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L Souza

Publications and source records attributed to L Souza.

At least 19 recordsLinked to original sources
PubMed1994

Production of functional myeloid cells from CD34-selected hematopoietic progenitor cells using a clinically relevant ex vivo expansion system.

There is increasing clinical interest focused on ex vivo manipulation and expansion of hematopoietic cells. In this study, we demonstrate that a simple combination of growth factors can expand progenitors to yield functional myeloid cells. Furthermore, this system can produce mature, functionally competent cells in the absence of fetal bovine serum (FBS), which will enhance the clinical utility of this approach. Hematopoietic progenitor cells obtained from normal bone marrow and from leukapheresis products were studied. The mononuclear fraction was enriched for CD34 cells using the Ceprate CD34 biotin kit (CellPro #LC34-1 or LC34-2). The selected cells were expanded for two weeks in Iscove's medium supplemented with 20% FBS and various combinations of interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF) and interleukin -6 (IL-6) added either simultaneously or sequentially. The optimal combination of these factors identified for myeloid expansion was simultaneous addition of IL-3, SCF and G-CSF (at 50 ng/ml each), resulting in an average 773 +/- 133-fold expansion of nucleated cells (n = 5). When corrected for the purity of CD34 cells in the starting population, the mean fold expansion with IL-3, SCF and G-CSF was 2,265 +/- 729. A mean of 74.7 +/- 10.5% (n = 3) of the expanded cells was positive for CD11b; 86-91% (n = 2) of the cells were promyelocytes or more mature granulocytes. Functional assays demonstrated normal phagocytosis and intracellular killing of Staphylococcus aureus (S. aureus) by the expanded cell population. Studies performed using cells expanded in defined serum-free media demonstrated that fold expansion was decreased and that the cells produced were less mature and functionally less competent than cells expanded with FBS. The decreased expansion could be partially reversed, and the functionality almost completely restored by the addition of autologous plasma.

Antigens, CD↗
PubMed1992

In vivo effects of interleukin-6 on thrombopoiesis in healthy and irradiated primates.

We have studied the in vivo effects of recombinant human interleukin-6 (rhIL-6) on hematopoiesis in eight healthy and nine irradiated cynomolgus monkeys. Of the healthy animals, three received rhIL-6 alone (10 micrograms/kg/d, subcutaneously [SC]), one received rhIL-6 in combination with rhIL-3 (10 micrograms/kg/d, SC), one received rhIL-6 in combination with recombinant cynomolgus granulocyte-macrophage colony-stimulating factor (rcGM-CSF; 10 micrograms/kg/d, SC), two received rhIL-6 in combination with recombinant human granulocyte-CSF (rhG-CSF; 10 micrograms/kg/d, SC), and one received rhIL-6 in combination with recombinant human leukemia inhibitory factor (rhLIF; 10 micrograms/kg/d, SC). All animals were treated for at least 2 weeks with rhIL-6 or the above mentioned combinations. rhIL-6 alone significantly increased the peripheral blood platelet counts (2- to 3.5-fold). The platelets reached a plateau between days 10 and 15 of treatment. No synergistic effects on platelet numbers were observed when rhIL-6 was combined with rhIL-3, rcGM-CSF, rhG-CSF, or rhLIF. In addition to rhIL-6, only rhLIF increased the platelet numbers when administered alone. To test whether rhIL-6 might also protect the animal from thrombocytopenia or shorten the time of thrombocytopenia after irradiation, we treated nine animals with total body irradiation (3.8 Gy). Six of the animals were additional treated with rhIL-6 (4 with 10 micrograms/kg/d; and 2 with 100 micrograms/kg/d) from day -1 or +1 to day 28 post irradiation. In these animals, rhIL-6 at the same dose effective in healthy animals (10 micrograms/kg/d) was not capable of protecting the animals from platelet nadir. However, when pegylated rhIL-6 was used at a dosage of 100 micrograms/kg/d post irradiation, the mean of the nadirs was 71,000/microL as compared with 39,000/microL in control animals and the time of thrombocytopenia was shorter (3 v 5 days). In all animals (healthy and irradiated), rhIL-6 did not increase the number of bone marrow megakaryocytes but induced a right shift of DNA ploidy in megakaryocytes. These data suggest that IL-6 acts as "thrombopoietin"-like activity, but not as "megakaryocyte-CSF"-like activity.

