The mammary gland iodide transporter is expressed during lactation and in breast cancer.

The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.

Deposition of fibronectin and laminin in the basement membrane of the rat parietal yolk sac: immunohistochemical and biosynthetic studies.

Rat parietal yolk sacs (PYS) at gestational ages 7.5, 9.5, 11.5, 13.5, 14.5, and 16.5 d were reacted with antibodies against laminin or plasma fibronectin. At all times studied, laminin consistently gave a positive reaction with Reichert's membrane and with the cytoplasm of PYS cells. In contrast, fibronectin gave a negative reaction with Reichert's membrane at day 7.5, was weakly positive at day 9.5, and from then on was increasingly positive with maximum reactivity at 14.5 d. By electron microscopic immunohistochemistry, antilaminin reacted strongly with 14.5-d Reichert's membrane and with the contents of the rough endoplasmic reticulum RER cisternae of the PYS cells. Antifibronectin had some spotty reactivity with Reichert's membrane, but the cytoplasm of the PYS cells was negative. The contents of the vitelline vessels and the interface between trophoblast and Reichert's membrane were strongly positive. Metabolic labeling of PYS cells in organ culture clearly demonstrated the presence of laminin, type IV procollagen, and entactin both in the medium and in tissues, but fibronectin was absent. No component in the medium bound to gelatin-Sepharose columns. These studies demonstrate that PYS cells, which actively synthesize and secrete basement membrane components, do not synthesize any detectable fibronectin. Furthermore, the anti-fibronectin staining pattern in the vitelline vessels and trophoblast-Reichert's membrane interface strongly suggests that the fibronectin present in Reichert's membrane is derived from the maternal circulation and is merely "trapped" in the membrane.

Characterization of a renal tubular epithelial cell line which secretes the autologous target antigen of autoimmune experimental interstitial nephritis.

Proximal tubular epithelial cells from mice which develop autoimmune interstitial nephritis were found to express the nephritogenic target antigen, 3M-1. Anti-3M-1 mAbs (alpha 3M-1-Ab) were used to positively select for 3M-1-secreting tubular epithelium and, after stabilization in culture, this new cell line (MCT) was examined for the production of several moieties important to either immune interactions or to the development of extracellular matrix. Alkaline phosphatase-staining MCT cells also express epithelial growth factor receptors with a Kd of 0.87 nM and an epithelial growth factor receptor constant (Ro) of 2.1 X 10(4) receptors/cell. MCT culture supernatants contain greater amounts of laminin, and types IV and V procollagens compared to types I and III procollagens, and growing MCT cells on type I collagen matrix causes them to preferentially secrete even more type IV and V procollagen. The 30,000-Mr 3M-1 antigen could be immunoprecipitated from biosynthetically labeled MCT cell supernatants with alpha 3M-1-Ab. An identical-sized moiety was isolated by immunoaffinity chromatography from collagenase-solubilized mouse kidney tubular basement membranes. The 3M-1 antigen can be found on the MCT cell surface by radioimmunoassay, or deposited in a linear array in the extracellular matrix surrounding the MCT cells in culture by immunofluorescence. Mature messenger RNA species for both class I and class II major histocompatibility complex (MHC) molecules were detected by Northern hybridization, and their corresponding cell surface gene products were detected by cytofluorography of MCT cells stained with haplotype-specific antibodies. Both the cell surface 3M-1 and the small amounts of detected class II MHC molecules appear to be biologically functional, as MCT cells can support the proliferation of 3M-1-specific, class II MHC-restricted helper T cells in culture. These findings suggest that MCT cells provide all the necessary biological parameters for interfacing both as the target of a nephritogenic immune response, and as a potential source for new extracellular matrix which develops as a fibrogenic response to interstitial nephritis.

The expression of drug resistance gene products during the progression of human prostate cancer.

