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David E Burstein

Publications and source records attributed to David E Burstein.

At least 19 recordsLinked to original sources
PubMed2006

Cellular swirls in fine needle aspirates of papillary thyroid carcinoma: a new diagnostic criterion.

No single cytologic feature is specifically diagnostic for papillary thyroid carcinoma. We report herein the presence of swirl-like cellular aggregates in fine needle aspirates of papillary thyroid carcinoma but not in other thyroid entities. Cellular swirls are defined as concentrically organized aggregates of tumor cells in which many of the most peripherally situated cells have ovoid rather than round nuclei that are oriented perpendicular to the radius of the swirl. One hundred Papanicolaou- and/or Diff-Quik-stained FNAs of the thyroid diagnosed as papillary carcinoma, including seven fine needle aspirates of cervical lymph nodes showing metastatic papillary carcinoma, with or without cell blocks, were reviewed for the presence of cellular swirls. An additional 100 thyroid FNAs, similarly stained and prepared, diagnosed as nodular goiter, Hashimoto's thyroiditis and follicular neoplasm were also reviewed for the presence of cellular swirls. Cellular swirls were easily observed at screening magnification and confirmed at high magnification. Seventeen of 100 FNAs (17%) of papillary carcinoma contained cellular swirls. No cases diagnosed as nodular goiter, Hashimoto's thyroiditis or follicular neoplasm contained these structures. Thirteen cases with swirls had histologic follow-up. These comprised seven papillary carcinomas with classical histopathology, two designated 'differentiated papillary carcinoma,' two with follicular variant histopathology; one with a minor component of follicular variant histopathology; one papillary carcinoma metastatic to a cervical lymph node with classic histopathology. Swirls occurred in cases with relatively little pleomorphism, or in well-differentiated regions of papillary carcinoma that also displayed less well-differentiated components. Cellular swirls are a finding that is highly specific to papillary thyroid carcinoma. They are easily seen at screening magnification. Their presence in a FNA specimen may be helpful in cases where classic criteria for papillary thyroid carcinoma are scarce, particularly in well-differentiated papillary thyroid carcinoma. While the size and scope of this study are insufficient to conclude that cellular swirls alone are diagnostic of papillary thyroid carcinoma in the absence of other criteria, we believe these structures should be added to the list of diagnostic criteria.

Adenocarcinoma, Follicular↗
PubMed2006

Polyoma virus infection is a prominent risk factor for bladder carcinoma in immunocompetent individuals.

Despite various reports of BK viral (BKV) DNA sequences or proteins in tumors of the urogenital tract, there has been no study statistically linking infection by this polyoma virus (PV) to tumor development. All PV are potential transforming viruses, the large T-antigen of which interacts with tumor suppressor proteins. Here, we have performed a cross-sectional study of 3,782 patients having had urine cytologic analyses, comparing those diagnosed with PV infection with those not so diagnosed. In order to focus on immunocompetent individuals, renal transplant patients, for whom a diagnosis of PV infection followed immunosuppressive therapy, were excluded. Among the 133 immunocompetent patients diagnosed with PV infection, the most frequently occurring neoplasms were bladder carcinoma (15.8%) and prostate carcinoma (3.8%). The incidence of bladder carcinoma was sufficient to statistically establish temporality in a two-sided test, linking a prior diagnosis of PV infection to a subsequent diagnosis of bladder carcinoma (odds ratio = 3.419, P < 0.001).

BK Virus↗
PubMed2006

Immunohistochemical detection of p63 in testicular germ cell neoplasia.

p63 is a novel transcription factor-encoding gene with sequence homology to p53. p63 proteins have epithelial stem-cell regulatory functions and play a critical role in tissue development. Study of p63 expression in testicular germ cell tumors has been limited. Thirty-four archival cases of testicular germ cell neoplasia were examined and stained with monoclonal anti-p63 antibody 4A4 using standard methods. Included were 19 seminomas, 1 pure teratoma, 3 pure embryonal carcinomas, 1 pure yolk sac tumor, and 10 mixed germ cell tumors. p63 staining was consistently positive in teratomas in areas of squamous differentiation and in basal reserve-like cells in foci of respiratory/endodermal differentiation. Strong p63 staining was observed within cytotrophoblasts of choriocarcinoma (1/1), whereas focal positivity was detected in embryonal carcinomas (4/10) and yolk sac tumors (2/5). Seminomas and intratubular germ cell neoplasia were p63-negative. These findings may suggest the presence of pluripotent p63-positive stem cell-like nests in yolk sac tumors and embryonal carcinomas or may represent areas of an occult teratoma phenotype undetectable histopathologically on hemotoxylin-eosin sections. p63 positivity in cytotrophoblasts of choriocarcinoma is consistent with gynecologic studies, possibly reflecting the role of p63 in the oncogenesis of neoplastic trophoblasts. The consistent p63 negativity in seminomas may reflect a precommitted embryonic precursor-like phenotype.

