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Biomedical subjects

John M Stewart

Publications and source records attributed to John M Stewart.

17 recordsLinked to original sources
PubMed2005

Discovery of a dual-function peptide that combines aminopeptidase N inhibition and kinin B1 receptor antagonism.

Previous analyses support that aminopeptidase N is a major inactivation pathway for high-affinity peptide ligands of the human and rabbit forms of the kinin B(1) receptor (agonists or antagonists). In this study, we found that the high-affinity antagonist B-9958 (Lys-Lys-[Hyp(3), CpG(5), D-Tic(7), CpG(8)]des-Arg(9)-BK; des-Arg(9)-BK, des-arginine(9)-bradykinin) is an aminopeptidase N substrate based on its capacity to compete for the hydrolysis of the chromogenic substrate L-Ala-p-nitroanilide by membranes isolated from human or rabbit arterial smooth muscle cells, its inactivation in the presence of these membranes (radioreceptor assay) and on its intense potentiation by the aminopeptidase N inhibitor amastatin in the rabbit aorta contractility assay (gain of 0.84 units in the pA(2) scale). Analogs of B-9958 in which the N-terminal Lys residue was substituted by D-Lys or D-Arg (B-10352 and B-10356, respectively) showed reduced affinity at the human or rabbit B(1) receptors (1.2-2.8-fold), as estimated by the displacement of [(3)H]Lys-des-Arg(9)-BK binding, but were more potent antagonists of des-Arg(9)-BK-induced contraction of the rabbit aorta than B-9958 in the absence of amastatin; they were not potentiated by the latter inhibitor. Unexpectedly, B-10356 inhibited L-Ala- p-nitroanilide hydrolysis without being inactivated, suggesting that it is an aminopeptidase N inhibitor. This was verified because B-10356 (but not B-10352) potentiated peptides unrelated to kinins but susceptible to aminopeptidase N inactivation (angiotensin III, thrombin receptor hexapeptide agonist). B-10356 inhibits dual molecular targets (aminopeptidase N enzyme K(i), 0.9-2.2 microM; kinin B(1) receptor binding K(i), 0.5-1.5 nM), and this may be an advantage for specific therapeutic applications (e.g., inhibition of angiogenesis).

Animals↗
PubMed2005

Endogenous aminopeptidase N decreases the potency of peptide agonists and antagonists of the kinin B1 receptors in the rabbit aorta.

The B(1) receptor for kinins is selectively stimulated by bradykinin-related fragments lacking the C-terminal arginine, des-arginine(9)-bradykinin (des-Arg(9)-BK), and Lys-des-Arg(9)-BK. The latter peptide is the optimal agonist at the human and rabbit receptor. The B(1) receptor is inducible as a function of inflammatory conditions in the vasculature. We studied the effect of endogenously expressed peptidases on the potency of ligands of this receptor in an established bioassay, the rabbit aorta contractility. The potency measured for agonists (EC(50)) or antagonists (pA(2) scale) in this assay was compared with the affinity of each agent determined using [(3)H]Lys-des-Arg(9)-BK binding competition in cultured aortic smooth muscle cells and with the competition K(i) for the hydrolysis of the aminopeptidase chromogenic substrate L-Ala-p-nitroanilide by smooth muscle cell membranes. The contractile potency of the agonist Lys-des-Arg(9)-BK is decreased by in situ metabolism, and aminopeptidase N mediates most of the distortion (inhibited by amastatin but not efficiently by puromycin). At the other end of the spectrum, the fully protected agonist Sar-[D-Phe(8)]des-Arg(9)-BK is not significantly potentiated by peptidase inhibitors. A similar distortion of apparent potency was observed for some peptide antagonists used in the contractility assay, B-10350 (Lys-Lys-[Hyp(3), Igl(5), d-Tic(7), CpG(8)]des-Arg(9)-BK) and Lys-[Leu(8)]des-Arg(9)-BK being intensely potentiated by amastatin treatment and effective L-Ala-p-nitroanilide competitors. N-Protected peptide antagonists or a nonpeptide antagonist of the B(1) receptor were not potentiated by amastatin. The coexpression of aminopeptidase N and the kinin B(1) receptor in rabbit arterial tissue is of interest for the inactivation of the high-affinity agonist Lys-des-Arg(9)-BK and for the design of hydrosoluble antagonist drugs.

