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J Rincon

Publications and source records attributed to J Rincon.

16 recordsLinked to original sources
PubMed2001

Streptococcal erythrogenic toxin B induces apoptosis and proliferation in human leukocytes.

BACKGROUND: Previous reports have shown the presence of erythrogenic toxin type B (ETB), apoptosis, proliferation, and leukocyte infiltration in biopsies from patients with acute poststreptococcal glomerulonephritis (APSGN). METHODS: Attempting to correlate the apoptotic and proliferative events with the interaction of ETB or its precursor (ETBP) with leukocytes, mononuclear leukocytes from 12 healthy subjects were cultured with ETB or ETBP to analyze the levels of apoptosis, proliferation, expression of modulatory apoptosis gene products, and oxidative metabolism. After four days of incubation, cells were assessed for apoptosis by morphological criteria, annexin V assay, and terminal deoxy transferase uridine triphosphate nick end-labeling (TUNEL) assay. The expression of regulatory apoptosis genes was assessed by relevant monoclonal antibodies; proliferation was by incorporation of radioactive thymidine; and oxidative metabolism was by oxidation of 2',7'-dichlorofuorescein diacetate to 2',7'-dichlorofuorescein. Neutralization of Fas-L and cysteine protease activity of ETB were performed by incubation of ETB-treated leukocyte cultures with anti-human Fas-L mAb or with E64, respectively. RESULTS: Elevated levels of apoptosis in ETBP/ETB-treated leukocytes were found when compared with controls: morphological criteria (P < 0.01), Annexin V (control, 5.01 +/- 0.61; ETBP, 10.60 +/- 1.98%, P = 0.0005), and TUNEL (control, 12.5 +/- 2.6; ETBP, 20.56 +/- 3.06%, P = 0.001; ETB, 30.69 +/- 5.05%, P = 0.001). Increased expression of apoptosis was accompanied by increased expression of Fas (control, 20.15 +/- 5.28; ETBP, 43.51 +/- 5.6%, P = 0.03; ETB, 47.16 +/- 5.54%, P = 0.01), Fas ligand (control, 5.64 +/- 2.38; ETBP, 11.66 +/- 3.65%, P = 0.04; ETB, 16.39 +/- 5.05%, P = 0.02) and p53 products (control, 9.22 +/- 3.44; ETBP, 22.82 +/- 5.72%, P = 0.01; ETB, 24.60 +/- 5.20%, P = 0.01). Treatment of ETB-leukocyte cultures with anti-human Fas-L exhibited 2.2-fold lower apoptosis expression. Treatment with E64 significantly abrogated the apoptotic effect of ETB. There was no increment on leukocyte oxidative metabolism. Mononuclear leukocytes also showed elevated levels of proliferation when treated with different concentrations (from 50 to 6.2 microg/mL) of streptococcal proteins (Stimulation index ranging: ETBP, 5.6 +/- 1.9 to 6.4 +/- 1.9; ETB, 9.9 +/- 2.8 to 13.9 +/- 3.8). CONCLUSIONS: These results delineate an additional pathway for the pathogenesis of APSGN related to the role of cationic streptococcal ETB or ETBP on the induction of apoptosis and proliferation during the course of the disease.

Antibodies, Monoclonal↗
PubMed2001

Evidence against high glucose as a mediator of ERK1/2 or p38 MAPK phosphorylation in rat skeletal muscle.

Hyperglycemia leads to multiple changes in insulin signaling in skeletal muscle from people with type 2 diabetes. We hypothesized that mitogen-activated protein kinase (MAPK) signaling cascades may be directly activated by an acute exposure to high extracellular glucose concentrations. We determined whether an elevation in the extracellular glucose concentration would induce signal transduction in skeletal muscle via MAPK cascades. Epitrochlearis muscles were incubated in the presence of 5 or 25 mM glucose. Exposure of muscle to either hyperosmosis (600 mM mannitol) or insulin (6 nM) led to a marked increase in extracellular signal-regulated protein kinase (ERK)1/2 phosphorylation. Hyperosmosis elicited a 5.2-fold increase in p38 phosphorylation (P < 0.05), whereas insulin was without effect. ERK1/2 phosphorylation was not increased by high glucose exposure. After a 20-min exposure to 25 mM glucose, a tendency toward repressed (23%) p38 phosphorylation was observed (P = 0.06). No effect of high glucose was noted on signal transduction to signal transducer and activator of transcription 3 and Akt. In conclusion, short-term exposure of skeletal muscle to high levels of glucose does not appear to alter ERK1/2 or p38 MAPK phosphorylation.