Carcinoma, Embryonal↗
PubMed2006

Expression of p53 in virally infected tubular cells in renal transplant patients with polyomavirus nephropathy.

Polyomavirus (PV) infection is associated with ureteral stenosis, hemorrhagic cystitis, and interstitial nephritis in renal transplant patients. The 3 PVs detected in human beings-BK virus, JC virus, and simian virus 40-each encode highly homologous forms of a large T antigen, a transcriptional and replicational regulatory protein. We describe immunohistochemical findings in 5 renal transplant patients who developed PV nephropathy (PVN) and a sixth patient with both PVN and PV infection of the bladder mucosa. Polyomavirus infection was confirmed by immunohistochemical detection of T antigen in kidney and bladder biopsies. We report on the expression of p53 specific to virally infected cells in all biopsies positive for T antigen. Examination of posttransplant biopsies obtained from these 6 patients before they were diagnosed with PVN revealed no expression of T antigen or p53. Accumulation of p53 in PV-infected cells may occur in response to binding of p53 by T antigen, resulting in stabilization of p53. These results provide the first evidence for intracellular actions of PV T antigen in the context of nonneoplastic diseases.

Antigens, Viral, Tumor↗
PubMed2006

A comparative study of 200 fine needle aspiration biopsies performed by clinicians and cytopathologists.

Fine needle aspiration (FNA) biopsy is a useful tool in the diagnosis and management of suspicious masses. Most FNA biopsies of palpable masses can be performed without radioguidance by either clinicians or cytopathologists; however, it is unclear if there is a difference in the diagnostic yield of the procedure based on who performs the FNA. We reviewed the FNA biopsy results of 200 patients presenting with head and neck masses to a tertiary care center from 2003 to 2004. One hundred FNA biopsies were performed by clinicians and 100 performed by cytopathologists. Seventy-one underwent subsequent surgical biopsy or definitive surgery. Results of the FNA biopsies performed by the clinicians and the cytopathologists were compared based on the percentages of FNAs that were diagnostic, suspicious/suggestive, and nondiagnostic. Additionally, the pathology results of the 71 surgical biopsies or resections were compared with the preoperative FNA results. Of the 100 FNA biopsies performed by cytopathologists, 83% were diagnostic, 10% were suspicious/suggestive, and 7% were nondiagnostic. Of the 100 FNA biopsies performed by clinicians, 24% were diagnostic, 43% were suspicious/suggestive, and 33% were nondiagnostic. Cytopathologists achieved significantly better results (P<.0001, two-tailed t-test). Of the 71 cases with surgical follow up (50 by cytopathologists and 21 by clinicians), 94% of cases performed by cytopathologists and 67% of those performed by clinicians show agreement with final surgical pathology results. Overall, the FNAs performed by cytopathologists show significantly better diagnostic accuracy (P=.0002134, two-tailed t-test). FNA provides valuable information in the workup of suspicious head and neck masses. Cytopathologists may achieve significantly better results.

Biopsy, Fine-Needle↗
PubMed2006

Renal transplant patient with polyoma virus bladder infection and subsequent polyoma virus nephropathy.

Polyoma virus nephropathy (PVN) is a significant cause of renal allograft dysfunction in transplant patients. A 58-year-old male received a cadaveric renal transplant and 12 weeks later presented with fever, diarrhea, and dysuria. He was diagnosed with a polyoma virus infection of the bladder by a transurethral bladder biopsy. One year post-transplant, he presented with renal allograft dysfunction and was diagnosed by biopsy with PVN of the non-native kidney. The diagnosis of a polyoma virus infection was confirmed by immunoreactivity to the polyoma T-antigen. We suggest that polyoma virus infection of the bladder be included in the differential diagnosis of urinary dysfunction in post-transplant patients, as such infections might be an under-recognized comorbidity in individuals with PVN.

