be obtained by the use of AgNOR. In continuously proliferating cells, AgNOR indicates the extent of ribosomal biogenesis, which is strictly related to the rapidity of cell proliferation. Therefore, AgNOR can be considered to represent a marker of cell proliferation rate and, in tumour pathology, should be used only for prognostic purposes. The predictive value of AgNOR, the only parameter which indicates the cell growth rate in situ in routinely processed cyto-histological samples, is strengthened by the combination with markers of cell growth kinetics (e.g. Ki67/MIB1).

Biomarkers, Tumor↗
PubMed2000

Nucleolar size indicates the rapidity of cell proliferation in cancer tissues.

In order to define the importance of the nucleolus in tumour pathology, the relationship between nucleolar size and function and tumour mass growth rate was studied in vivo. Ten established human cancer cell lines from colon carcinomas and neuroblastomas were inoculated subcutaneously in athymic mice and the doubling time (DT) of the xenograft tumour mass was calculated. The tumour DTs ranged from 3.2 to 15.7 days. Nucleolar size was evaluated in sections from formalin-fixed and paraffin-embedded tumour samples after silver staining for AgNOR proteins, using a specific image analysis system. The nucleolar area values were inversely related to the xenograft tumour mass DTs (r=-0.90; p<0.001). Nucleolar functional activity was also evaluated using rapid, intermediate, and slow growing tumours (one each). The values of RNA polymerase I activity measured in vitro were strongly related to the corresponding tumour DTs (r=-0. 99; p=0.03). The labelling indices (LIs) of three proliferation markers, MIB1, PCNA, and bromodeoxyuridine (BrdU), were also evaluated. As revealed by the MIB1 and PCNA LIs, almost all the cells of the xenograft tumours were cycling (86.6+/-5.6 SD and 95. 5+/-2.0 SD, respectively). Neither the MIB1, PCNA or BrdU LIs were related to the xenograft tumour mass DT, showing that the different growth rates of tumour xenografts were not due to different growth fractions, but were mainly related to different cell proliferation rates. The present data demonstrate that the size and function of the nucleolus are related to the cell proliferation rate of cancer tissue. Evaluation of nucleolar size after silver staining of AgNOR proteins represents a unique parameter for the histological assessment of rapidity of cell proliferation in tumour lesions.

Animals↗
PubMed2000

p120 expression provides a reliable indication of the rapidity of cell duplication in cancer cells independently of tumour origin.

p120 is a nucleolar protein that has been immunocytochemically detected in rapidly proliferating cells of a variety of human malignancies. In the present study, the relationship between p120 expression and the rapidity of cell proliferation was evaluated in 48 human tumours of different origins. The cell proliferation rate of cancer cells was determined by quantitative analysis of AgNOR proteins. p120 immunostaining and AgNOR protein quantity were measured by image cytometry and a highly significant correlation was found between the two variables, as evaluated by linear regression analysis (r=0.98, p<0.0001). The relationship between p120 expression and the rapidity of cell duplication was also studied in vitro, in six human cancer cell lines derived from different tumour types, characterized by various doubling times (ranging from 20 to 77 h). p120 expression was determined on western blots using specific anti-p120 monoclonal antibodies. Densitometric analysis revealed a highly significant inverse correlation between the integrated optical density values of the chemoluminescence bands at 120 kD and the cell line doubling times (r=-0.93; p=0.007). The same result was obtained in situ by correlating p120 immunostaining of the cytological preparations obtained from the six cancer cell lines with the corresponding doubling time (r=-0.98, p<0.0001). These results indicate that in cancer cells, the quantitative expression of p120 is directly related to the rapidity of cell duplication, independently of the tumour origin.

Antibodies, Monoclonal↗
PubMed2000

The AgNORs.

The structure and the function of interphase AgNORs and the importance of the "AgNOR" parameter in tumor pathology have been reviewed. Interphase AgNORs are structural-functional units of the nucleolus in which all the components necessary for ribosomal RNA synthesis are located. Two argyrophilic proteins involved in rRNA transcription and processing, nucleolin and nucleophosmin, are associated with interphase AgNORs and are responsible for their stainability with silver methods, thus allowing interphase AgNORs to be visulaized at light microscopic level, also in routine cyto-histopathological preparations. The number of interphase AgNORs is strictly related to rRNA transcriptional activity and, in continuously proliferating cells, to the rapidity of cell proliferation. Evaluation of the quantitative distribution of interphase AgNORs has been applied in tumor pathology both for diagnostic and prognostic purposes. The "AgNOR" parameter has been proved to represent a reliable tool for defining the clinical outcome of cancer disease, being an independent prognostic factor in many types of tumors.

Animals↗
PubMed2000

AgNORs in breast tumours.