Animals↗
PubMed1992

Treatment of hairy cell leukemia with granulocyte colony-stimulating factor and recombinant consensus interferon or recombinant interferon-alpha-2b.

Patients with hairy cell leukemia and neutropenia (absolute neutrophil count less than 1.5 x 10(9)/L) were treated with recombinant granulocyte colony-stimulating factor (G-CSF) at doses of 3.6 and 7.2 micrograms/kg by daily subcutaneous injection, until normalization of neutrophil counts occurred. Patients then received either recombinant interferon-alpha-2b (r-IFN-alpha-2b) or a unique IFN, recombinant consensus IFN (rIFN-con-1), each given at doses of 10 micrograms/m2 subcutaneously three times a week, coupled with continued daily G-CSF therapy, for 3 months. After 3 months the G-CSF was discontinued; patients continued to take IFN for 1 year. All 10 patients responded to G-CSF with normalization of neutrophil counts within 2 weeks; the increase in neutrophil counts was greater in previously splenectomized patients. Four patients were treated with r-IFN-alpha-2b, and six were treated with rIFN-con-1. No patients developed recurrent neutropenia with the initiation of IFN therapy. Nine patients are evaluable for response to IFN. Five of six patients demonstrated hematologic improvement with rIFN-con-1, with two patients obtaining complete responses. All three patients receiving r-IFN-alpha-2b demonstrated hematologic improvement; one complete response was observed. Toxicities of both IFNs included influenza-like symptoms. We conclude that G-CSF can abrogate the myelosuppressive effects of IFN, and may be a useful adjunct to this therapy in neutropenic patients. We conclude that rIFN-con-1, the product of a synthetic gene, has activity in the treatment of hairy cell leukemia, and merits clinical investigation in other settings.

Drug Evaluation↗
PubMed1991

Comparative analysis of the in vivo radioprotective effects of recombinant granulocyte colony-stimulating factor (G-CSF), recombinant granulocyte-macrophage CSF, and their combination.

The purpose of the present study was to evaluate and compare the in vivo radioprotective effects of pre-total body irradiation (TBI) conditioning with recombinant granulocyte colony-stimulating factor (rG-CSF) and recombinant granulocyte-macrophage CSF (rGM-CSF) in a large series of lethally and supralethally irradiated mice. Also analyzed were the radioprotective effects of simultaneous as well as sequential combinations of rG-CSF and rGM-CSF. Our findings in 1,180 mice provide direct evidence that in vivo administration of rG-CSF or rGM-CSF before TBI protects a significant fraction of mice from the lethal effects of LD100/30 TBI. At equivalent doses, rG-CSF displayed a more potent radioprotective activity than rGM-CSF. Not only was rG-CSF radioprotective at much smaller doses than rGM-CSF, the survival rate after lethal TBI was also significantly higher in mice receiving optimally radioprotective doses of rG-CSF as compared with mice receiving optimally radioprotective doses of rGM-CSF. Pretreatment of mice with rGM-CSF markedly attenuated the radioprotective affects of rG-CSF in lethally as well as supralethally irradiated mice. Pretreatment with rG-CSF followed by rGM-CSF was slightly more effective than rG-CSF alone in supralethally irradiated mice but not in lethally irradiated mice. Notably, marked differences among different strains of mice were noted regarding the optimally radioprotective doses of rG-CSF or rGM-CSF as well as probability of survival and median survival time after lethal or supralethal TBI. This report confirms and extends previous studies concerning the potential of cytokines in prevention or therapy of lethal radiation injury.

Animals↗
PubMed1991

Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine.