Animals↗
PubMed2005

Cytologic features of renal medullary carcinoma.

BACKGROUND: Renal medullary carcinoma is a rare tumor that is most common in young black men with sickle cell disease or trait. Patients often present with advanced disease at the time of diagnosis, and their prognosis is poor, even with aggressive therapy. The clinical and pathologic features of renal medullary carcinoma have been described in several articles, but reports describing the cytologic features are rare. METHODS: In the current report, the authors describe the cytologic features of three cases of renal medullary carcinoma. The patients were young black men with sickle cell trait ages 20 years, 33 years, and 33 years. RESULTS: All three patients presented with hematuria, flank pain, and a renal mass. The cytologic specimens from all three patients showed primarily cohesive groups of cells with vacuolated cytoplasm that often displaced or indented the nuclei. The nuclei often had irregular membranes, coarse or vesicular chromatin, and prominent nucleoli. Both of the two patients who were tested with fluorescence in situ hybridization were negative for the bcr/abl rearrangement. CONCLUSIONS: Renal medullary carcinoma should be considered in the differential diagnosis of patients who present with hematuria or a renal mass, especially in young black men with sickle cell disease or trait. Cytologically, renal medullary carcinoma cells appear similar to the cells in high-grade carcinoma. Immunohistochemical studies can be helpful in distinguishing renal medullary carcinoma from other poorly differentiated kidney tumors, except for collecting duct carcinoma. The clinical findings are key to diagnosing renal medullary carcinoma.

Adult↗
PubMed2005

Treatment of severe pulmonary hypertension: a bradykinin receptor 2 agonist B9972 causes reduction of pulmonary artery pressure and right ventricular hypertrophy.

Bradykinin is an important modulator of endothelial cell function and has also a powerful cardioprotective effect. Here we report that treatment of severely pulmonary hypertensive rats (that recapitulate several of the physiological and pathological characteristics of the human pulmonary vascular disease, including dramatic right ventricular hypertrophy, pericardial effusion and death) with a newly synthesized long-acting bradykinin B2 receptor agonist B9972 caused reduction of the pulmonary artery pressure (PAP=51+/-2.0 versus 68+/-2.8 of untreated animals) and of right ventricular hypertrophy (Rv/Lv+S=0.55+/-0.02 versus 0.73+/-0.03 of untreated rats) and activation of Akt. Long-term stimulation with B9972 in our animal model of SPH resulted in decreased expression of the B2 receptor in lung vasculature. Treatment with B9972 decreased the number of plexiform lesions in the lungs by inducing cell apoptosis in the obliterated vessels and by restoring caveolin-1 expression. B9972 also promoted eNOS activation. In vitro B9972 caused activation of caspase-3 as well as Erk and induction of prostacyclin production in rat pulmonary microvascular EC. Taken together our data suggest that a stable bradykinin B2 agonist B9972 demonstrates the capacity to reduce severe pulmonary hypertension, right ventricular hypertrophy and induce apoptosis of hyperproliferative cells in pre-capillary pulmonary arterioles.

Animals↗
PubMed2005

Combination cancer chemotherapy with one compound: pluripotent bradykinin antagonists.

Lung and prostate cancers are major health problems worldwide. Treatments with standard chemotherapy agents are relatively ineffective. Combination chemotherapy gives better treatment than a single agent because the drugs can inhibit the cancer in different pathways, but new therapeutic agents are needed for the treatment of both tumor types. Bradykinin (BK) antagonists offer advantages of combination therapy in one compound. These promising multitargeted anti-cancer compounds selectively stimulate apoptosis in cancers and also inhibit both angiogenesis and matrix metalloprotease (MMP) action in treated lung and prostate tumors in nude mice. The highly potent, metabolism-resistant bradykinin antagonist peptide dimer, B-9870 [SUIM-(DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg)2] (SUIM=suberimidyl; Hyp=4-hydroxyproline; Igl=alpha-(2-indanyl)glycine; Oic=octahydroindole-2-carboxylic acid) and its non-peptide mimetic, BKM-570 [2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-L-tyrosine-N-(4-amino-2,2,6,6-tetramethylpiperidyl)amide] are superior to the widely used but toxic chemotherapeutic drugs cisplatin and taxotere. In certain combinations, they act synergistically with standard anti-cancer drugs. Due to its structure and biological activity, BKM-570 is an attractive lead compound for derivatization and evaluation for lung and prostate cancer drugs.