Prostate cancer progresses from a localized disease to a widely disseminated malignancy. Each step along this progression pathway involves multiple genetic alterations that impart a survival advantage to the tumor cell over its normal counterparts and may confer resistance to therapy. Because metastatic prostate cancer is one of the most therapy-resistant human neoplasms, we studied the expression of certain molecular determinants of drug resistance in the context of tumor progression. Paraffin-embedded formalin-fixed resected prostates were chosen based on Gleason grade and surgical stage. Immunohistochemistry was used to detect the expression of multidrug resistance protein (MRP), topoisomerase II alpha, p53, glutathione S-transferase pi, Bcl-2, and P-glycoprotein in these specimens. We found that all of the proteins were expressed in resected prostate except for P-glycoprotein. The expression of MRP, topoisomerase II alpha, p53, and Bcl-2 increased with the Gleason grade. In addition, the expression of MRP, topoisomerase II alpha, and p53 increased with the surgical stage. In contrast, the glutathione S-transferase pi and Bcl-2 expression decreased with the increasing surgical stage. Stage was the strongest indicator of protein expression. These results suggest that drug resistance gene products are expressed in prostate cancer at the time of surgical resection. Thus, although the emergence of the "pan-resistance" phenotype in prostate cancer may partly be a function of the selection pressure exerted by therapeutic interventions, certain determinants of chemoresistance may be caused by genetic changes accompanying tumorigenesis.

Effect of aging on intestinal ischemia and reperfusion injury.

Intestinal ischemia/reperfusion (I/R) is a serious disorder that is prevalent in elderly patients. Reactive oxygen species are implicated in the pathogenesis of intestinal I/R injury. Reactive oxygen species are also implicated in cellular senescence and aging. To test the hypothesis that aging exacerbates intestinal I/R injury, the effects of intestinal I/R on tissue injury were compared between young (3 month old) and aged (12 month old) mice. Intestinal ischemia was induced by occluding the superior mesenteric artery with a microbulldog clamp. Reperfusion was initiated by removing the clamp. Mortality due to intestinal ischemia followed by reperfusion was significantly higher in aged mice. There were no differences in the baseline levels of malondialdehyde or myeloperoxidase activity (indicators of lipid peroxidation and neutrophil infiltration, respectively) between young and aged mice. Although intestinal I/R caused a significant increase in malondialdehyde levels and myeloperoxidase activity in aged mice, similar increases were also observed in young mice. There were no significant differences in the activities of antioxidant enzymes including superoxide dismutase, glutathione peroxidase and catalase between young and aged mice that underwent sham operation. Intestinal I/R caused a significant decrease in catalase activity only in aged mice. In conclusion, our results indicate that aged mice are more susceptible to mortality due to intestinal I/R and that an age-dependent decrease in catalase activity may contribute to the observed mortality.

Connective tissue of rat lung. II: Ultrastructural localization of collagen types III, IV, and VI.

We localized collagen types III, IV, and VI in normal rat lung by light and electron immunohistochemistry. Type IV collagen was present in every basement membrane examined and was absent from all other structures. Although types III and VI had a similar distribution, being present in the interstitium of major airways, blood vessels, and alveolar septa, as in other organs, they had different morphologies. Type III collagen formed beaded fibers, 15-20 nm in diameter, whereas type VI collagen formed fine filaments, 5-10 nm in diameter. Both collagen types were found exclusively in the interstitium, often associated with thick (30-35 nm) cross-banded type I collagen fibers. Occasionally, type III fibers and type VI filaments could be found bridging from the interstitium to the adventitial aspect of some basement membranes. Furthermore, the association of collagen type VI with types I and III and basement membranes suggests that type VI may contribute to integration of the various components of the pulmonary extracellular matrix into a functional unit.

Type XV collagen in human colonic adenocarcinomas has a different distribution than other basement membrane zone proteins.