Twenty-two patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex and multilineage hematopoietic defects were treated with recombinant granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) in a phase I/II trial. All patients were neutropenic and anemic after withdrawal of all bone marrow-suppressive drugs. Daily, G-CSF was subcutaneously self-administered until an absolute neutrophil count (ANC) greater than 6,000/microL was achieved and maintained for 2 weeks. Subcutaneous EPO was added to the regimen and the dose increased until an increase of 15 g/L of hemoglobin was observed. Groups of patients were administered increasing doses of zidovudine to determine their tolerance. G-CSF and EPO therapy was continued with dose modification to maintain an ANC greater than 1,500/microL and hemoglobin greater than 100 g/L. The dose of zidovudine was not altered. All 22 patients responded to G-CSF with a mean 10-fold increase in neutrophils occurring in less than 2 weeks. Significant increases in CD4 and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in all 20 evaluable patients within 8 weeks. Sixteen patients received 1,000 mg and four patients received 1,500 mg of zidovudine per day. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in eight of the 20 patients, six of whom had the study medications stopped. No patient had the study medications stopped because of neutropenia or thrombocytopenia. Toxicities were mild and did not require dose modifications. Limiting dilution plasma and lymphocyte co-cultures for HIV as well as serum p24 antigen levels did not change significantly during G-CSF or combined G-CSF and EPO therapy. HIV p24 antigen decreased significantly with zidovudine therapy. Opportunistic infections occurred in 14 patients but were successfully treated with myelosuppressive antimicrobial agents, including ganciclovir, without the development of neutropenia. These results suggest that combined therapy with G-CSF and EPO may improve the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of full-dose zidovudine in most patients intolerant of the hematologic effects of zidovudine without apparent alteration of HIV expression or the efficacy of zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Recombinant human granulocyte colony-stimulating factor increases circulating burst forming unit-erythron and red blood cell production in patients with severe human immunodeficiency virus infection.

Erythropoietin (EPO) is a major regulatory factor controlling red blood cell (RBC) production in humans. Although other humoral factors can alter the proliferation of committed early erythroid progenitors in vitro, no factor other than EPO has been clearly shown to induce proliferation of these cells in vivo. In a clinical trail of recombinant granulocyte colony-stimulating factor (G-CSF) and recombinant EPO in patients with advanced human immunodeficiency virus (HIV) infection, we noted reticulocytosis and increases in hemoglobin when G-CSF was administered before the administration of EPO. Subsequent studies demonstrated a significant increase in circulating burst forming unit-erythron (BFU-E) during daily recombinant G-CSF therapy. This increase was both time- and dose-dependent. The magnitude of increase in BFU-E correlated with the magnitude of increase in neutrophils and was associated with a mean increase in reticulocytes of 32,363/microL and a significant increase in mean hemoglobin of 1.04 +/- 0.34 g/dL over an 18-day interval. There was a significant increase in iron binding capacity and decreases in iron saturation and ferritin levels. In patients who were not recently transfused, there was an associated fall in endogenous erythropoietin levels. The increase in RBC production was most marked in patients who were severely anemic, transfusion-dependent, and who had elevated pretreatment EPO levels. There was no correlation between the increase in BFU-E and endogenous EPO levels or the time since last dose of zidovudine. The addition of recombinant EPO therapy three times weekly to patients did not result in further significant increases in BFU-E but did significantly increase hemoglobin. Our data suggest that recombinant G-CSF may be one of the hematopoietic factors that influences production of BFU-E and RBCs in humans.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Synthesis of granulocyte colony-stimulating factor and its requirement for terminal divisions in chronic myelogenous leukemia.

In this paper we demonstrate that maturing neoplastic cells from patients with chronic myelogenous leukemia (CML) constitutively produce G-CSF and are also receptive for this molecule. G-CSF functions as an autocrine growth factor in stable phase CML, and thus is responsible for divisions of maturing leukemic cells leading to an expansion of the compartment of mature cells. This observation is well in line with in vivo features of CML in stable phase, i.e., the hyperplasia of the mature granulocyte compartment. In acute blastic phase of CML expression of the G-CSF gene seems to be less common and not related to autonomous blast growth.

