KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis.

BACKGROUND: The KISS1/KISS1R system has been implicated in the physiology of reproduction and many studies have documented the stimulatory effect of kisspeptin on Gonadotropin-releasing Hormone (GnRH) and gonadotropin secretion. In addition, the KISS1/KISS1R system has been implicated in several pathophysiological processes, including cancer. MATERIALS AND METHODS: We examined the pattern of KISS1 and KISS1R expression in eutopic and ectopic endometrium tissues which were obtained from 24 women suffering from endometriosis and 16 control women who underwent laparoscopic excision for other benign gynecological diseases. RESULTS: Significant KISS1R expression was detected in 10 out of the 24 samples of eutopic endometrial biopsies of women suffering from endometriosis, while their matched biopsies of ectopic endometrial lesions did not reveal any KISS1R expression. KISS1R expression was not detected in the endometrial biopsies of control women. In addition, KISS1 expression was not detected in practically any the endometrial tissues of either control women or women with endometriosis. CONCLUSION: The expression of KISS1R in 10/24 samples of human endometrial biopsies of women suffering from endometriosis and the loss of its expression in the samples of matched ectopic endometrial tissues, suggests that the KISS1/KISS1R system may play a role in the pathophysiology of endometriosis only for a particular group of patients. Since KISS1 is not expressed by the endometrium and endometriotic tissue, it is conceivable that the activation of KISS1R in this particular group is mediated by KISS1 expression by non-endometrial tissues (endocrine action).

Oxalate nephropathy in a diabetic patient after gastric by-pass.

We report a case of 48-year-old woman with history of diabetes and hypertension, who presented with acute to chronic kidney injury. Sixteen months before presentation, she had undergone Roux-en-Y gastric by-pass (RYGB) for morbid obesity. Kidney biopsy showed lesions consistent with oxalate nephropathy and deposition of calcium oxalate crystals. An extensive workshop excluded other causes of kidney injury. The patient subsequently required dialysis with no improvement of renal function on follow-up. The mechanism by which patients develop hyperoxaluria after RYGB remains obscure; it is suggested that RYGB provokes fat malabsorption, which results in increased load of free fatty acid in the intestine. Thus, calcium binds to free fatty acids provoking reduced synthesis of calcium oxalate. Consequently, increased quantity of oxalate remains free and is absorbed in the intestine causing hyperoxaluria. Similar to our case, oxalate nephropathy after RYGB is seen in patients with diabetes, hypertension and chronic kidney injury. Treatment includes low-fat, low-oxalate diet along with administration of calcium supplements. Unfortunately, prognosis is rather poor with the majority of patients eventually requiring permanent dialysis. Therefore, patients with history of chronic kidney disease undergoing RYGB should be closely monitored, particularly those with long standing history of diabetes and hypertension.

Co-expression of KLK6 and KLK10 as prognostic factors for survival in pancreatic ductal adenocarcinoma.

Kallikreins play an important role in tumour microenvironment and as cancer biomarkers in different cancer entities. Previous studies suggested an upregulation of KLK10 and KLK6 in pancreatic ductal adenocarcinoma (PDAC). Therefore, we evaluated the clinicopathological role of these kallikreins and their value as biomarkers in PDAC.Differential expression was validated by DNA-microarrays and immunohistochemistry in normal and malignant pancreatic tissues. Sera concentrations of both kallikreins were evaluated using ELISA. In silico analysis of possible protein interactions and gene silencing of KLK10 in vitro using siRNAs gave further insights in the pathomechanisms.Gene expression analysis and immunohistochemistry demonstrated a strong expression for KLK10 and KLK6 in PDAC. Statistical analysis showed that co-expression of these kallikreins correlated with an R1-resection status (P=0.017) and worse outcome for overall survival (P=0.031). Multivariate analysis proofed that co-expression is an independent prognostic factor for survival (P=0.043). Importantly, KLK10 knockdown in AsPC-1 cells significantly reduced cell migration, whereas computational analysis suggested interaction of KLK6 with angiogenetic factors as an important mechanism.Co-expression of KLK10 and KLK6 plays an unfavourable role in PDAC. Our results suggest that this effect is likely mediated by an interaction with the factors of the extracellular matrix and enhancement of cancer cell motility.