Antigens, Polyomavirus Transforming↗
PubMed2006

Nephrogenic adenoma: immunohistochemical evaluation for its etiology and differentiation from prostatic adenocarcinoma.

CONTEXT: Nephrogenic adenoma is a rare benign lesion of the urinary tract. Owing to its strong association with a history of urinary tract irritation, nephrogenic adenoma was initially thought to originate from urothelial metaplasia; however, no solid proof of this association has been found. More recent investigation has pointed to a renal tubular cause. In addition to its uncertain origin, there can be diagnostic difficulty in distinguishing nephrogenic adenoma from prostatic carcinoma, particularly when dealing with lesions from the prostatic urethra. OBJECTIVE: To elucidate a possible histogenic relationship between nephrogenic adenoma and renal tubules, and also to evaluate the role of immunohistochemistry in the diagnostic distinction between nephrogenic adenoma and prostate carcinoma. DESIGN: Immunohistochemical studies were performed for P504S, prostate-specific antigen, CD10, p63, and epithelial membrane antigen on 9 cases of nephrogenic adenoma, 10 cases of normal renal parenchyma, and 10 cases of prostatic tissue, both benign and malignant. RESULTS: Nephrogenic adenoma shares the same immunohistochemical profile as distal renal tubules: both are positive for P504S and epithelial membrane antigen and negative for p63, CD10, and prostate-specific antigen. Prostatic adenocarcinoma tissue was positive for P504S and prostate-specific antigen, and normal prostatic gland tissue was positive for prostate-specific antigen and negative for P504S; p63-stained basal cells in normal prostatic gland tissue but did not react with prostatic adenocarcinoma tissue. The CD10 inconsistently stained normal and neoplastic prostatic gland tissue. Epithelial membrane antigen stain was negative in prostatic carcinoma, with rare occasional reactivity in normal prostatic glands. CONCLUSION: These findings provide supporting evidence that nephrogenic adenoma is derived from distal renal tubules. Our results also demonstrated that the combination of P504S and prostate-specific antigen with epithelial membrane antigen is a valuable tool in distinguishing prostatic carcinoma from nephrogenic adenoma.

Adenocarcinoma↗
PubMed2005

p63 immunostaining in destained bronchoscopic cytological specimens.

The p53 homologous squamous stem-cell regulatory protein p63 is expressed in squamous carcinomas but is not characteristically detected in small-cell carcinomas (SCCs). A panel of thyroid transcription factor (TTF) 1 and p63 has been shown to be useful in distinguishing SCCs from poorly differentiated squamous carcinoma of the lung (PDSLC) in small biopsies and cytological cell blocks. Because tumor samples frequently are limited to cytological smears, we attempted to detect p63 in destained slides from a spectrum of pulmonary malignancies. Archival alcohol-fixed smears from 60 cases of cytologically diagnosed malignancies in bronchoscopically (n = 59) or fine-needle aspiration-obtained specimens (n = 1) were destained in acid alcohol, postfixed in 10% formalin, subjected to citrate-based antigen retrieval, and immunostained by exposure to anti-p63 monoclonal antibody 4A4, followed by reagents from a streptavidin-biotin immunoperoxidase kit, and diaminobenzidine as the chromogen. Postfixation in 10% formalin was found to be necessary for immunostaining. Normal ciliated and goblet cells were p63 negative, but reserve cells were p63 positive. All cases of squamous-cell carcinoma were positive for p63. Of 10 tumor samples originally diagnosed as SCC, only 6 samples were p63 negative and 4 samples exhibited positive staining. However, proper interpretation of the immunohistochemical (IHC) staining pattern and careful scrutiny of the cytological features and biopsy specimens in three of four cases led us to reclassify three cases into PDSLC. All adenocarcinomas (ACAs; n = 12), large-cell carcinomas (n = 4), and metastatic ACAs (n = 5) were p63 negative. Positive staining was seen in 9/16 tumors designated as non-SCCs; these tumors were not classified further into distinct histological categories.p63 staining in destained slides may be of value in facilitating the differential diagnosis between PDSLC and SCC. Criteria for conservative interpretation of results are discussed and include examination of reserve cells and ciliated cells on the same slide as internal positive and negative controls.

Biomarkers, Tumor↗
PubMed2005

Cytology applications of p63 and TTF-1 immunostaining in differential diagnosis of lung cancers.