Animals↗
PubMed1999

Changes in glucose transport and protein kinase Cbeta(2) in rat skeletal muscle induced by hyperglycaemia.

AIMS/HYPOTHESIS: We have previously reported that hyperglycaemia activates glucose transport in skeletal muscle by a Ca(2+)-dependent pathway, which is distinct from the insulin-signalling pathway. The aim of this study was to explain the signalling mechanism by which hyperglycaemia autoregulates glucose transport in skeletal muscle. METHODS: Isolated rat soleus muscle was incubated in the presence of various concentrations of glucose or 3-O-methylglucose and protein kinase C and phospholipase C inhibitors. Glucose transport activity, cell surface glucose transporter 1 and glucose transporter 4 content and protein kinase C translocation was determined. RESULTS: High concentrations of 3-O-methylglucose led to a concentration-dependent increase in [(3)H]-3-O-methylglucose transport in soleus muscle. Dantrolene, an inhibitor of Ca(2+) released from the sarcoplasmic reticulum, decreased the V(max) and the K(m) of the concentration-response curve. Protein kinase C inhibitors (H-7 and GF109203X) inhibited the stimulatory effect of high glucose concentrations on hexose transport, whereas glucose transport stimulated by insulin was unchanged. Incubation of muscle with glucose (25 mmol/l) and 3-O-methylglucose (25 mmol/l) led to a three fold gain in protein kinase Cbeta(2) in the total membrane fraction, whereas membrane content of protein kinase Calpha, beta(1), delta, epsilon and theta were unchanged. A short-term increase in the extracellular glucose concentration did not change cell surface recruitment of glucose transporter 1 or glucose transporter 4, as assessed by exofacial photolabelling with [(3)H]-ATB-BMPA bis-mannose. CONCLUSION/INTERPRETATION: Protein kinase Cbeta(2) is involved in a glucose-sensitive, Ca(2+)-dependent signalling pathway, which is possibly involved in the regulation of glucose transport in skeletal muscle. This glucose-dependent increase in 3-0-methylglucose transport is independent of glucose transporter 4 and glucose transporter 1 translocation to the plasma membrane and may involve modifications of cell surface glucose transporter activity.

3-O-Methylglucose↗
PubMed1998

Exercise in the management of non-insulin-dependent diabetes mellitus.

The incidence of non-insulin-dependent diabetes mellitus (NIDDM) has increased worldwide during the last decades, despite the development of effective drug therapy and improved clinical diagnoses. NIDDM is one of the major causes of disability and death due to the complications accompanying this disease. For the well-being of the patient, and from a public healthcare perspective, the development of effective intervention strategies is essential in order to reduce the incidence of NIDDM and its resulting complications. For the patient, and for society at large, early intervention programmes are beneficial, especially from a cost-benefit perspective. Physical activity exerts pronounced effects on substrate utilisation and insulin sensitivity, which in turn potentially lowers blood glucose and lipid levels. Exercise training also improves many other physiological and metabolic abnormalities that are associated with NIDDM such as lowering body fat, reducing blood pressure and normalising dyslipoproteinaemia. Clearly, regular physical activity plays an important role in the prevention and treatment of NIDDM. Since physical activity has been shown in prospective studies to protect against the development of NIDDM, physical training programmes suitable for individuals at risk for NIDDM should be incorporated into the medical care system to a greater extent. One general determinant in a strategy to develop a preventive programme for NIDDM is to establish a testing programme which includes VO2max determinations for individuals who are at risk of developing NIDDM. Before initiating regular physical training for people with NIDDM, a complete physical examination aimed at identifying any long term complications of diabetes is recommended. All individuals above the age of 35 years should perform an exercise stress test before engaging in an exercise programme which includes moderate to vigorously intense exercise. The stress test will identify individuals with previously undiagnosed ischaemic heart disease and abnormal blood pressure responses. It is important to diagnose proliferative retinopathy, microalbuminuria, peripheral and/or autonomic neuropathy in patients with NIDDM before they participate in an exercise programme. If any diabetic complications are present, the exercise protocol should be modified accordingly. The exercise programme should consist of moderate intensity aerobic exercise. Resistance training and high intensity exercises should only be performed by individuals without proliferative retinopathy or hypertension. Once enrolled in the exercise programme, the patient must be educated with regard to proper footwear and daily foot inspections. Fluid intake is of great importance when exercising for prolonged periods or in warm and humid environments. With the proper motivation and medical supervision, people with NIDDM can enjoy regular physical exercise as a means of enhancing metabolic control and improving insulin sensitivity.

