A soluble form of the human Fc receptor Fc gamma RIIA: cloning, transcript analysis and detection.

The Fc gamma receptors (Fc gamma R) are glycoproteins that bind the Fc region of immunoglobulin G. Human hematopoietic cells express three biochemically distinct classes of Fc gamma receptors: Fc gamma RI (CD64), Fc gamma RII (CD32) and Fc gamma RIII (CD16). Complementary DNA (cDNA) clones for each of the human Fc gamma receptors have been isolated from myeloid and lymphoid cells. We describe the isolation and characterization of four Fc gamma RII clones from a cDNA library obtained from a megakaryocyte-like cell line, human erythroleukemia (HEL). Three clones encode the Fc gamma RIIA transmembrane (TM) form, while one novel clone lacks the TM region but retains the cytoplasmic domain. By conducting reverse transcription coupled to polymerase chain reaction (PCR), we found transcripts coding for this unique form of receptor in RNA from platelets, HEL cells and a second megakaryocyte-like cell line, CHRF-288-11. These results were confirmed by RNase protection analysis of RNA from HEL cells. The structure of the novel cDNA suggested that it codes for a soluble form of Fc gamma RIIA. A soluble Fc gamma RII protein was detected in the conditioned medium from HEL cells but not from the Fc gamma RII-negative T cell line, Jurkat, by immunoprecipitation with the anti-Fc gamma RII monoclonal antibody (mAb), IV.3. The immunoprecipitated protein was of the expected size for a soluble Fc gamma RII lacking the TM region but retaining the cytoplasmic domain. Soluble Fc gamma RIIA may be important in modulating the interaction between immune complexes and membrane-associated Fc gamma RII.

Developmental pathways: Sonic hedgehog-Patched-GLI.

Developmental pathways are networks of genes that act coordinately to establish the body plan. Disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Environmental exposures can be associated with poor pregnancy outcomes, including dysmorphic offspring or children with a variety of diseases. An important goal of environmental science should be reduction of these poor outcomes. This will require an understanding of the genes affected by specific exposures and the consequence of alterations in these genes or their products, which in turn will require an understanding of the pathways critical in development. The ligand Sonic hedgehog, the receptors Patched and Smoothened, and the GLI family of transcription factors represent one such pathway. This pathway illustrates several operating principles important in the consideration of developmental consequences of environmental exposures to toxins.

Prolonged survival of a patient with sickle cell trait and metastatic renal medullary carcinoma.

PURPOSE: The treatment and outcome of a patient with sickle cell trait and metastatic renal medullary carcinoma is described. PATIENT AND METHODS: A 12-year-old boy with sickle cell trait had metastatic renal medullary carcinoma. After surgical resection of the primary tumor, he received chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. The carcinoma progressed after a 6-month period of stable disease. At that time, he received chemotherapy including ifosfamide, etoposide, carboplatin, and topotecan. RESULTS: The patient died of progressive disease 15 months from diagnosis. The patient's tumor in this report showed no progression while he was receiving methotrexate, vinblastine, doxorubicin, and cisplatin, but eventually became refractory to these and other cytotoxic agents. CONCLUSION: Renal medullary carcinoma is a highly chemotherapy-resistant tumor. Average survival after diagnosis is 15 weeks; the longest survival reported in the literature is 12 months from diagnosis. The patient in this report survived longer than the previously described patients before dying from progressive disease.

Aortic stiffness in the DOCA-hypertensive pig.

Pulsatile changes in aortic diameter and pressure were monitored in order to obtain an index of aortic stiffness in the conscious pig during the development of mineralocorticoid hypertension. The aortic stiffness index increased but to a much lesser extent than it did in response to a similar pressure elevation produced by phenylephrine infusion. This observation suggests that chronic exposure to an elevated pulsatile pressure reduces the stiffness index at the elevated pressure.

Management of an acute hemorrhagic ovarian cyst in a female patient with hemophilia A.

PURPOSE: This case report represents a description of a hemorrhagic ovarian cyst in a patient with hemophilia A. PATIENT: An 18-year-old female patient with severe factor VIII deficiency presented with the acute onset of a hemorrhagic ovarian cyst, meeting the standard indications for surgical intervention. Instead, because of the underlying coagulopathy, factor VIII therapy was instituted. RESULT: Within 1 day of starting the factor VIII therapy, the hemorrhage had clinically resolved and surgical intervention was avoided. CONCLUSIONS: Hemorrhagic ovarian cysts in the setting of hemophilia may respond to factor VIII replacement therapy without the need for surgical intervention. Because the incidence of functional ovarian cysts is high in the general population, female patients with hemophilia should be counseled regarding its possibility of occurrence. Moreover, if a female patient with hemophilia displays a propensity toward the development of ovarian cysts, the administration of prophylactic oral contraceptive pills should strongly be considered.

High-dose chemotherapy followed by peripheral blood stem cell rescue for metastatic rhabdomyosarcoma: the experience at Chicago Children's Memorial Hospital.