The pathologic distinction of small cell from non-small cell-lung carcinoma is of considerable therapeutic significance. In particular, the ability to distinguish poorly differentiated non-small-cell lung cancer from small-cell lung carcinoma (SCLC) is at times difficult based upon morphology alone; available immunohistochemical markers such as neuroendocrine markers are of limited utility. We have demonstrated the role of p63 and thyroid transcription factor-1 (TTF-1) in the differential diagnosis of poorly differentiated squamous-cell carcinoma (PDSCC) versus SCLC, mostly in biopsy samples (Wu et al., American Journal of Clinical Pathology 2003;119:696-702). Here, we examine further the utility of this panel in cytologic cell-block samples of lung cancers including both primary and metastatic cancers of pulmonary origin, and cases of nonpulmonary cancers metastatic to lung in which differential diagnoses included a lung primary.Four-micron thick sections of 30 alcohol-fixed paraffin-embedded cell blocks from 14 lung FNAs, 6 liver FNAs, 3 bronchial washings, 1 subcarinal lymph node FNA, 1 iliac lymph node FNA, 1 pelvic mass FNA, 1 neck lymph node FNA, 1 adrenal FNA, and 1 pleural effusion were deparaffinized and stained with monoclonal antibodies reactive to p63 (1:800, Santa Cruz Biotechnology) and TTF-1 (1:50, Dako). Slides were stained for p63 using a streptavidin-biotin kit (BioGenex) and diaminobenzidine as chromagen, and counterstained with hematoxylin. Slides were stained for TTF-1 using a Dako Autostainer. Thirty cases were examined, including 8 primary SCLCs, 8 extra-pulmonary metastases of lung SCLCs, 4 PDSCCs and 4 primary pulmonary adenocarcinomas, and 6 nonpulmonary adenocarcinomas metastatic to lung or other sites. Fifteen out of 16 (94%) SCLC cases were p63-/TTF-1+, ranging in intensity from focal-weak to diffuse-strong; 1/16 SCLCs from a bronchial washing was p63-/TTF-1- but synaptophysin was positive. All 4 primary lung adenocarcinoma cases were p63-/TTF-1+; contrasting with nonpulmonary adenocarcinomas that were all p63-/TTF-1-. All 4 PDSCC cases were p63+/TTF-1-. The panel of p63 and TTF-1 appears to be useful in the diagnostic evaluation of cytologic cell-block samples of pulmonary malignancy.

Adenocarcinoma↗
PubMed2005

p63 Immunohistochemistry in the distinction of adenoid cystic carcinoma from basaloid squamous cell carcinoma.

Morphologic distinction of high-grade adenoid cystic carcinoma from basaloid squamous cell carcinoma can be difficult. Equivocal diagnoses can mislead treatment. We have investigated the possibility that immunohistochemical staining for the presence of p63, a novel epithelial stem-cell regulatory protein, could be a useful means of distinguishing these two neoplasms. Archival, routinely processed slides were subjected to citrate-based antigen retrieval, exposure to anti-p63 monoclonal 4A4, and developed with a streptavidin-biotin kit and diaminobenzidine as chromogen. p63 was detected in 100% of the adenoid cystic carcinomas (n=14) and 100% of basaloid squamous cell carcinomas (n=16). Basaloid squamous cell carcinomas consistently displayed diffuse p63 positivity, with staining of nearly 100% of tumor cells. In contrast, adenoid cystic carcinoma displayed a consistently compartmentalized pattern within tumor nests. Compartmentalization was manifested in two patterns: (1) selective staining of a single peripheral layer of p63-positive cells surrounding centrally located tumor cells that were p63-negative and (2) tumor nests consisting of multiple contiguous glandular/cribriform-like units of p63-positive cells surrounding or interspersed with p63-negative cells. p63 immunostaining constitutes a specific and accurate means of distinguishing adenoid cystic carcinoma from basaloid squamous cell carcinoma. p63 positivity in adenoid cystic carcinoma appears to be homologous to that seen in the basal and/or myoepithelial compartments of salivary gland and other epithelia, and may signify a stem-cell-like role for these peripheral cells. Diffuse p63 positivity in basaloid squamous cell carcinoma suggests dysregulation of p63-positive stem cells in poorly differentiated squamous carcinoma.

Carcinoma, Adenoid Cystic↗
PubMed2005

Immunocytochemical detection of XIAP in body cavity effusions and washes.