Antigens, CD↗
PubMed1990

Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized by severe neutropenia secondary to a maturational arrest at the level of promyelocytes. We treated five patients with SCN with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for 42 days and subsequently, between 1 and 3 months later, with rhG-CSF for 142 days. The objective was to evaluate the safety and ability of these factors to elicit a neutrophil response. rhGM-CSF was administered at a dose of 3 to 30 micrograms/kg/d (30 to 60 minutes, intravenously). In all patients, a specific, dose-dependent increase in the absolute granulocyte counts was observed. However, in four patients this increase was due to an increase in eosinophils, and in only one patient it was due to an increase in the absolute neutrophil counts (ANC). Subsequently, all patients received rhG-CSF at a dose of 3 to 15 micrograms/kg/d subcutaneously. In contrast to rhGM-CSF treatment, all five patients responded to rhG-CSF during the first 6 weeks of treatment with an increase in the ANC to above 1,000/microL. The level of ANC could be maintained during maintenance treatment. In one patient, the increase in ANC was associated with an improvement of a severe pneumonitis caused by Peptostreptococcus and resistant to antibiotic treatment. No severe bacterial infections occurred in any of the patients during CSF treatment. All patients tolerated rhGM-CSF and rhG-CSF treatment without severe side effects. These results demonstrate the beneficial effect of rhG-CSF in SCN patients.

Agranulocytosis↗
PubMed1990

In vivo radioprotective effects of recombinant human granulocyte colony-stimulating factor in lethally irradiated mice.

The purpose of this study was to investigate the in vivo radioprotective effects of recombinant human granulocyte colony stimulating factor (rhG-CSF) in lethally irradiated BALB/c mice. We initially analyzed the effects of increasing doses of rhG-CSF on survival of mice receiving 700 cGy (LD100/30) single dose total body irradiation (TBI). While 1 microgram/kg to 100 micrograms/kg doses of rhG-CSF were not radioprotective, a dose-dependent radioprotection was observed at 200 micrograms/kg to 4,000 micrograms/kg rhG-CSF. We next compared four different rhG-CSF treatment regimens side by side for their radioprotective effects in LD100/30 irradiated mice. One hundred percent of control mice receiving phosphate buffered saline died within 21 days after TBI with a median survival of 14 days. The median survival was prolonged to 20 days and the actuarial 60-day survival rate was increased to 27% when mice received 2,000 micrograms/kg rhG-CSF 24 hours before TBI (P = .0002; Mantel-Peto-Cox). Similarly, the median survival time was prolonged to 24 days and the actuarial 60-day survival rate was increased to 33%, when mice were given 2,000 micrograms/kg rhG-CSF 30 minutes before TBI. Optimal radioprotection was achieved when 2,000 micrograms/kg rhG-CSF was administered in two divided doses of 1,000 micrograms/kg given 24 hours before and 1,000 micrograms/kg given 30 minutes before TBI. This regimen prolonged the median survival time of LD100/30 irradiated mice to more than 60 days and increased the actuarial 60-day survival rate to 62% (P = .0001; Mantel-Peto-Cox). By comparison, no survival advantage was observed when mice received rhG-CSF 24 hours post-TBI. Similar radioprotective effects were observed when mice were irradiated with 650 cGy (LD80/30). The presented findings provide conclusive evidence that rhG-CSF has significant in vivo radioprotective effects for mice receiving LD100/30 or LD80/30 TBI.

Animals↗
PubMed1990

CSF in vivo: effects on hematopoiesis.

A summary of the biological models that Amgen and its collaborators have used to document the biological effects of granulocyte colony-stimulating factor (G-CSF), in particular its profound ability to stimulate granulopoiesis, was presented. Cloned human, bovine and canine G-CSF molecules have been investigated. G-CSF is a highly conservative molecule having 80% homology between human, bovine and canine, and 76% homology with cloned murine G-CSF. Preliminary evidence was advanced on a canine cyclic neutropenic model which affords an excellent opportunity to dissect in vivo homeostasis of neutrophil production. From these studies, it appears that G-CSF is important in the day-to-day maintenance of the neutrophil lineage. The efficacious use of G-CSF was advanced for a variety of non-neutropenic infectious states. These included preclinical burn and pneumonia studies in which animals received G-CSF-supportive treatment.