Animals↗
PubMed2004

Characterization of the B2 receptor and activity of bradykinin analogs in SHP-77 cell line by Cytosensor microphysiometer.

The Cytosensor microphysiometer device (Molecular Devices, Sunnyvale, CA) is capable of measuring the rate at which cells acidify their environment in response to ligand-receptor binding. By measuring the extracellular acidification response (ECAR) we characterized some aspects of ligand-B2 receptor interaction in SHP-77 cell line. SHP-77 cells maximally acidified their environment within 30 s after the exposure to bradykinin (BK) or the BK agonist, B9972, with the maximum effect seen at a ligands concentration of 1 microM. Fetal bovine serum (FBS) modulated the binding of BK or B9972, showing that B9972 is a partial agonist. In addition, the binding of BK agonist or antagonist to the B2 receptor showed different ECAR and different interaction with other intracellular and plasma membrane proteins. Our microphysiometrical results showed that two parameters, antagonist binding affinity (pD2) and antagonist potency (pIC50) are required to characterize BK antagonist activity for the B2 receptor in the SHP-77 cell line. The previously used parameter of B2 antagonist activity, pA2, had high variation and poor correlation with the inhibition of SHP-77 cell growth in vitro and suppression of tumor growth when SHP-77 cells were injected to mice. Our results permit us to conclude that BK agonists and antagonists differ in their interactions with the B2 receptor and consequently elicit different cell responses. Based on our results, we have developed a new microphysiometrical assay for analyzing the activity of BK agonists and antagonist in SHP-77 cells, which may facilitate the discovery of new potent anticancer drugs.

Amino Acid Sequence↗
PubMed2004

Evidence for bradykinin as a stimulator of thirst.

Angiotensin-converting enzyme inhibition (ACEI) with captopril has been shown to increase water intake and urine output in rats, but the mechanism is unknown. ACEI impairs the conversion of ANG I to ANG II, a dipsogenic hormone, and impairs the degradation of bradykinin. The goal of this study was to examine the role of bradykinin in the polydipsia and polyuria associated with ACEI. Male Sprague-Dawley rats received captopril (CPT; 20 mg.kg(-1).day(-1)) in ground chow for 48 h. Water intake, food intake, and urine output were monitored and compared with control rats (CTL), rats receiving captopril treatment with limited water intake (CPT-LIM), and rats receiving captopril treatment with ad libitum water intake plus 24-h treatment with the bradykinin antagonist B-9430 (CPT-BK1). CPT rats consumed significantly more water and produced more urine vs. CTL. Urine osmolality was significantly decreased in CPT rats vs. CTL. Inner medullary aquaporin-2 (AQP2) protein abundance was also markedly decreased in CPT rats vs. CTL. These findings were reversed in CPT-LIM rats, suggesting captopril-induced primary polydipsia. CPT-BKI rats demonstrated parameters no different from CTL despite ad libitum water intake. Mean arterial pressure and 24-h creatinine clearance did not differ among groups. We conclude that ACEI with captopril induces primary polydipsia despite impaired production of the dipsogen ANG II and that this primary increase in water intake is likely the cause of the decreased protein abundance of inner medullary AQP2. Furthermore, this dipsogenic effect was reversed by antagonism of bradykinin, thus implicating this hormone in thirst regulation in the rat.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Bradykinin antagonists: discovery and development.

Practical bradykinin antagonists were discovered in 1984 by Vavrek and Stewart and reported in "Peptides." At that time there was already much evidence for involvement of bradykinin in inflammation and pain, so the specific, competitive antagonists were widely accepted and applied. The key to conversion of bradykinin into an antagonist was replacement of the proline residue at position 7 with a D-aromatic amino acid. Other modifications converted the initial weak antagonists into modern peptides which are totally resistant to all degrading enzymes, are orally available, and have been used in clinical trials. Non-peptide bradykinin antagonists have also been developed.