Body cavity effusions may be the first manifestation of malignancy or of recurrence or relapse. We surveyed effusions and washes for expression of X-linked inhibitor of apoptosis (XIAP), a potent constituent of the inhibitor of apoptosis (IAP) family of proteins. IAPs prevent apoptosis by blocking the activation of caspases, thereby preventing caspase-mediated cell degradation. Elevated expression of XIAP could be an underpinning of relapse and/or resistance to apoptosis-inducing cancer therapy. We performed an immunocytochemical survey of XIAP expression in cell blocks from benign and malignant body cavity effusions and washes. In all, 116 alcohol-fixed, formalin postfixed paraffin-embedded cell block specimens from 82 pleural effusions, 22 ascites, 11 pelvic/peritoneal washes and one pericardial effusion were evaluated immunocytochemically with monoclonal anti-XIAP (#610763, BD Biosciences, San Jose, USA) 1:250, 4 degrees C x 72 h, and developed using EnVision-Plus reagents (Dako) and diaminobenzidine as chromagen. Particulate cytoplasmic staining was considered positive. The prevalence of staining for specific malignancies varied with the tissue of origin as follows: ovarian (13/13, 100%); lung (9/11, 82%), breast (6/13, 46%); gastric (4/7, 57%), colon (0/4, 0%), pancreas (2/3, 67%), gallbladder (1/1, 100%), fallopian tube (1/3, 33%), endometrial (6/7, 86%), mesothelioma (4/5, 80%), carcinoma of unknown primary (5/5, 100%) and hematopoietic malignancies (3/9, 33%). Overall, 54 out of 81 (67%) malignant effusions displayed XIAP positivity. Benign effusions (n = 35) were virtually XIAP-negative except for two cases (6%) in which histiocytes showed moderate staining. Weak nonspecific staining was sometimes noted in inflammatory cells or histiocytes. XIAP immunostaining, when strong, allows for ready distinction of malignant from benign and reactive cell populations. Strong XIAP staining was most prevalent in ovarian carcinomas and less prevalent in mammary carcinomas. The degree of XIAP staining of tumor cells may be a means of identifying the most therapy-resistant cases (ie, those with strong XIAP expression), and allow additional triaging to XIAP-blocking drugs presently being developed and clinically tested.

Apoptosis↗
PubMed2005

Immunohistochemical detection of glucose transporter GLUT1 in benign and malignant fallopian tube epithelia, with comparison to ovarian carcinomas.

CONTEXT: Enhanced expression of GLUT1, a facilitative glucose transporter found on red blood cells, blood-brain barrier, and perineurium, has been described in a large spectrum of epithelial malignancies. OBJECTIVE: We present an immunohistochemical survey of GLUT1 expression in benign and malignant fallopian tube epithelia, and compare serous carcinomas of the fallopian tube and ovary. DESIGN: One hundred two routinely fixed and processed archival specimens (36 benign fallopian tubes, 29 primary tubal adenocarcinomas, and 37 primary ovarian adenocarcinomas) were immunostained with rabbit anti-GLUT1 and developed with streptavidin-biotin/diaminobenzidine. Only distinct membrane staining was scored positively (1+ to 3+). RESULTS: Benign tubes (n = 36) were either negatively stained (58.3%) or displayed rare weak staining (0.5+ to 1+, rarely 2+; 41.7%); of the latter, 4 specimens showed chronic salpingitis, and 6 showed hyperplasia (epithelial tufting and stratification). A case of florid hyperplasia with atypia in a BRCA1-positive patient was GLUT1 negative. Twenty-three (79.3%) of 29 tubal carcinomas were positively stained. Staining ranged from focal/scattered foci (n = 15) to multifocal/extensive (n = 8). Of the 6 nonstaining tubal carcinomas, 3 were undifferentiated. Nineteen tubal carcinoma sections showed residual benign epithelium, which was consistently nonstaining. Very frequently, GLUT1 staining intensified in cells furthest from stroma/ stromal capillaries and/or bordering necrotic zones. On average, GLUT1 staining in primary fallopian tube cancers was less extensive than in primary ovarian adenocarcinomas. CONCLUSIONS: GLUT1 immunostaining of fallopian tube adenocarcinomas was substantially stronger and more extensive than staining of benign tubal epithelium, consistent with previously described findings in carcinomas versus benign tissues from many primary sites. The frequent localization of GLUT1 positivity to regions most distal from stroma/stromal capillaries is consistent with known activation of GLUT1 expression by hypoxia-sensing cellular pathways and may constitute a survival advantage under hypoxic conditions present in malignancy. The difference in extent of GLUT1 staining between primary tubal and primary ovarian serous adenocarcinomas is discussed.