Animals↗
PubMed1990

Use of recombinant human hematopoietic growth factors and autologous bone marrow transplantation to attenuate the neutropenic trough of high-dose therapy.

This manuscript summarizes our experience with recombinant human granulocyte colony-stimulating factor (rhG-CSF) with high-dose Cytoxan, carmustine and etoposide (CBV in Hodgkin's disease). rhG-CSF regularly shortened the neutropenic phase following autologous bone marrow transplantation. However, this effect was more marked on the latter part of neutrophil recovery than the early part of granulocyte recovery to 100 granulocytes/microliters. The frequency of afebrile episodes was not reduced by rhG-CSF administration, but there was a tendency for the duration of fever to be shortened. Increasing doses and continuous infusion did not hasten the early part of neutrophil recovery needed to prevent the onset of infection, but was more effective than bolus infusion in increasing the rate of late neutrophil recovery. If fevers are to be prevented in this patient population, the duration of an absolute granulocyte count of less than 100/microliters will have to last only a few days. Recombinant hematopoietic growth factors alone do not hasten recovery fast enough to prevent the onset of afebrile episodes. Studies are described using both recombinant growth factor and peripheral blood and bone marrow cells to see if the neutropenic trough can be further shortened over that achievable with growth factor and autologous transplant alone.

Agranulocytosis↗
PubMed1990

Dose-response relationships between porcine somatotropin, muscle composition, muscle fiber characteristics and pork quality.

The dose-dependent effects of porcine somatotropin (pST) on cellular aspects of skeletal muscle growth, muscle composition and measures of pork quality were investigated in growing barrows and gilts. Eighty crossbred pigs weighing 46 kg were assigned randomly to receive daily subcutaneous injections of 0, 30, 60, 120 or 200 micrograms pST/kg BW until they weighed 100 kg. Semitendinosus muscle weights were increased with pST dose (linear, P less than .001) by 21%. Percentage of type I and type II muscle fibers was not changed with pST, but cross-sectional area of type I and type II fibers was increased in parallel with muscle weight. Percentage of moisture increased (P less than .01) and percentage of lipid decreased (P less than .01) as pST dose increased. The pH of the longissimus 24 h postmortem increased (P less than .01) .1 to .2 units with increasing pST dose, but subjective evaluation for color, firmness and wateriness of the longissimus indicated no discernible treatment effect. Gardner color difference meter "Rd" and "A" values decreased (P less than .01) with a pST dose of 60 micrograms/kg or more, signifying a slightly darker and less red color, respectively, of the longissimus muscle. Weight loss of loin chops 2.54 cm thick cooked to 71 degrees C (20.3% to 23.7%) and shear force of cores 1.27 cm in diameter (2.89 to 3.76 kg) were not related to pST treatment or dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation.

Granulocyte colony-stimulating factor (G-CSF) was administered by continuous subcutaneous infusion to 15 patients with non-myeloid malignancies treated by high-dose chemotherapy and autologous bone marrow infusion. G-CSF was given at variable dosage based on neutrophil count. Sustained serum levels of G-CSF were achieved. Neutrophil recovery was accelerated in G-CSF treated patients compared with 18 historical controls and exceeded 0.5 x 10(9)/l at a mean of 11 days after marrow infusion compared with 20 days for controls, a significant difference. This reduction led to significantly fewer days of parenteral antibiotic therapy, 11 versus 18 days in controls, and less isolation in reverse-barrier nursing, 10 versus 18 days.

Agranulocytosis↗
PubMed1989

Effects of recombinant growth factors on radiation survival of human bone marrow progenitor cells.