BACKGROUND: Because outcome for metastatic rhabdomyosarcoma remains poor with standard therapy, and because some patients with extensive unresectable metastatic rhabdomyosarcoma are unable to tolerate standard therapy with the associated large radiation fields, peripheral blood stem cell rescue (PBSCR) following high-dose chemotherapy was offered as consolidative therapy for patients with Stage 4/Group IV rhabdomyosarcoma. PATIENTS AND METHODS: Eight patients with Stage 4/Group IV rhabdomyosarcoma were diagnosed from May, 1992, through November, 1994. Consolidative PBSCR following thiotepa 300 mg/M2 on days -7, -6, and -5; cyclophosphamide 1,500 mg/M2 on days -5, -4, -3, and -2; and carboplatin 600 mg/M2 on days -3 and -2 was offered to those patients who achieved a complete remission with multimodality therapy. Patients with extensive metastatic disease who did not receive full doses of radiation to all sites of disease remained eligible for high-dose chemotherapy and PBSCR. RESULTS: Five of eight patients achieved a complete response. Four patients underwent PBSCR. One of the four patients is alive without evidence of disease 53 months post-PBSCR. All other patients died of progressive disease. CONCLUSIONS: These results, along with the existing literature, show no advantage of high-dose chemotherapy followed by PBSCR as consolidative therapy for patients with Stage 4/Group IV rhabdomyosarcoma over standard dose chemotherapy, radiation, and surgery. For patients with extensive, unresectable disease at diagnosis who cannot receive radiation to all areas of disease based on concerns of marrow reserve, high-dose chemotherapy followed by PBSCR does not appear to provide adequate local control and cannot be offered as curative therapy.

GLI1 localization in the germinal epithelial cells alternates between cytoplasm and nucleus: upregulation in transgenic mice blocks spermatogenesis in pachytene.

The zinc finger transcription factor GLI1 is the mediator of signaling by members of the Hedgehog (Hh) family. Male mice in which Desert hedgehog (Dhh), an Hh homologue expressed in Sertoli cells of the testis, was knocked out are sterile, suggesting that the Dhh/GLI1 pathway plays a role in spermatogenesis. Using an antiserum raised against human GLI1, we found that during the first round of spermatogenesis, GLI1 expression is initially cytoplasmic, then shifts to the nuclei of Sertoli and germ cells, and finally shifts back to the cytoplasm. In the adult mouse testis, GLI1 expression localized to the nuclei of germ cells, beginning with pachytene cells and persisting through round spermatids. Localization of GLI1 in elongating spermatids shifted from the nucleus to the cytoplasm and became associated with microtubules. We also examined a line of transgenic mice that overexpressed human GLI1. Male mice in this line were sterile. Spermatogenesis was blocked at the pachytene stage, and a subset of the morphologically indistinguishable pachytene cells underwent apoptosis. Patched-2, which is a Dhh receptor, and Fused, another component of the signal transduction pathway, are expressed in Leydig cells and in primary and secondary spermatocytes. Expression of GLI1 in the same cell types as Patched-2 and Fused and the disruption of spermatogenesis by GLI1 overexpression suggest that GLI1 is the mediator of the Dhh signal in the testis, and that it may be a regulator of spermatogenesis.

Rhabdomyosarcoma of the parotid region occurring in childhood and adolescence. A report from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND: Rhabdomyosarcoma (RMS) of the parotid region is rare and to the authors' knowledge little information is available regarding the site of tumor origin, clinical presentation, and outcome in these patients. Therefore, the authors reviewed the files of all patients with RMS of the parotid region who were registered on the Intergroup Rhabdomyosarcoma Studies (IRS) I-IV. METHODS: Patient charts and the Intergroup Rhabdomyosarcoma Study Group (IRSG) database were reviewed. RESULTS: Sixty-two patients presenting with a mass in the parotid region were identified. None of the tumors was localized exclusively to the parotid gland, so the primary site was referred to as the "parotid region." The tumor invaded a parameningeal site in 30 patients. These cases have been designated as parameningeal-parotid tumors to distinguish them from 32 cases that did not invade a parameningeal site and were designated as nonparameningeal-parotid tumors. The majority of patients had Group III tumors in both the nonparameningeal-parotid and parameningeal-parotid subgroups. However, although there were 16 patients with Group I or II tumors in the nonparameningeal-parotid subgroup, no patients with Group I or II tumors were found in the parameningeal-parotid subgroup (P = 0.001). Fifty-six of 62 patients (90%) received radiotherapy. The parameningeal primary site designation resulted in intensification of both chemotherapy and radiotherapy for patients with parameningeal-parotid RMS. The 5-year failure-free survival rate was 81% and the 5-year survival rate was 84%. There were no deaths reported among patients with Group I or II tumors. The 5-year failure-free survival did not appear to differ when comparing patients with parameningeal-parotid tumors with patients with nonparameningeal-parotid tumors (P = 0.21). CONCLUSIONS: Treatment as defined by the IRS protocols has been reported to be highly effective for patients with RMS of the parotid region. Outcome for the more aggressively treated patients with parameningeal-parotid RMS appears similar to that for patients with nonparameningeal-parotid RMS.