Adenocarcinoma↗
PubMed2004

Immunohistochemical detection of p53 homolog p63 in solid cell nests, papillary thyroid carcinoma, and hashimoto's thyroiditis: A stem cell hypothesis of papillary carcinoma oncogenesis.

Most models suggest that the cell of origin of papillary carcinoma is the mature thyroid follicular epithelial cell. In a recent study, p63 was detected in papillary carcinoma, Hashimoto's thyroiditis, and in squamoid aggregates and solid cell nests (SCNs), embryonic remnants found sporadically in the fully developed thyroid. In the present study, the relationship between solid cell nests and papillary carcinoma was investigated further. Four-micrometer sections from 88 routinely fixed and processed archival thyroidectomy specimens were pretreated with citric acid pH 6.0 for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained with a streptavidin-biotin kit and diaminobenzidine as chromogen and were counterstained with hematoxylin. Squamoid aggregates or SCNs were noted in 21 specimens. Several morphologic variants of SCNs were found, all of which displayed p63 positivity. These included undifferentiated SCNs and those displaying commitment toward squamoid and ciliated glandular differentiation. Small, morphologically inconspicuous aggregates of p63-positive cells were commonly found in Hashimoto's thyroiditis. Commitment of p63-positive undifferentiated cells toward thyroid follicular epithelial differentiation was occasionally noted. One SCN variant, also associated with Hashimoto's thyroiditis, was a floretlike arrangement of p63-positive cells with fusiform nuclei. p63 staining was strong and uniform in some SCNs, but in other SCNs it was compartmentalized and homologous to stem cell-staining patterns in normal squamous or bronchial epithelia. Stem cell-like staining, associated with compartmentalized p63 staining or p63-positive undifferentiated cells, was noted in 7 of 27 papillary carcinomas. p63 immunostaining is a highly sensitive means of detecting SCNs. p63 expression patterns in SCNs and a subset of papillary carcinomas are closely homologous to stem cell-associated p63 staining patterns that have been described elsewhere in squamous and bronchial epithelia. We propose a stem-cell-associated model of papillary carcinoma oncogenesis that suggests that (1) p63-positive embryonal remnants rather than mature follicular cells are the cells of origin of a subset of papillary carcinomas; (2) these p63-positive cells are pluripotent and may stay undifferentiated or undergo benign squamoid or glandular maturation, may undergo thyroid follicular epithelial differentiation, may undergo oncogenic change leading to papillary carcinoma, or may trigger an immune reaction, resulting in lymphoid infiltration and Hashimoto's thyroiditis; and (3) Hashimoto's thyroiditis and papillary carcinoma may therefore be linked etiologically, because both disorders may be initiated by the same population of pluripotent p63-positive embryonal stem cell remnants.

Carcinoma, Papillary↗
PubMed2004

Fine needle aspiration.

Fine needle aspiration (FNA) has been widely used as a diagnostic tool for the past half century. Differing from large bore cutting needle biopsy, FNA utilizes 22- to 27-gauge needles. The cell samples aspirated from a lesion are characteristically smeared on glass slides for immediate microscopic evaluation. An adequacy report and a preliminary diagnostic impression are rendered in approximately 10 to 15 minutes. A final report is generally rendered within 24 hours. The method has been used as one of the most cost-effective, complication-free, and rapid techniques for preoperative investigation of tumors and tumor-like conditions. Its usefulness in the diagnosis and management of oncology patients is emphasized in this article.

Aged↗
PubMed2004

A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease.