Amino Acids↗
PubMed2003

Pediatric soft tissue sarcomas.

Many of the soft tissue sarcomas that occur in children are of the same histology as those in adults; however, the relative prevalence of these sarcomas is different between children and adults. In some cases, the biologic behavior of pediatric sarcomas is more benign than that in adults. Treatment for sarcomas in children is also different. Pediatric sarcomas are more commonly responsive to chemotherapy. Furthermore, in children who are still growing, surgery and radiation are associated with higher morbidity than in adults. This article discusses the diagnosis and treatment of rhabdomyosarcoma and undifferentiated sarcomas, with an emphasis on surgical considerations, and the diagnosis and treatment of nonrhabdomyosarcomatous soft tissue sarcomas in children.

Child↗
PubMed2003

Extensive pigmented villonodular synovitis with markedly pigmented lymphadenopathy and its implication for differential diagnosis with malignant melanoma.

A 51-year-old male presented with a 5 cm left knee mass. Fine needle aspiration revealed large epithelioid cells with prominent nucleoli and abundant cytoplasmic pigment, consistent with malignant melanoma. Left inguinal lymphadenopathy was present, which was suspicious for metastatic disease by ultrasound examination. A dark perianal skin lesion was also identified, therefore raising the possibility of a primary melanoma. The knee and perianal lesions were resected and inguinal sentinel node biopsy was performed. In the specimen from the knee, there were clusters and fascicles of spindle and epithelioid cells with prominent nucleoli. Many of the cells displayed abundant, granular, brown, cytoplasmic pigment. The lymph node showed clusters of similar cells located in the subcapsular sinus. Immunohistochemical study showed that the cells expressed CD68, but failed to express S-100, MART-1, and gp100. The cytoplasmic pigment was positive for iron staining. The final diagnosis was pigmented villonodular synovitis. This case illustrates that pigmented villonodular synovitis may present with lymphadenopathy, mimicking a malignant process, including melanoma. Immunohistochemical studies may be essential for establishing the correct diagnosis.

Biopsy, Fine-Needle↗
PubMed2002

Bradykinin antagonists as new drugs for prostate cancer.

Bradykinin (BK) is an autocrine growth factor for lung and prostate cancers. BK also facilitates tumor extension by increasing tissue permeability and stimulating angiogenesis. Peptide BK antagonists are in development as potential new drugs for lung cancer. Newer nonpeptide BK antagonists have even higher potency against lung cancer, in vitro and in vivo. These compounds have now been applied to the study of prostate cancers, and have been found to be effective. Prostate cancer cell line PC3 is derived from a late-stage, hormone-independent, metastatic tumor; its growth is difficult to inhibit. Our established BK antagonists, while less effective against this line of prostate cancer in xenografts in nude mice than against lung cancer, are active and have led the way to development of new peptide and nonpeptide agents for prostate cancer. In addition to inhibiting cancer cell growth directly, they inhibit angiogenesis mediated by vascular endothelial growth factor, and inhibit increased tissue permeability mediated by membrane metalloproteases in these tumors. This class of compounds offers hope for development of new drugs for refractory prostate cancer.

Angiogenesis Inhibitors↗
PubMed2002

Correlation of secondary structures of bradykinin B1 receptor antagonists with their activity.