In situ carcinomas must penetrate their own basement membrane to be classified as invasive, and subsequently infiltrate surrounding connective tissue and cross vascular basement membranes to metastasize hematogenously. Accordingly, in many studies, integral basement membrane components, including type IV collagen, laminin, and heparan sulfate proteoglycan, have been localized in a spectrum of tumors to gain insight into their role in neoplasia. A number of recently identified extracellular matrix molecules and isoforms of the aforementioned proteins have been localized to the basement membrane zone, illustrating another level of biochemical heterogeneity in these structures. As the complexity of these matrices becomes more apparent, their roles in maintaining homeostasis and in tumor biology falls into question. Of the new group of collagens localized to the basement membrane zone, type XV was the first to be characterized (Cell Tissue Res, 286:493-505, 1996). This nonfibrillar collagen has a nearly ubiquitous distribution in normal human tissues via a strong association with basement membrane zones, suggesting that it functions to adhere basement membrane to the underlying stroma. To begin investigation of this protein in malignant tumors, we have localized type XV in human colonic adenocarcinomas and compared its distribution with that of type IV collagen and laminin. Collagens XV and IV and laminin were found in all normal and colonic epithelial, muscle, fat, neural, and vascular basement membrane zones, as shown previously. In moderately differentiated, invasive adenocarcinomas, laminin and type IV collagen were sometimes observed as continuous, linear deposits around some of the malignant glands, but more often they were seen in either discontinuous deposits or were completely absent. In contrast, type XV collagen was characterized as virtually absent from the basement membrane zones of malignant glandular elements in moderately differentiated tumors. Nevertheless there were also similarities; all 3 proteins were usually present in the stroma and adjacent vascular basement membrane zones surrounding invasive glands. The loss of type XV collagen from these malignant epithelial basement membrane zones and its increased interstitial expression suggests a role for this protein in the invasive process and the possibility that it may provide a sensitive indicator of tumor invasion.

Expression and potential role of the extracellular matrix in hepatic ontogenesis: a review.

Studies from a number of laboratories have provided information on the temporal and spatial expression of a variety of extracellular matrix (ECM) components in the developing liver and insight into their potential roles in hepatogenesis. Collagen type IV and laminin are present in the basement membranes of the capsular mesothelium, vascular structures of the portal and hepatic vein branches, and the ductular elements of the developing liver. The mesothelial, vascular, and ductular epithelial cells synthesize laminin and type IV collagen. In contrast, fibronectin and type I collagen are restricted to the adjacent or surrounding interstitium of those ductal and vascular elements, but are not within the basement membrane proper. The hepatic perisinusoidal space (Space of Disse) of the fetal rat develops a delicate extracellular matrix by 12.5 days of gestation, which is characterized by banded collagen fibrils and bundles associated with filamentous and flocculent material. Fibronectin, laminin, and collagen types I, III, and IV are present in the developing perisinusoidal space by this early gestational date, with laminin being the most prevalent component detected. The laminin chains localized to that region in the fetal/neonatal period are alpha 2, beta 1, beta 2, and gamma 1, whereas the alpha 1 chain of laminin is absent from the developing Space of Disse. Similar data have been reported on the laminin phenotype in the perisinusoidal space during hepatic regeneration. Electron microscopy immunohistochemistry studies have demonstrated that the sinusoidal lining cells and hepatocytes synthesize these ECM proteins during hepatogenesis. By 6 to 8 weeks of postnatal life, laminin is not detectable in the perisinusoidal space. Both the transient expression of laminin and the similarity of the laminin chain phenotype expressed in the perisinusoidal space in the developing and regenerating liver suggests a role for this protein in the organization of the hepatic lobule in those forms of hepatic morphogenesis.

Effects of genistein and structurally related phytoestrogens on cell cycle kinetics and apoptosis in MDA-MB-468 human breast cancer cells.