Abrupt and durable remission of Henoch-Schönlein purpura nephritis with cyclosporine A.

Henoch-Schönlein purpura glomerulonephritis (HSP-GN) is a common form of systemic small vessel vasculitis in children. Although prognosis is usually favourable, the disease is occasionally associated with a risk of renal insufficiency. Various immunosuppressive agents have been used in patients with severe HSP-GN, but none have shown convincing favourable effects. We report a case of biopsy-proven HSP-related GN in a 4-year-old girl that responded remarkably well to cyclosporine A (CsA), following failure to respond to other immunosuppressive agents. At 8 months post-CsA treatment, repeat renal biopsy findings were consistent with histological improvement. We conclude that CsA treatment not only exerts beneficial effects on resistant HSP-related GN but may also arrest progression of the disease.

Histopathological changes induced by therapies in the benign prostate and prostate adenocarcinoma.

The effect of androgen deprivation and other hormonal therapies, radiation therapy, thermal ablation therapies, chemotherapy, and other systemic treatments is evident in the histology of non-neoplastic and neoplastic human prostate gland. Androgen deprivation may be achieved with: a. orchidectomy, b. exogenous oestrogen administration, c. drugs with the capacity to deplete the hypothalamus of luteinizing hormone-releasing hormone, d. antiandrogens administration: drugs, which block the conversion of testosterone to its active form of 5-alpha dihydrotestosterone (i.e. finasteride, dutasteride), and drugs which block the androgen receptor on individual cells (i.e. flutamide). Androgen deprivation therapies cause atrophy of non-neoplastic and neoplastic prostatic epithelium, as the result of apoptosis, and are mainly used as a palliative measure in metastatic prostate cancer or as neoadjuvant or adjuvant treatment, in clinically localized prostate cancer. Morphological tumour regression may complicate the recognition and grading of treated carcinomas in radical prostatectomy specimens. Radiation therapy may be applied in the form of external beam, interstitial implantation (brachytherapy), or a combination, as a mainstay or adjuvant (external beam) treatment in localized prostate cancer. The primary effect is the damage of endothelial cells, which cause ischemia that leads to atrophy. The difficulty of post-radiation prostate needle biopsy interpretation includes the distinction of treatment effect in normal prostatic tissue from recurrent or residual tumour. Histological changes after thermal ablation mainly include lesions observed in prostatic infarcts due to periurethral coagulative type necrosis of variable volume. The correlation between the histopathological effects of the above therapies and their clinical significance is not absolutely clear.

Immunohistochemical localization of human kallikreins 6, 10 and 13 in benign and malignant prostatic tissues.