The secondary structure of a bradykinin B(1)receptor antagonist B-10324 (F5C-Lys-(1)- Lys(0)-Arg(1)-Pro(2)- Hyp(3)-Gly(4)-CpG(5)- Ser(6)-DTic(7)-CpG(8)) was determined by NMR at 800MHz. The conformational data are compared with those obtained previously for two bradykinin B(1) receptor antagonists, namely B-9858 (Lys-(1)- Lys(0)-Arg(1)-Pro(2)- Hyp(3)-Gly(4)-Igl(5)- Ser(6)-DIgl(7)-Oic(8)) and B-10148 (Lys-(1)-Lys(0)-Arg(1)- Pro(2)-Hyp(3)-Gly(4)- Igl(5)-Ser(6)-DF5F(7)- Oic(8)). The abnormal amino acids are: Hyp, trans-4- hydroxyproline; Tic, 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid; Oic, (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid; Igl, alpha(2- indanyl)glycine; F5F, 2,3,4,5,6-pentafluorophenylalanine; CpG, alpha- cyclopentylglycine. F5C, pentafluorocinnamoyl, is the N-terminal protecting group and is not involved in the peptide secondary structure. B-10324 contains an N-terminal Pro(2)- CpG(5) distorted type II beta-turn whereas the rest of the peptide is random. A salt bridge is not observed between the carboxylate group at the C-terminal end and the Arg(1) side chain, in contrast to that previously observed for B-9858 and B- 10148. The conformations are correlated with the measured B(1) receptor antagonist activities (J.-F. Larrivée, L. Gera, S. Houle, J. Bouthillier, D. R. Bachvarov, J. M. Stewart and F. Marc au, Br. J. Pharmacol. 131, 885-892 (2000)). The importance of the N-terminal beta-turn is highlighted.

Bradykinin↗
PubMed2002

Bradykinin-related compounds as new drugs for cancer and inflammation.

Bradykinin (BK) (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is an important growth factor for small-cell lung cancer (SCLC) and prostate cancer (PC). These cancers have cells of neuroendocrine origin and express receptors for a variety of neuropeptides. BK receptors are expressed on almost all lung cancer cell lines and on many PC cells. Our very potent BK antagonist B9430 (D-Arg-Arg-Pro-Hyp-Gly-lgl-Ser-D-Igl-Oic-Arg) (Hyp, trans-4-hydroxy-L-proline; Ig1, alpha-2-indanylglycine; Oic, octahydroindole-2-carboxylic acid) is a candidate anti-inflammatory drug but does not inhibit growth of SCLC or PC. When B9430 is dimerized by N-terminal cross-linking with a suberimide linker, the product B9870 is a potent growth inhibitor for SCLC both in vitro and in vivo in athymic nude mice. Daily i.p. injection at 5 mg x kg(-1) day(-1) beginning on day 8 after SCLC SHP-77 cell implantation gave 65% inhibition of tumor growth. B9870 stimulates apoptosis in SCLC by a novel "biased agonist" action. We have also developed new small mimetic antagonists. BKM-570 (F5C-OC2Y-Atmp) (F5C, pentafluorocinnamic acid; OC2Y, O-2,6-dichlorobenzyl tyrosine; Atmp, 4-amino-2,2,6,6-tetramethylpiperidine) is very potent for inhibition of SHP-77 growth in nude mice. When injected daily i.p. at 5 mg x kg(-1), M-570 gave 90% suppression of tumor growth. M-570 is more potent than the well-known anticancer drug cisPlatin (60% inhibition) or the recently developed SU5416 (40% inhibition) in this model. M-570 also showed activity against various other cancer cell lines in vitro (SCLC, non-SCLC, lung, prostate, colon, cervix) and inhibited growth of prostate cell line PC3 in nude mice. M-570 and related compounds evidently act in vivo through pathways other than BK receptors. These compounds have clinical potential for treatment of human lung and prostate cancers.

Animals↗
PubMed2002

A bradykinin antagonist and a caspase inhibitor prevent severe pulmonary hypertension in a rat model.