We have studied the effects of phytoestrogens (genistein, quercetin, daidzein, biochanin A and kaempferol) on proliferation, cell cycle kinetics, and apoptosis of MDA-MB-468 breast cancer cells. Genistein and quercetin inhibited cell growth with IC50 values of 8.8 and 18.1 muM, respectively, while the other phytoestrogens were less effective. Flow cytometric analysis showed G2/M cell cycle arrest with 25 muM and higher concentrations of genistein. At 100 muM, genistein, quercetin and kaempferol caused accumulation of 70, 60 and 35% of cells, respectively, in G2/M phase by 24 h. In contrast, biochanin A and daidzein were ineffective. APO-BRDU analysis revealed apoptosis with 10 muM genistein (19.5%), reaching 86% at 100 muM. Apoptosis by genistein was confirmed by Hoechst 33342 staining and fluorescence microscopy. With 100 muM quercetin, 47% of the cells were apoptotic, while the other bioflavonoids had little effect. Genistein treatment resulted in a biphasic response on cyclin B1: 70% increase in cyclin B1 level at 25 muM, and 50 and 70% decrease at 50 and 100 muM, respectively. In contrast, the action of quercetin involved an increase in cyclin B1 level. Genistein had no effect on cdc2 level up to 50 muM concentration; however, there was a decrease in the phosphorylated form of the protein at 100 muM. Quercetin had no effect on cdc2 levels. Our results suggest that the action of genistein and quercetin involves G2/M arrest and apoptosis in MDA-MB-468 cells. Biochanin A and daidzein, although structurally related to genistein, did not share this mechanism. Thus, structurally related phytoestrogens have discrete target sites and mechanisms in their growth inhibitory action on breast cancer cells.

Concurrent focal segmental glomerulosclerosis and membranous nephropathy.

Focal segmental glomerulosclerosis and membranous glomerulonephropathy are two entities that may result in the nephrotic syndrome. Two young women exhibited concurrent focal segmental glomerulosclerosis and focal segmental membranous nephropathy on renal biopsy. Although the lesions were severe, both patients had asymptomatic proteinuria, normal renal function, and a benign clinical course. The concurrence of these glomerulopathies may portend a more benign clinical course than expected for a patient presenting with either lesion alone.

An unusual extramedullary relapse of acute nonlymphocytic leukemia after allogeneic bone marrow transplantation.

Recurrent leukemia following allogeneic bone marrow transplantation (BMT) for acute nonlymphocytic leukemia (ANLL) continues to be a cause of morbidity and mortality. Most relapses occur within the first 6-12 months, although disease-free survival curves do not begin to plateau until 24 months posttransplant. The majority of relapses occur in the bone marrow. Extramedullary relapses usually occur in "sequestered sites," i.e., the testis and central nervous system. Although the true incidence of extramedullary relapse in "nonsequestered" sites after allogeneic BMT for ANLL is unknown, it appears that this type of relapse is distinctly unusual. The authors present a case of an unusual extramedullary relapse of ANLL in the breast at day +613 after allogeneic BMT for ANLL. In addition, we briefly review the English BMT literature and discuss the differential diagnosis of breast masses in women who survive allogeneic BMT for ANLL.

Diagnosis and management of malignant perirenal schwannoma.

Malignant retroperitoneal schwannoma is an extremely rare tumor, with only six cases previously reported occurring in the perirenal space. We herein report the seventh case. A 50-year-old woman presented with an abdominal mass suggestive of renal cell carcinoma by standard preoperative evaluation. The tumor required surgical exploration and pathologic evaluation for diagnosis. The final histologic diagnosis was made with the aid of electron microscopy and immunohistochemical staining with antibodies for S-100 protein.

Cerebral Pseudallescheria boydii infection: unique occurrence of fungus ball formation in the brain.

Pseudallescheria (Petriellidium) boydii is the most frequent etiologic agent of mycetoma in temperate regions of the world. In addition, it may also occur as a systemic infection in immunocompromised patients. Infection of the central nervous system is rare, and only eleven cases of Pseudallescheria brain abscess have been documented. We report a leukemic patient in whom disseminated pseudallescheriasis was diagnosed only after death. This case is unique in that a white matter cavitation was present containing a fungoma of Pseudallescheria, the first report of a cerebral fungus ball caused by this organism. The previous cases of Pseudallescheria brain abscess are reviewed, and the histopathologic features of Pseudallescheria which permit its differentiation from Aspergillus and other fungi are discussed.

Platelets in renal scleroderma.