Human kallikreins 6, 10 and 13 (hK6, hK10 and hK13) are expressed by many normal, mainly glandular tissues, including prostatic epithelium. Some kallikreins may function as tumor suppressors or are downregulated during cancer progression. The aim of this study was to evaluate the immunoexpression of these kallikreins in benign and malignant prostatic tissues and correlate their expression with prostate cancer (PC) prognosis. Included in the study were 25 cases of nonmalignant prostate and 179 cases of PC. Among them, 122 PC cases were immunostained for hK6, 94 for hK10 and 113 for hK13, respectively. The follow-up period for a subset of 68 patients who had undergone radical prostatectomy (RP) was 1-58 months (mean=13.4 +/- 1.7 and median=8.0 months). A cutoff value of 0.2 microg/l of serum PSA was established as a biochemical recurrence threshold. Follow-up information was available for 26/55 RP cases stained for hK6, 14/32 cases stained for hK10 and 25/59 cases stained for hK13. Gleason score (GS) 7 carcinomas were stratified as 7a and 7b, according to the primary grade. PC with GS 2-7a were histologically categorized as low malignant (LM) and PC with GS 7b-10 as high malignant (HM). The immunohistochemical method of streptavidin-biotin-peroxidase using monoclonal and polyclonal antibodies was performed. In the benign prostate and in prostatic intraepithelial neoplasia, a cytoplasmic immunostaining of varying intensity was evident. In PC, the immunoexpression of all kallikreins was decreased: 102/122 cases (84%) were positive for hK6, 73/94 (78%) for hK10 and 97/113 (86%) for hK13, respectively. A statistically significant difference in expression was found, in comparison to nonmalignant prostates (P=0.029, 0.009 and 0.045, respectively). Also, a positive correlation was observed between the immunoexpression of these three kallikreins. Concerning the histological grade, HM-PC expressed all three kallikreins with a slightly higher percentage than LM-PC: 79 vs 88% for hK6, 76 vs 79% for hK10 and 76 vs 92% for hK13. These differences were statistically significant only in the case of hK13 (P=0.024). Serum PSA did not correlate with kallikrein immunoexpression in PC. Furthermore, there was no significant correlation between kallikrein expression and pathological stage or recurrence, in the cases of RP. All three kallikreins are expressed in the nonmalignant and malignant prostate, with cancer tissues demonstrating slightly lower expression. Expression levels did not correlate with aggressiveness and they do not seem to have value for prostate cancer prognosis.

Xanthogranulomatous pyelonephritis--the "great imitator" justifies its name.

A case of focal xanthogranulomatous pyelonephritis (XGP) clearly imitating renal tumour is presented. The authors underline the need to include focal XGP in the preoperative differential diagnosis of a renal mass even in the absence of typical characteristics.

The spectrum of human kallikrein 6 (zyme/protease M/neurosin) expression in human tissues as assessed by immunohistochemistry.

The KLK6 gene is a new member of the human kallikrein gene family and encodes for a secreted protease, human kallikrein 6 (hK6; also known as zyme/protease M/neurosin). No study has as yet reported detailed immunohistochemical localization of hK6 in human tissues. Our purpose was to examine the expression of hK6 in human tissues by immunohistochemistry. We have analyzed 199 paraffin blocks from archival, current, and autopsy material prepared from almost every normal human tissue. We employed an hK6-specific polyclonal rabbit antibody and avidin-biotin to localize hK6 by IHC. The staining pattern, the distribution of the immunostaining, and its intensity were studied in detail. The IHC expression of zyme was generally cytoplasmic. Various normal human tissues expressed the protein abundantly. Glandular epithelia constituted the main immunoexpression sites, with representative organs being the breast, prostate, kidney, endometrium, colon, appendix, salivary glands, bile ducts, and gallbladder. The small intestine, stomach, endocervix, Fallopian tube, epididymis, bronchus, and upper respiratory tract showed a focal expression as well. Choroid plexus epithelium, peripheral nerves, and some neuroendocrine cells (including the islets of Langerhans, cells in the anterior pituitary gland, and adrenal medulla) expressed the protein strongly and diffusely. A characteristic immunostaining was observed in the Hassall's corpuscles of the thymus, the oxyphilic cells of the thyroid and parathyroid glands, the primordial follicles of the ovary, dendritic cells mainly in the spleen, and in various cells of the placenta.

Binding of heterochromatin protein 1 to the nuclear envelope is regulated by a soluble form of tubulin.

We have previously shown that the mouse heterochromatin protein 1 homologue M31 interacts dynamically with the nuclear envelope. Using quantitative in vitro assays, we now demonstrate that this interaction is potently inhibited by soluble factors present in mitotic and interphase cytosol. As indicated by depletion and order-of-addition experiments, the inhibitory activity co-isolates with a 55-kDa protein, which binds avidly to the nuclear envelope and presumably blocks M31-binding sites. Purification of this protein and microsequencing of tryptic peptides identify it as alpha2/6:beta2-tubulin. Consistent with this observation, bona fide tubulin, isolated from rat brain and maintained in a nonpolymerized state, abolishes binding of M31 to the nuclear envelope and aborts M31-mediated nuclear envelope reassembly in an in vitro system. These observations provide a new example of "moonlighting," a process whereby multimeric proteins switch function when their aggregation state or localization is altered.