Among the earliest invariant neuropathological changes in Alzheimer's disease (AD) is the degeneration of vulnerable hippocampal CA1 and subicular pyramidal neurons. Semaphorin 3A (Sema3A) is a secreted protein that functions in signaling growth cone collapse, chemorepulsion and neuronal apoptosis during early development of the central nervous system. In this report we show that accumulation of an internalized form of Sema3A is associated with degeneration of neurons in vulnerable fields of the hippocampus during AD. Accumulation of Sema3A overlaps the appearance of phosphorylated MAP1B and tau in many neurons, suggesting that Sema3A signaling at some level may be coupled to these previously identified cytoskeletal markers of neurodegeneration. Consistent with this, we isolated and partially characterized a multiprotein complex from the hippocampus of patients with AD that contains phosphorylated MAP1B, collapsin-response mediator protein 2 (CRMP-2), Plexins A1 and A2, and a processed form of Sema3A. A model is presented in which aberrant release of Sema3A from expressing neurons in the subiculum during AD results in the internalization and transport of Sema3A from this field to CA1. Within the context of the myriad of potential insults that contribute to Alzheimer's and other neurodegenerative diseases, the bioactivity of Sema3A may contribute either directly to neurodegeneration by inducing neuronal collapse, or indirectly by abrogating the recovery capabilities of adult neurons faced with these insults.

Aged↗
PubMed2003

Expression of p63 in papillary thyroid carcinoma and in Hashimoto's thyroiditis: a pathobiologic link?

p63 proteins are p53 homologs that are postulated to regulate squamous stem cell commitment. An immunohistochemical survey of p63 expression in normal thyroid and in reactive, neoplastic, and inflammatory thyroid disorders was performed. Sections from routinely fixed and processed archival thyroidectomy specimens were pretreated with citric acid, pH 6.0, for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained using a streptavidin-biotin kit and diaminobenzidine as a chromagen, and then were counterstained with hematoxylin. The results showed that p63 expression was negative in normal thyroid tissue, nodular goiters, and oncocytic follicular adenomas. Positivity was rare and weak in follicular adenomas. p63-positive foci were commonly found in Hashimoto's thyroiditis (1 or more foci in 78.8% of cases), but rare in Graves' disease. Twenty-seven of 33 papillary thyroid carcinomas (81.8%) displayed p63-positive foci. Staining was uncommon in follicular carcinomas and rare in medullary carcinomas. One case of insular carcinoma was p63-positive. All squamoid structures were p63-positive; p63-positive structures morphologically consistent with solid cell nests were also identified. Based on the results of this study, we conclude that p63 is commonly expressed in papillary thyroid carcinoma and in Hashimoto's thyroiditis. Given the debated association of papillary thyroid carcinoma with Hashimoto's thyroiditis, it is possible that p63 expression may be a potential pathobiologic link between the two disorders. The finding of p63 in benign squamoid nests supports a possible interrelationship between these structures and both Hashimoto's thyroiditis and papillary carcinoma. The high percentage of papillary carcinomas with p63-positive foci appears to distinguish papillary carcinoma from other neoplasms originating in the thyroid.

Adenocarcinoma, Papillary↗
PubMed2003

Immunohistochemical visualization of histone H1 phosphorylation in squamous intraepithelial lesions of the gynecologic tract.

Immunohistochemical staining was performed on gynecologic tract squamous intraepithelial lesions using a novel phosphorylation-specific monoclonal antibody (designated 12D11) that detects histone H1 when phosphorylated at a cyclin-dependent kinase (CDK)-responsive epitope. Findings were compared to immunostaining by MIB-1, an extensively studied antibody probe of proliferation. Routinely fixed and processed archival sections were subjected to distinct antigen retrieval and staining protocols for each antibody and were processed for immunodetection of either Ki-67 (with MIB-1) or phosphohistone H1, using a streptavidin-biotin kit and diaminobenzidine as chromagen. For 12D11 staining, antigen retrieval was performed at pH 4.0, and the antibody incubation buffer was supplemented with 1.0 M NaCl. Both 12D11 and MIB-1 stained parabasal cells in normal squamous epithelium. Staining by 12D11 and MIB-1 of cells in progressively higher strata was found to correlate with the severity of lesions. The mean proportion of positively stained cells was higher in MIB-1-stained sections than in 12D11-stained sections in normal squamous epithelium and in all grades of squamous intraepithelial lesions. We conclude that the changes in expression patterns of CDK-phosphorylated histone H1 in the spectrum of gynecologic squamous intraepithelial lesions are similar to staining patterns obtained with the proliferation probe MIB-1. The differing proportion of cells stained by MIB-1 and 12D11 suggests that phosphohistone H1 may be a useful alternative proliferation marker that detects a different subpopulation of cycling cells in premalignant squamous lesions.

Antibodies, Monoclonal↗