Adipose Tissue↗
PubMed1997

Differential regulation of phosphoinositide 3-kinase adapter subunit variants by insulin in human skeletal muscle.

The role of phosphoinositide 3-kinase (PI 3-kinase) in insulin signaling was evaluated in human skeletal muscle. Insulin stimulated both antiphosphotyrosine-precipitable PI 3-kinase activity and 3-O-methylglucose transport in isolated skeletal muscle (both approximately 2-3-fold). Insulin stimulation of 3-O-methylglucose transport was inhibited by the PI 3-kinase inhibitor LY294002 (IC50 = 2.5 microM). The PI 3-kinase adapter subunits were purified from muscle lysates using phosphopeptide beads based on the Tyr-751 region of the platelet-derived growth factor receptor. Immunoblotting of the material adsorbed onto the phosphopeptide beads revealed the presence of p85alpha, p85beta, p55(PIK)/p55gamma, and p50 adapter subunit isoforms. In addition, p85alpha-NSH2 antibodies recognized four adapter subunit variants of 54, 53, 48, and 46 kDa, the latter corresponding to the p50 splice variant. Serial immunoprecipitations demonstrated that these four proteins were associated with a large proportion of the total PI 3-kinase activity immunoprecipitated by p85alpha-NSH2 domain antibodies. Antibodies to p85beta, p55(PIK)/p55gamma, and the p50 adapter subunit also immunoprecipitated PI 3-kinase activity from human muscle lysates. A large proportion of the total cellular pool of the 53-kDa variant, p50, and p55(PIK) was present in antiphosphotyrosine immunoprecipitates from unstimulated muscle, whereas these immunoprecipitates contained only a very small proportion of the cellular pool of p85alpha, p85beta, and the 48-kDa variant. Insulin greatly increased the levels of the 48-kDa variant in antiphosphotyrosine immunoprecipitates and caused smaller -fold increases in the levels of p85alpha, p85beta, and the 53-kDa variant. The levels of p50 and p55(PIK) were not significantly changed. These properties indicate mechanisms by which specificity is achieved in the PI 3-kinase signaling system.

3-O-Methylglucose↗
PubMed1997

Involvement of phosphoinositide 3-kinase in insulin stimulation of MAP-kinase and phosphorylation of protein kinase-B in human skeletal muscle: implications for glucose metabolism.

Isolated skeletal muscle from healthy individuals was used to evaluate the role of phosphoinositide 3-kinase (PI 3-kinase) in insulin signalling pathways regulating mitogen activated protein kinase (MAP-kinase) and protein kinase-B and to investigate whether MAP-kinase was involved in signalling pathways regulating glucose metabolism. Insulin stimulated glycogen synthase activity (approximately 1.7 fold), increased 3-o-methylglucose transport into human skeletal muscle strips (approximately 2 fold) and stimulated phosphorylation of the p42 ERK-2 isoform of MAP-kinase. This phosphorylation of p42 ERK2 was not blocked by the PI 3-kinase inhibitors LY294002 and wortmannin although it was blocked by the MAP-kinase kinase (MEK) inhibitor PD 98059. However, PD98059 (up to 20 micromol/l) did not block insulin activation of glycogen synthase or stimulation of 3-o-methylglucose transport. Wortmannin and LY294002 did block insulin stimulation of protein kinase-B (PKB) phosphorylation and stimulation of 3-o-methylglucose transport was inhibited by wortmannin (IC50 approximately 100 nmol/l). These results indicate that MAP-kinase is activated by insulin in human skeletal muscle by a PI 3-kinase independent pathway. Furthermore this activation is not necessary for insulin stimulation of glucose transport or activation of glycogen synthase in this tissue.