Prognostic significance of matrix metalloproteinases 2 and 9 in bladder cancer.

BACKGROUND: The levels of matrix metalloproteinases MMP-2 and MMP-9 (type IV collagenases), which degrade the extracellular matrix of the basement membrane, were evaluated as prognostic indicators of metastasis in urothelial carcinoma. MATERIALS AND METHODS: Quantitative gel zymography and immunohistochemistry were used and compared with clinical data at the follow-up period of 36 months. RESULTS: Zymographical analysis of the levels of MMP-9 and active MMP-2 showed a statistically significant increase with tumor grade and invasiveness. This correlation was confirmed by immunohistochemical analysis of MMP-9 expression. However, the correlation between the levels of both gelatinases with recurrence in superficial tumours or progression in invasive tumours was not statistically significant. CONCLUSION: MMPs may have an important role in the invasion mechanism of urothelial cancer and could be useful prognostic markers for patients with bladder carcinoma. The relationship between MMP-2 and MMP-9 expression and the metastatic potential of bladder carcinoma needs further evaluation in subsequent clinical studies.

Human kallikrein 6 as a biomarker of alzheimer's disease.

OBJECTIVES: Alzheimer's disease (AD) is a major cause of dementia in the elderly. It is generally difficult to diagnose accurately early AD. A few biomarkers, including tau protein and amyloid beta-42, are now used as aids for diagnosis and monitoring of AD. Our aim was to examine the possible use of cerebrospinal fluid, blood and tissue, and human kallikrein 6 (hK6) concentration as a marker of AD. METHODS: We have used a highly sensitive and specific immunofluorometric procedure for measuring hK6. We measured hK6 in tissue extracts from AD brain or normal individuals, in cerebrospinal fluids of AD patients or normals and in whole blood of AD patients and normals and compared the findings. We have used ten pairs of AD/normal controls in all cases. RESULTS: We found that hK6 concentration is tissue extracts from AD brain were approximately twofold lower than extracts from normal controls. Further, we found that cerebrospinal fluid hK6 concentration is approximately a threefold increase, in comparison to cerebrospinal fluid controls (p = 0.001). We have also found that the whole blood hK6 concentration in AD patients is about ten times higher than hK6 concentration in normal controls (p = 0.002). We have immunohistochemically localized the expression of hK6 in epithelial cells of the chorioid plexus. CONCLUSIONS: This is the first report describing significant elevations of cerebrospinal fluid and plasma and whole blood hK6 concentration in AD patients, in comparison to controls. These data suggest that hK6 may constitute a new biomarker for diagnosis and monitoring of AD.

The contribution of cavernous body biopsy in the diagnosis and treatment of male impotence.

This study concerns the results of penile biopsies in 50 patients aged 27 to 80, with secondary impotence removed with a biopty gun or during penile surgery. The biopty gun specimens were equally representative as the open biopsy ones. The cause and the degree of erectile dysfunction were determined by clinical and laboratorial investigation. The histological study of the cavernous bodies in the patients with psychogenic impotence revealed normal erectile tissue. In patients with organic impotence, histological lesions were graded as mild, moderate or severe. The most severe lesions were observed in the erectile tissue and in particular in the smooth muscle of the trabeculae and the helicine arteries, which had been reduced and replaced by connective tissue. Histological lesions were found not only in the arterial but also in the venous leak cases. There was a correlation between their severity and the degree of impotence, although of no statistical significance. The penile biopsy determines the condition (state) of the functional cavernous smooth muscle tissue, the integrity of which is essential for the erectile mechanism as well as for the action of the vasoactive drugs and the results of vascular surgery. Its important role is evident as it contributes not only to the diagnosis of the cause, but also to the choice of treatment of male impotence.