There is evidence that the quantitative distribution of AgNOR proteins is a proliferation-related parameter that can be used as a prognostic index in tumour pathology. In breast cancer, some authors found a significant prognostic correlation of AgNOR protein quantity, whereas other did not. However, in all the reports dealing with AgNOR area (as opposed to count) this parameter was always turned out to be an independent prognostic indicator. The present study tests the significance of AgNOR proteins in a large series of primary breast carcinomas, exploring the associations between the AgNOR protein amount, as evaluated by image cytometry, and the other well-established prognostic markers commonly considered for breast cancer, along with patients' survival. Our results demonstrated a highly significant association between AgNOR protein quantity and tumour prognosis. Moreover, when the AgNOR area values were entered in multivariate analysis together with the other predictive parameters commonly considered in breast carcinomas, they showed an independent prognostic value together with Ki67-labelling index (LI), N-status and tumour size. Considering node-negative and -positive cases separately, the AgNOR protein area and Ki67-LI both come out as a independent predictors only in the latter group: the short follow-up time of our series (36 months median) could be responsible for this discrepancy.

Adenocarcinoma↗
PubMed2000

Can large cell change and high proliferative activity predict hepatocellular carcinoma in patients with hereditary hemochromatosis?

OBJECTIVE: Patients with hereditary hemochromatosis are at high risk of developing hepatocellular carcinoma. This study was undertaken to define whether large cell change and nucleolar organizer regions proliferative index (marker of high proliferative activity) predict hepatocellular carcinoma development in hereditary hemochromatosis. METHODS: Histological staining for large cell change and high proliferative activity were done on baseline liver biopsies of 74 patients with hereditary hemochromatosis (52 with and 22 without cirrhosis), prospectively followed-up for 83 +/- 53 months (range, 1-230 months). RESULTS: Large cell change and high proliferative activity were found only in cirrhotic patients; 16 of 52 patients (31%) had either the large cell change or high proliferative activity. Large cell change was more frequent in patients with hepatitis B surface antigen than in those positive for hepatitis C virus (57% vs 14%, p = 0.04). Hepatocellular carcinoma developed in 7 of 16 (44%) and in 6 of 36 patients (16%) of the patients positive or negative for these morphological variables. The probability of developing hepatocellular carcinoma at 7 yr of follow-up was significantly higher in patients with large cell change or high proliferative activity than in those without. The length of follow-up from baseline histology to hepatocellular carcinoma occurrence was shorter in patients with large cell change or high proliferative activity than in those without these changes (46 +/- 36 and 109 +/- 34 months, p = 0.01). A multivariate analysis indicated that in patients with cirrhosis, large cell change or high proliferative activity (considered as a single variable), and age >55 yr were the only independent variables significantly associated with the risk of developing hepatocellular carcinoma, with a risk ratio of 4.8 (confidence interval 1.2-18.2) and 4.0 (confidence interval 1.1-15.6), respectively. CONCLUSIONS: In hereditary hemochromatosis, the presence of large cell change or high proliferative activity in patients older than 55 yr with cirrhosis should be considered a strong predictor of hepatocellular carcinoma development, especially if hepatitis B virus infection coexists.

Adult↗
PubMed1999

c-erbB-2 over-expression in amplified and non-amplified breast carcinoma samples.

We investigated c-erbB-2 oncogene amplification and over-expression in 79 invasive breast carcinoma samples using fluorescence in situ hybridization (FISH) and immunohistochemistry, with the aim of studying relationships between neoplasms over-expressing c-erbB-2 with or without amplification and bio-pathological parameters used in clinical breast cancer. Nineteen samples showed amplification, and all of these were positive by immuno-histochemistry. Moderate or intense immunostaining was present in a further 22 samples without c-erbB-2 amplification and was not related to any increased number of c-erbB-2 signals: 15 samples exhibited chromosome 17 polysomy, 3 monosomy and 4 no FISH abnormalities. Thirty-eight samples were immunonegative: 18 exhibited chromosome 17 polysomy, 9 monosomy and 11 no alterations. Samples having c-erbB-2 over-expression associated with amplification showed DNA aneuploidy and hormonal receptor loss to a greater extent than those expressing c-erbB-2 without amplification or immunonegative samples (chi2 test, p = 0.007, 0.008 and 0.008, respectively). The proliferation rate, detected by Ag-NOR staining, was highest in amplified samples (Kruskal Wallis test, p = 0.009). Our results indicate that tumours showing both c-erbB-2 over-expression and amplification exhibit more aggressive biological characteristics than those with only over-expression or immunonegative tumours. Since both c-erbB-2 amplification and over-expression have been related to negative responses to chemotherapy and poor prognosis, these differences might have clinical implications. The combination of FISH and immuno-histochemistry may be helpful to achieve this aim.

Breast Neoplasms↗
PubMed1999

Inhibition of [3H]thymidine incorporation into DNA of rat regenerating liver by 2',2'-difluorodeoxycytidine coupled to lactosaminated poly-L-lysine.