3-O-Methylglucose↗
PubMed1997

Adhesion molecule CD11a/CD18-deficient Burkitt's lymphoma cells lack the transcript for the beta, but not the alpha, integrin subunit.

Adhesion to cells and matrices participates in the regulation of lymphocyte proliferation, maturation and tissue localization. Consequently, abnormal patterns of adhesion molecule expression may contribute to the pathophysiology of lymphoproliferative disorders. Integrins are major cell-surface adhesive proteins composed by alpha and beta subunits. In contrast to normal lymphocytes, Burkitt's lymphoma (BL) cells lack the beta2 integrin CD11a/CD18. To study the molecular mechanism underlying this deficiency, presence of the transcript for each subunit was analysed by Northern blotting in group I BL lines (BL biopsy-like) and, for comparison, Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs). While transcripts for both CD11a (alpha subunit) and CD18 (beta subunit) were readily detected in LCLs, BL lines contained the transcript for the alpha subunit only. Treatment of BL cells with phorbol ester for 72 h induced expression of the beta subunit mRNA and the CD11a and CD18 antigens on the cell surface. The results indicate that the CD11a/CD18 deficiency of BL is due to absence of the beta subunit transcript and that this defect is restored by stimulation of the cells.

Blotting, Northern↗
PubMed1997

Effect of insulin on GLUT4 cell surface content and turnover rate in human skeletal muscle as measured by the exofacial bis-mannose photolabeling technique.

Insulin-stimulated glucose transport across the skeletal muscle cell membrane is a major regulatory step in postprandial glucose disposal. To estimate the total molar concentration of GLUT4 as well as the turnover rate of GLUT4 in human vastus lateralis muscles at the cell surface in the basal state and after insulin exposure, we have applied the sensitive exofacial bis-mannose photolabeling technique on in vitro incubated human skeletal muscle strips from healthy subjects. In addition, we have measured 3-O-methylglucose transport in other muscle strips prepared from the same surgically removed human skeletal muscle biopsies to compare glucose transport with cell surface level of GLUT4. Maximal in vitro insulin stimulation (2,400 pmol/l) resulted in a twofold increase compared with basal in both surface GLUT4 content (0.38 +/- 0.05 vs. 0.19 +/- 0.03 pmol/g wet muscle wt, P < 0.005) and 3-O-methylglucose transport (1.24 +/- 0.13 vs. 0.63 +/- 0.08 pmol x ml(-1) x h(-1), P < 0.005). The insulin-induced increment in 3-O-methylglucose transport was strongly correlated with the insulin-induced increase in cell surface GLUT4 content (r2 = 0.91; P < 0.005). The calculated turnover rate of human skeletal muscle GLUT4 amounted to approximately 8 x 10(4) min(-1) at 35 degrees C and was unaffected by insulin. In conclusion, maximal in vitro insulin stimulation of vastus lateralis muscle strips from healthy subjects resulted in a twofold rise in glucose transport as well as in cell surface content, whereas the turnover rate of GLUT4 was unaffected by insulin under the chosen experimental conditions.

3-O-Methylglucose↗
PubMed1996

Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment.