The prognostic importance of the morphological subdivision of the grade II superficial bladder cancer.

UNLABELLED: In this study a morphological subdivision of grade (g)II superficial bladder cancer is proposed and correlated with recurrence and progression rate. Forty patients, 33 males and 7 females, of 70 years mean age, with initial gII superficial transitional bladder cancer were treated with transurethral resection between January and December 1987 with follow-up for a mean period of 4 years. Recurrences were observed in 24 patients. All histological specimens were reviewed and reclassified to gIIa and gIIb mainly according to the variation in nuclear size, the degree of nuclear atypia and the number of mitoses. 42.1% (8/19) of the gIIa and 76.2% (16/21) of the gIIb tumors recurred. The observed difference in recurrence rate was statistically significant (s.s)-p < 0.05. The disease-free interval after the initial presentation was over two years in 50% (4/8) of gIIa and in 6.25% (1/16) of gIIb patients (s.s. difference-p < 0.05). None of the patients with gIIa, but 37.5% (6/16) with gIIb urothelial cancer had more than two recurrences (s.s. difference-p < 0.05). All gIIa recurred as gIIa superficial cancers, 62.5% (10/16) of gIIb as gIIb (5 superficial and 5 invasive) and the remainder 37.5% (6/16) as invasive gIII tumors. Only one patient with repeated recurrences died two years after the initial presentation. 3 patients died from other causes. IN CONCLUSION: 1. The morphological subdivision of gII urothelial cancer into gIIa and gIIb has a prognostic significance, as it is related to the recurrence rate, the disease-free interval after the initial resection, the number of recurrences and the progression rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of ras p21 and myc p62 oncoproteins in small cell and non small cell carcinoma of the lung.

Ras p21 and myc p62 expression has been examined immunohistochemically in seventy specimens of bronchial carcinomas. Both ras and myc oncoproteins were found to be overexpressed at a higher frequency in non small cell carcinomas (squamous cell carcinomas and adenocarcinomas) compared to the small cell carcinoma specimens; however only myc p62 overexpression was found to be statistically significant. Also, ras p21 oncoprotein expression was frequently overexpressed in adenocarcinomas compared to squamous cell carcinomas (p less than 0.05). Overexpression of c-myc p62 was found to correlate with poorly differentiated squamous cell carcinomas compared to the well and moderately differentiated tumors. The results of this study indicate that both the ras and myc oncogenes are important in the progression of bronchial carcinomas.

The reliability of histologically negative axillary lymph nodes in breast cancer. Preliminary report.

In an effort to evaluate the reliability of negative axillary lymph nodes in breast cancer patients, we did recuts in three levels in order to detect occult metastases. Our material consisted of 50 breast cancer cases with negative axilla. From each lymph node two routine sections were reviewed. Consequently, we examined six additional sections from the recuts. Out of the 50 cases, 7 (14%) had occult metastases in one or more section. Our results suggest that a negative axilla in the routine study can show in a considerable percentage occult metastases corresponding to the number of recuts. This means that a sufficient number of patients have only theoretically negative axillary lymph nodes and for that reason may show a low survival rate and a worse prognosis than the one expected. On the other hand, the need for axillary dissection or the appropriate postoperative treatment for carcinoma of the breast is supported.

Immunohistochemical study of the ras oncogene expression in human breast lesions.

An immunohistochemical study of ras oncogene expression in human breast lesions was carried out using a monoclonal antibody, Y13 259, to the ras encoded p21 protein. A total of 75 cases of breast disease examined included: 33 simple and complex cystic disease; 22 simple and hyperplastic fibroadenomas; 18 ductal, lobular and mixed carcinomas and 2 in situ carcinomas. Most of the complex cystic disease, hyperplastic fibroadenomas and all types of carcinomas showed high p21 expression as indicated by staining intensity. These results suggest that elevated ras expression may play an important role in the development of some premalignant and malignant breast lesions.