The expression of asialoglycoprotein receptor (ASGP-R) on human hepatocarcinoma cells might be exploited to reduce the extrahepatic toxicity of DNA synthesis inhibitors by their conjugation with galactosyl- terminating peptides. We conjugated 2',2'-difluorodeoxycytidine (dFdC), an inhibitor of DNA synthesis active on solid tumors, with lactosaminated poly-L-lysine (L-poly(LYS)). In experiments in vitro, L-poly(LYS)-dFdC inhibited proliferation of Hep G2 cells, a human hepatocarcinoma cell line which maintains the ASGP-R. Inhibition was rescued by asialofetuin. To study the pharmacological action of the conjugate in vivo, we used rats 18-24 hr after 2/3 hepatectomy and observed that regenerating hepatocytes expressed ASGP-R on their surface and internalized L-poly(LYS)-dFdC. Conjugate uptake by bone marrow, spleen, and intestine was negligible. We also found that L-poly(LYS)-dFdC inhibited [3H]thymidine incorporation into DNA of regenerating liver. These results indicated that hepatectomized rats were a suitable animal model to study the pharmacological action, on DNA-synthesizing hepatocytes, of conjugates binding to ASGP-R and carrying inhibitors of DNA synthesis. L-poly(LYS)-dFdC also inhibited [3H]thymidine incorporation in bone marrow, spleen, and intestine. Evidence was obtained that inhibition of DNA synthesis in extrahepatic tissues was a consequence of drug release from hepatocytes into blood-stream after the bond with the carrier has been broken down within liver cells. Possible ways of reducing the exit of dFdC from liver cells, thereby obtaining an inhibition of DNA synthesis restricted to dividing hepatocytes, were discussed.

Amino Sugars↗
PubMed1999

Ischemia-reperfusion injury in rat fatty liver: role of nutritional status.

Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P <.01). Accordingly, fasting and fatty degeneration had a synergistic effect in exacerbating liver injury. Mitochondrial damage was a predominant feature of ultrastructural hepatocyte injury in fasted fatty livers. Glucose supplementation partially prevented the fasting-induced depletion of glycogen and improved the 7-day rat survival to 45%. These data indicate that rat fatty livers exposed to normothermic ischemia-reperfusion injury are much more sensitive to fasting than histologically normal livers. Because glucose supplementation improves both the hepatic glycogen stores and the rat survival, a nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

Alanine Transaminase↗
PubMed1999

The Feulgen reaction 75 years on.

The Feulgen reaction proposed by Feulgen and Rossenbeck 75 years ago is one of the cytohistochemical reactions most widely used in biology and medicine. It allows DNA in situ to be specifically stained based on the reaction of Schiff or Schiff-like reagents with aldehyde groups engendered in the deoxyribose molecules by HCl hydrolysis. The staining intensity is proportional to the DNA concentration. Current applications of the Feulgen reaction are mainly concerned with DNA quantification in cell nuclei by image cytometry for ploidy evaluation in tumor pathology. From the morphological point of view, specific demonstration of DNA in cell structures at the light microscopic level is very little used nowadays. On the other hand, application of the Feulgen principles to electron microscopy have recently allowed specific DNA-staining procedures to be developed for the study of the structural organization of DNA in situ.

Animals↗
PubMed1999

The asialoglycoprotein receptor in human hepatocellular carcinomas: its expression on proliferating cells.

The expression of the asialoglycoprotein receptor (ASGP-R) on human hepatocellular carcinoma (HCC) cells might be exploited to reduce the extrahepatic toxicity of DNA synthesis inhibitors by their conjugation with galactosyl-terminating peptides. In the present study we first assessed the frequency of ASGP-R expression in 60 HCCs. Secondly, we investigated whether the receptor was maintained on the plasma membranes of DNA synthesizing cancer cells. Needle biopsies of HCC were evaluated. Diagnosis and grading of HCC were performed on routine haematoxylin and eosin-stained sections according to Edmondson and Steiner (1953). Thirty-five tumours were grade I and II and were classified as well differentiated, while 25 tumours were grade III and IV and were classified as poorly differentiated. Sections from formalin-fixed, paraffin-embedded samples were incubated, after antigen retrieval, with an anti-ASGP-R monoclonal antibody revealed by secondary biotinylated antibody and streptavidin-biotin-peroxidase-diaminobenzidine reaction. A clear immunolabelling of plasma membranes of HCC cells was observed in 28 out of 35 (80%) well differentiated (grade I and II) and in five out of 25 (20%) poorly differentiated (grade III and IV) HCCs. The presence of the ASGP-R on the surface of DNA synthesizing cancer cells was also investigated after in vitro bromodeoxyuridine (BrdU) labelling of HCC samples by immunohistochemical visualization of both the ASGP-R and incorporated BrdU on the same section. The results obtained clearly demonstrated that DNA synthesizing cancer cells expressed the ASGP-R on their surface. The presence of ASGP-R on cell plasma membrane in the majority of differentiated HCCs and its maintenance on proliferating cells encourages studies in order to restrict the action of the inhibitors of DNA synthesis of HCC cells by their conjugation with galactosyl-terminating carriers internalized through this receptor.

Aged↗