Chronically hypoxic rats (exposed to 5000 m elevation for 3 weeks) develop pulmonary hypertension (PH) that is reversed upon return to normoxia and is blocked by bradykinin (BK) antagonist B9430 treatment (100 microg/kg s.c. three times per week). Treatment of rats with both the synthetic VEGF receptor-1/2 antagonist 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin-2-one (SU5416) (200 mg/kg, single s.c. injection) and hypoxia (3 weeks) causes irreversible severe PH characterized by marked elevation of pulmonary artery pressure (PAP), right ventricular hypertrophy, and obliteration of pulmonary arteries by proliferating endothelial cells (EC). Between weeks I and 2 of treatment, there is increased apoptotic EC death and caspase-3 activity. The combination of hypoxia with VEGFR-1 and -2 blockade appears to cause death of normal lung EC and proliferation of an apoptosis-resistant proliferating EC phenotype. Cotreatment with BK antagonist B9430 and (or) the broad caspase inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp) (2 mg/kg three times per week) prevented development of severe PH and caused significant reduction of PAP: 39.7 +/- 4.6 mmHg in Z-Asp + SU5416, 37.1 +/- 1.2 mmHg in BK antagonist B9430 + SU5416, 27.2 +/- 0.7 mmHg in Z-Asp alone, and 36.6 +/- 3.0 mmHg in BK antagonist alone versus 48 +/- 1.7 mmHg in SU5416-treated rats and 32.8 +/-1.4 mmHg in vehicle-treated controls. The PAP correlated with the right ventricular mass. Pulmonary arteries of rats treated with Z-Asp and BK antagonist B9430 had a marked reduction of intravascular EC, yet there was still evidence of medial muscular hypertrophy, similar to that observed in chronically hypoxic rats not treated with SU5416. We conclude that EC death induced by VEGFR-2 blockade with SU5416 may trigger an EC selection process that allows for the expansion of apoptosis-resistant EC, possibly driven by mechanisms independent of VEGF and VEGFR-2.

Animals↗
PubMed2002

Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines in vitro and in vivo and produces synergistic growth inhibition in combination with other antitumor agents.

Small cell lung cancers (SCLCs), many non-SCLCs, and other cancers have neuroendocrine features, including paracrineand autocrine growth stimulation by various neuropeptides. Interference with this pathway is an attractive target for novel therapies. We developed a novel bradykinin antagonist dimer, CU201 (B9870), that acts as a "biased agonist" for neuropeptides by blocking G(alphaq) signaling and activating G(alpha12,13) signaling. CU201 induced apoptosis and complete growth inhibition in various lung cancer and other cancer cell lines. CU201 was 10-fold more potent than substance P derivatives and was stable in serum for >7 days. In this study, we evaluated the ability of CU201 to produce additive or synergistic growth inhibition in combination with various antitumor agents used in lung cancer therapy. We found that CU201 produced additive or synergistic growth inhibition when combined with doxorubicin, etoposide, cisplatin, vinorelbine, and paclitaxel for SCLC lines and with paclitaxel and ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, for non-SCLC cell lines. Pharmacokinetic parameters associated with the i.v. administration of CU201 were evaluated in normal mice, and the effects of CU201 on the growth of human lung cancer xenografts were evaluated in athymic nude mice. In CD2F1 mice given an i.v. bolus infusion of 5 mg/kg, the c(max) was 5773 ng/ml (5 microM), and the decay was biexponential. When fitted to a two-compartment model, the t(1/2alpha) was 14.4 min, and the t(1/2beta) was 44.3 h, indicating a long terminal half-life consistent with the prolonged in vitro effects. CU201 inhibited the growth of human lung cancers in athymic nude mice by the intratumoral, s.c., and i.p. routes at a dose of 5 mg/kg/day. This dose is >10-fold less than the dose of substance P derivatives used to inhibit SCLC xenografts in nude mice. We conclude that CU201 should undergo further preclinical toxicology studies in its development as a novel targeted therapy for the treatment of lung cancers with neuroendocrine features. These studies are in progress through the NCI RAID mechanism.

Animals↗
PubMedDate not supplied

Coccidioidomycosis osteomyelitis masquerading as a bone tumor. A report of 2 cases.

BACKGROUND: Coccidioidomycosis involving the lung is common in endemic areas. However, it is unusual for it to present as a solitary bone lesion. CASES: Two cases of Coccidioides immitis osteomyelitis clinically and radiographically mimicked a primary bone tumor. Fine needle aspiration (FNA) biopsy of these lytic bone lesions yielded diagnostic material. Aspirated material in 1 case showed a suppurative, granulomatous inflammation and scattered spherules with refractile walls, some containing endospores consistent with coccidioidomycosis. Smears in the other case showed acute inflammation and necrosis, and rare spherules were identified with the Gomori-mathenamine-silver stain. C immitis infection was confirmed by culture in both cases. CONCLUSION: Although rare, coccidioidomycosis can involve the bone and mimic a primary bone tumor. FNA biopsy is helpful in differentiating between inflammatory and neoplastic processes involving bone by acquiring material for cytologic studies and cultures.

Adult↗