The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral insulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). Whole-body insulin-mediated glucose uptake assessed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats (P < 0.001) and addition of testosterone treatment further decreased insulin-mediated glucose uptake in OVX + T rats by 48% (P < 0.001) compared with controls. GLUT4 protein expression in soleus muscles was unaltered in the OVX and OVX + T rats compared with controls. Insulin induced a 3.7-fold increase (P < 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma membrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. Glycogen synthase protein expression in muscle homogenates was decreased by 25% in the OVX group (P < 0.05) and by 37% in the OVX + T group (P < 0.05) when compared with the control group. Insulin receptor and tyrosine kinase activities in the basal and insulin-stimulated states did not differ between the OVX and OVX + T rats. In conclusion, the absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase. Testosterone treatment further impairs whole-body insulin-mediated glucose uptake, presumably by additional impairment of glycogen synthase expression.

5'-Nucleotidase↗
PubMed1992

Expression of integrins and other adhesion molecules in Epstein-Barr virus-transformed B lymphoblastoid cells and Burkitt's lymphoma cells.

Lymphocytes adhere to cells or extracellular matrices to perform functions relating to cytotoxicity, extravasation and tissue localization, as well as modulation of lymphocyte growth and maturation. This adherence is mainly mediated by 3 families of cell-surface adhesion molecules: integrins, immunoglobulin-related molecules and selectins. Since variations in the degree of adherence may affect the pathophysiology of lymphoproliferative disorders, the expression of a large number of adhesion molecules was analysed on Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs), and on EBV-positive or EBV-negative Burkitt's lymphoma (BL) lines, by immunofluorescence flow cytometry and immunoprecipitation with monoclonal antibodies. With regard to the beta 1, beta 2 and beta 3 integrin subfamilies, LCLs strongly expressed CD49d/CD29 (VLA-4), CD11a/CD18 (Leu-CAMa, LFA-1) and CD51/CD61 (vitronectin receptor). These cells also abundantly expressed CD54 (ICAM-1) and CD58 (LFA-3) as well as the "homing receptors" L-selectin (LECAM-1) and CD44. BL lines had considerably lower amounts of VLA-4 than LCLs, and ICAM-1 was expressed only by some of the tumor lines. All other adhesion molecules were absent or minimally expressed in the BL cells.

Antibodies, Monoclonal↗
PubMed1991

Bloodstream Trypanosoma cruzi parasites from mice simultaneously express antigens that are markers of acute and chronic human Chagas disease.

Several recombinant Trypanosoma cruzi proteins previously isolated were used as antigens to analyse antibody specificities present in sera from human infections. Some parasite proteins such as SAPA (Shed Acute Phase Antigen) are antigenic early after infection. Others, like antigens 1 and 30, are antigenic mainly during the chronic phase of the infection. To understand why different proteins are antigenic at different periods of infection, specificities of antibodies present in the sera of infected mice were compared with the antigens expressed by parasites collected directly from blood. Parasites collected during the acute parasitaemia peak expressed not only antigen SAPA, but also antigens 1 and 30. However, only antibodies against SAPA were frequently observed during the early period and also in the chronic phase of murine infection. Long-lasting antibodies against SAPA were detected regardless of the mouse and parasite strains used. Furthermore, all 8 recombinant clones detected in a T. cruzi expression library with pooled sera from acutely infected mice were homologous to the SAPA gene. These results show that even though parasites from the acute parasitaemia peak in mice may express simultaneously several proteins known to be antigenic, only antibodies against SAPA were consistently detected.

Acute Disease↗
PubMed1991

Ethanol impairs certain aspects of neutrophil adhesion in vitro: comparisons with inhibition of expression of the CD18 antigen.

Since ethanol impairs polymorphonuclear leukocyte (PMNL) delivery to inflammatory sites, the effect of ethanol on PMNL adhesiveness was studied in vitro. Ethanol inhibited PMNL aggregation induced by formylmethionylleucylphenylalanine (FMLP) but not by phorbol myristate acetate (PMA), whereas responses to both stimuli were abolished by treating PMNL with monoclonal antibody 60.3 (against the adhesion protein CD18). This antibody also abrogated spontaneous and FMLP-stimulated PMNL adhesion to plastic, whereas ethanol reduced spontaneous but not FMLP-induced adherence. Chemotaxis in Boyden or agarose systems was not diminished by ethanol, but high concentrations of MAb 60.3 inhibited migration under agarose. Nonetheless, upregulation of cell surface expression of CD18 (assessed by immunofluorescence flow cytometry) induced by FMLP or PMA was similarly reduced by ethanol. Thus, ethanol inhibited only certain of PMNL adhesion, and although the stimulated up-regulation of CD18 expression was reduced it is unlikely that ethanol effects were mediated only by this inhibition.