The purpose of this study was to evaluate the individual radioprotective effects of 4 distinct purified recombinant human hematopoietic growth factors, namely recombinant human granulocyte-macrophage colony stimulating factor (rGM-CSF), recombinant human granulocyte colony stimulating factor (rG-CSF), recombinant human interleukin 1 (rIL-1), and recombinant human interleukin 2 (rIL-2) on human myeloid (CFU-GM) and erythroid (BFU-E) bone marrow progenitor cells. We demonstrate that (a) preconditioning with rGM-CSF, rG-CSF, or rIL-1 enables CFU-GM to repair sublethal radiation damage and renders CFU-GM less radiosensitive, (b) preconditioning with rGM-CSF or rIL-1 enables BFU-E to repair sublethal radiation damage, and (c) preconditioning with rIL-2 does not increase the radiation survival of CFU-GM or BFU-E. The effects of recombinant growth factors, in particular rGM-CSF, on the radiation damage repair, radiosensitivity, and proliferative activity of bone marrow progenitor cells resulted in a substantial increase in the mean numbers of progenitor cell-derived hematopoietic colonies in irradiated marrow samples. The effects of rGM-CSF on the radiation response of CFU-GM and BFU-E, and the effects of rG-CSF as well as rIL-1 on the radiation response of CFU-GM did not appear to require the presence of T-cells/T-cell precursors, NK-cells, B-cells/B-cell precursors, monocytes, macrophages, MY8 antigen positive non-CFU-GM myeloblasts, promyelocytes, myelocytes, metamyelocytes, granulocytes, or glycophorin A positive erythroid cells since virtually identical results were obtained with unsorted marrow samples or highly purified fluorescence activated cell sorter (FACS) isolated progenitor cell suspensions. To our knowledge, this report represents the first study on recombinant human growth factor-induced modulation of the radiation responses of normal human bone marrow progenitor cells.

Cell Survival↗
PubMed1989

The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer.

Granulocyte colony stimulating factor (G-CSF) was given to 17 patients with advanced breast and ovarian cancer in order to increase the intensity and effectiveness of chemotherapy. Treatment with doxorubicin, at doses of 75 mg m-2 (n = 4 patients), 100 mg m-2 (n = 5), 125 mg m-2 (n = 6) and 150 mg m-2 (n = 2), was followed by infusion of G-CSF for 11 days. G-CSF administration resulted in a return of the absolute neutrophil count to normal or above normal levels within 12-14 days at all dose levels of doxorubicin used and allowed the administration of up to three cycles of high dose chemotherapy at 14 day intervals. An absolute neutrophil count greater than 2.5 x 10(9)l-1 was not reached until day 19-21 after 75 mg m-2 of doxorubicin given without G-CSF. At doses of doxorubicin of 125 mg m-2 and 150 mg m-2 all tumours regressed rapidly, although there was marked epithelial toxicity. The overall response rate in patients with advanced breast cancer was 80% with a median time to progression of 6 months. Two months after doxorubicin-G-CSF therapy there was a pronounced improvement of symptoms compared with before treatment. Thus the effectiveness of chemotherapy may be enhanced and treatment duration shortened by the use of G-CSF infusions. Further studies of this promising approach are warranted.

Adult↗
PubMed1989

The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo.

Cell proliferation in the bone marrow and blood of two patients with metastatic breast cancer who were treated with granulocyte colony-stimulating factor was studied by using [3H]thymidine labeling and autoradiography. Additionally, the fate of neutrophils labeled with 99mTc-hexamethylpropyleneamineoxime was observed following granulocyte colony-stimulating factor infusion. Proliferation increased in all stages of granulopoiesis, but a significant amount of the increased production stemmed from a greater input to the myeloblast compartment. Changes in the myelogram combined with the increased labeling indicated a faster throughput of cells, which resulted in labeled cells appearing in the circulation within 1 day compared to the normal 4 or 5 days. The 99mTc studies demonstrated no sequestration of circulating neutrophils by spleen, lungs, or liver. The half-life of the circulating neutrophils was not significantly changed, and calculations from the flow of labeled cells to the peripheral blood indicated an increase of 3.2 extra amplification divisions during neutrophil development. The dramatic neutrophil response to granulocyte colony-stimulating factor can therefore be accommodated by a relatively modest increase in granulopoietic activity.

Adult↗