Periacinar clefting and p63 immunostaining in prostatic intraepithelial neoplasia and prostatic carcinoma

The aim of the present study was to correlate the presence and extent of retraction clefting and the expression of p63 in neoplastic glands and glands with prostatic intraepithelial neoplasia (PIN) in needle core biopsies. We analyzed needle core biopsies from 28 patients with PIN and 41 patients with adenocarcinoma. Neoplastic glands and those with PIN were analyzed on high power field (400x) and classified in three groups according to the extent of clefting. Immunohistochemical staining was performed following Microwave Streptavidin ImmunoPeroxidase (MSIP) protocol on DAKO TechMate Horizon automated immunostainer. Periacinar retraction clefting was significantly more prominent in prostatic carcinoma compared to PIN (p<0.0001) and nonneoplastic glands (p<0.0001). There was no difference between normal glands and PIN regarding clefting (p=0.8064). p63 was positive around the whole circumference in 12 out of 28 cases with PIN, and discontinuously positive in remaining 16 PIN cases suggesting initial disruption of the basal cell layer. p63 immunostaining was also positive in all nonneoplastic glands, and negative in all carcinomas. We conclude that retraction clefting was associated with cancer and lack of basal cells, but not with PIN. The relationship between clefting and p63 immunostaining in prostatic cancer should be further analyzed

Microglandular hyperplasia: a model for the de novo emergence and evolution of endocervical reserve cells

Microglandular hyperplasia (MGH) of the cervix in human beings is associated early with gland proliferation and terminates in mature squamous metaplasia. Using antibodies to basal cell markers, we analyzed biopsies with MGH to profile the distribution and evolution of reserve cells and their relationship to these epithelial components. Serial sections of 24 MGHs were subdivided into (1) early MGH with microacinar proliferation, abundant subnuclear vacuoles, and a paucity of supporting stroma and (2) late MGH with more prominent supporting stroma and/or squamous metaplasia. Serial sections were stained with antibodies to p63, bcl-2, and keratin-5. Three patterns of p63 staining were observed corresponding to the age of the MGH: (1) scattered staining of columnar cells, (2) focal subcolumnar staining in a reserve cell distribution, and (3) linear subcolumnar arrays of p63-positive reserve cells that in some MGHs expanded into a squamous metaplasia. Early acinar proliferations showed weak and focal columnar cell staining followed by focal subcolumnar p63-positive cells. In late lesions, p63 staining was compartmentalized to the extraglandular (or subcolumnar) areas. Stainings of p63, bcl-2, and keratin-5 were concordant. Staining for keratin 14, which localizes to squamous cells, was variable. The immunohistochemical profile in MGH indicates that reserve cells are created in adulthood during specialized columnar proliferations. This columnar to reserve cell transition may produce a stable population of reserve cells or a transition to squamous metaplasia. Similar patterns are seen in cervical neoplasia, suggesting a link between benign and neoplastic cervical epithelial differentiation

p63 Coordinates Anogenital Modeling and Epithelial Cell Differentiation in the Developing Female Urogenital Tract

p63 is a p53 homologue required for cutaneous development that is expressed in immature squamous epithelium and reserve cells of the cervix. Humans with p63 mutations exhibit defects in limb, accessory organ (skin appendage, breast, prostate), and genitourinary development. Because p63 expression patterns imply a strong role of the gene in the female genital tract development, newborn female p63−/−, +/−, and +/+ mice were examined in situ, dissected, and compared. Nuclear p63 protein was localized to the skin, vagina, bladder, urethra, and basal columnar cells of the caudal uterus in p63+/+ and +/− animals. p63−/− mice exhibited abnormal genital morphogenesis with hypoplastic genitalia, a single cloacal opening, and persistence of columnar epithelium at lower genital tract sites that normally undergo squamous and urothelial differentiation. The defects observed support p63-dependent pathways of genital tract development that permit externally, ectodermal basal cell replenishment integral to reciprocal epithelial stromal signaling, urorectal septation, and modeling of the external genitalia; and internally, the emergence of basal epithelial cell populations capable of divergent epithelial cell differentiation in the vagina, cervix, and urinary tract. Defects in the first pathway explain imperforate anus, vaginal septum, genital hypoplasia, and micropenis reported in humans with p63 mutations. The second is necessary for the generation of multipotential reserve cells in the cervix and may be operative in other epithelial stromal interactions integral to the emergence of uterine basal cells later in life

A new gastric juice peptide, BPC - an overview of stomach (stress) organoprotection hypothesis and BPC befitial effects

The possibility that the stomach affected by general stress pathology initiates a conteracting response has not been considered in the stress theory until recently. In this, the stomach as the most sensitive part of gastrointestinal tract, the largest neuroendocrine organ in the body, has been suggested to be a crutial point, from where a full stress response against all noxius stress pathology could be purposefully initiated, mediated and organized. The end result would be a strong protection of all organs invaded by "stress". Consistent with this assumption, this coping response is best explained in terms of "organoprotection" and endogenous organoprotectors (e.g. prostaglandins, somatostatin, dopamine) are proposed as mediators. Such an endogenous counteraction could even be afforded by their suitable application. According to this concept, a new gastric juice peptide, M.W. 40, 000, named BPC, was recently isolated. In this, a 15 amino acid fragment (BPC 157) tought to be essential for this activity was fully characterized and effectively investigated. As it had previously been demonstrated for many organoprotective agents using different models of various tissue lesions, despite the poorly understood final mechanism, practically all organ systems appear to be included into BPC beneficial activity. Relative to the reference standards, these effects have been achieved in many species using very low dosages (mostly ug and ng/kg range) after intraperitoneal, intragastrical as well as intramucosal (local) application. The effect was obvious already after one application. A long lasting activity was also demonstrated. Likewise, it was highly efficacious when applied in many experiments simultaneously with noxious agent or in the already established damage conditions, as well as chronically during a prolonged period. Therefore, it seems that BPC treatment does not share any of the so far known limitations for "conventional organoprotectors". No influence on different basal parameters and no toxicity were observed. Thus, whether these findings would provide a purposeful breakthrough into the stress thepry and whether BPC, as a likely endogenous free radical scavenger and organoprotection mediator, would be a useful prototype of a new class of drugs, organoprotective agents, remains to be seen