Antigens, CD↗
PubMed1990

Leukocyte-cell adhesion: a molecular process fundamental in leukocyte physiology.

Leukocyte-cell adhesion is a form of physical contact characterized by fast (firm) stickiness between the cells. To analyze the biology and molecular basis of this process, an adhesion-specific assay was developed: the phorbol ester-induced aggregation of human lymphocytes. This rapid and antigen-independent intercellular adhesion requires cellular metabolism, an intact cytoskeleton and extracellular divalent cations, and is mediated by preformed cell-surface proteins referred to as CAMs. Phorbol ester also induces aggregation of monocytes and granulocytes, as well as adhesion of T lymphocytes to either B cells or monocytes and of the leukocytes to vascular endothelial cells. By using the adhesion-specific assay and blocking monoclonal antibodies, several CAMs have been identified, namely the Leu-CAM family (CD11a-c/CD18) and ICAM-1 (CD54). The Leu-CAM family is composed of Leu-CAMa (CD11a/CD18), Leu-CAMb (CD11b/CD18) and Leu-CAMc (CD11c/CD18), three glycoprotein heterodimers made of a common beta-chain and distinct alpha-chains. ICAM-1 is an adhesive ligand for Leu-CAMa. Expression and use of the various CAMs is selective in different types of leukocytes. The Leu-CAMs have been purified and partially characterized. CD18, whose gene is on human chromosome 21, contains 5-6 N-linked complex-type oligosaccharides, and CD11 binds Ca++. Another adhesion pathway is mediated by CD2 and CD58. CD2, a glycoprotein selectively expressed by T cells, is a receptor for CD58, a cell-surface adhesive ligand with broad tissue distribution. Antibodies to the latter CAMs do not block the phorbol ester-induced lymphocyte aggregation. Adhesion is involved in a large variety of leukocyte functions. Anti-Leu-CAM antibodies block induction of IL-2 production and lymphocyte proliferation. Lymphocyte-mediated cytotoxicity is also inhibited. Endogenous NK and LAK cells use Leu-CAMs, ICAM-1 and CD2, and sometimes RGD receptors, to bind and kill tumor cells. Endogenous compounds such as H2O2 and LTB4 also induce Leu-CAM-dependent adhesion in monocytoid cells and granulocytes, respectively, and degranulation of the latter cells is enhanced by the adhesion process. Homologous CAMs have been identified in rabbit and mouse. In in vivo studies in the former species, anti-Leu-CAM antibodies block adhesion of leukocytes to vascular endothelium and thereby their migration into extravascular tissues. The antibodies thus inhibit granulocyte accumulation and plasma leakage in inflammatory lesions, and induce lympho- and granulocytosis, indicating that cell-adhesion contributes to the distribution of leukocytes in the body.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

H2O2 activates CD11b/CD18-dependent cell adhesion.

Treatment of monoblastoid U-937 cells with low concentrations of H2O2 caused adhesion of the cells to plastic. The H2O2 induced adhesion was rapid with a t1/2 of congruent to 6 min and was optimally stimulated by 100 microM H2O2 with an ED50 of congruent to 50 microM. The response to H2O2 closely resembled the adhesive response of U-937 cells to phorbol esters in its time dependency, requirement for extracellular Mg2+ and inhibition by cytochalasin B as well as inhibition by monoclonal antibodies against the leucocyte adhesion molecules CD11b and CD18. Phorbol ester treatment of U-937 cells stimulated the phosphorylation of at least three endogenous substrates, pp28, pp34 and pp43, of which pp28 and pp43 also responded to H2O2-treatment with increased 32P-incorporation. The results suggest that H2O2 might be a physiological modulator of leucocyte adhesion, possibly operating by activating protein kinase C.

Antibodies, Monoclonal↗