Electron microscopic findings in a case of suspected scleroderma (progressive systemic sclerosis) showed platelet aggregates within numerous capillary lumens of the kidney. Evidence suggests that platelets may be a factor in the pathogenesis of renal scleroderma.

Metaplastic papillary tumor of the fallopian tube. Case report, immunohistochemical features, and review of the literature.

An example of a unique oncocytic and mucinous lesion of the fallopian tube epithelium, found incidentally in the postpartum period, is presented. The histogenetic nature of this lesion and its ultrastructural and immunohistochemical features are discussed.

The role for regional autopsy centers in the evaluation of covered deaths. Survey of opinions of US and Canadian chairs of pathology and major health insurers in the United States.

OBJECTIVE: To evaluate the advantages and disadvantages of, as well as the attitudes of health care professionals and insurers toward, the development of regional autopsy services. DESIGN: Survey of 150 medical school departments of pathology in the United States and Canada and 12 representative major health insurers in the United States. RESULTS: Of the 25 respondents from the pathology departments, most were in favor of regionalization of autopsy services, if properly underwritten. Of the five respondents from the health insurers, most were disinterested in the autopsy as a measure of outcome and unwilling to provide support. CONCLUSIONS: Health care is being regionalized around networks of insurers rather than hospitals. The networks are defined by a mixture of hospitals, physician groups, and other health care professionals. Within networks, the goal is to subscribe groups of patients, covered lives, for all medical needs from primary to complex care. As the economic risk of caring for patients is shifted to physicians, the incentive to provide service at the lowest possible cost grows, as does the need to assure that medical mismanagement does not occur. To provide quality care at affordable costs, it is necessary that outcomes, including deaths, be professionally evaluated. The present system of death investigation involves hospital colleagues and is potentially biased. Regional autopsy centers that provide timely expert information should be part of the health care system. Medical schools are potential sites for regional autopsy programs because they have the personnel needed to conduct appropriate death-related studies. Most schools are affiliated programmatically and economically with surrounding hospitals and physicians in a manner in which outcomes, costs, and quality of clinical service are of common interest.

Implications for the pathogenesis of aneurysm formation: metastatic choriocarcinoma with spontaneous splenic rupture. Case report and a review.

We report a case of ruptured intracranial aneurysm from metastatic choriocarcinoma in a patient presenting with intracerebral hemorrhage. Operative evacuation of the hematoma with clipping of a distal right middle cerebral artery aneurysm was performed. Postoperatively, the patient developed hypovolemic shock from spontaneous splenic rupture. Histopathologic examination of the cerebral aneurysm showed choriocarcinoma invading the vessel wall. Metastatic choriocarcinoma should be considered in the differential diagnosis of intracerebral or subarachnoid hemorrhage in women of child-bearing age.

Choriocarcinoma of the kidney.

Choriocarcinoma is a malignant germ cell tumor that usually arises from a previous gestation, but may also arise from germ cells anywhere along their known migratory pathway during fetal development. Gestational choriocarcinoma is highly sensitive to chemotherapy. This malignancy is known to undergo spontaneous regression of the primary tumor, which, in the face of metastases, may obscure the primary tumor site. The authors report the case of a patient with choriocarcinoma who was seen with pulmonary metastases and a single large lesion in the kidney 5 years posthysterectomy. The problems in resolving the primary site and the importance of a tissue diagnosis before nephrectomy are discussed.

Intracranial vertebral artery dissections: evolving perspectives.

Intracranial vertebral artery dissection (VAD) represents the underlying etiology in a significant percentage of posterior circulation ischemic strokes and subarachnoid hemorrhages. These lesions are particularly challenging in their diagnosis, management, and in the prediction of long-term outcome. Advances in the understanding of underlying processes leading to dissection, as well as the evolution of modern imaging techniques are discussed. The data pertaining to medical management of intracranial VADs, with emphasis on anticoagulants and antiplatelet agents, is reviewed. Surgical intervention is discussed, including, the selection of operative candidates, open and endovascular procedures, and potential complications. The evolution of endovascular technology and techniques is highlighted.