Immunohistochemical expression of PAX8, PAX2, and cytokeratin in melanomas.

BACKGROUND: Deviations from the classic melanocytic immunophenotype in melanoma can present a diagnostic challenge. PAX8 and PAX2 are common markers for renal or Müllerian differentiation. While most PAX8+ or PAX2+ carcinomas are seldom confused with melanoma, some cases may show a more ambiguous immunophenotype, especially when MiTF family altered renal cell carcinoma (MiTF-RCC) is in the differential diagnosis. Neither PAX8 nor PAX2 expression has been reported in melanoma to date. We aimed to better characterize PAX8, PAX2, and cytokeratin immunoreactivity in a large series of melanomas. METHODS: Tissue microarrays consisting of 263 melanomas were immunostained for PAX8, PAX2, and cytokeratin and graded by an h-score. RESULTS: PAX8 expression was seen in 7.9% of melanomas and was significantly associated with spindle cytomorphology. PAX2 was positive in one (0.4%) melanoma. Cytokeratin positivity was seen in three (1.2%) cases and was associated with metastases. CONCLUSIONS: PAX8 is expressed in a subset of melanomas and may be strong/extensive. As PAX8 positivity does not exclude a diagnosis of melanoma, it should be used in conjunction with other immunohistochemical markers, such as cytokeratin and PAX2, when melanoma, MiTF-RCC, and other PAX8+ tumors are in the differential diagnosis.

Olfactory mucosa stem cells: An available candidate for the treatment of the Parkinson's disease.

Olfactory ectomesenchymal stem cells (OE-MSCs) possess the immunosuppressive activity and regeneration capacity and hold a lot of promises for neurodegenerative disorders treatment. This study aimed to determine OE-MSCs which are able to augment and differentiate into functional neurons and regenerate the CNS and also examine whether the implantation of OE-MSCs in the pars compacta of the substantia nigra (SNpc) can improve Parkinson's symptoms in a rat model-induced with 6-hydroxydopamine. We isolated OE-MSCs from lamina propria in olfactory mucosa and characterized them using flow cytometry and immunocytochemistry. The therapeutic potential of OE-MSCs was evaluated by the transplantation of isolated cells using a rat model of acute SN injury as a Parkinson's disease. Significant behavioral improvement in Parkinsonian rats was elicited by the OE-MSCs. The results demonstrate that the expression of PAX2, PAX5, PITX3, dopamine transporter, and tyrosine hydroxylase was increased by OE-MSCs compared to the control group which is analyzed with real-time polymerase chain reaction technique and immunohistochemical staining. In the outcome, the transplantation of 1,1'-dioctadecyl-3,3,3'3'-tetramethyl indocarbocyanine perchlorate labeled OE-MSCs that were fully differentiated to dopaminergic neurons contribute to a substantial improvement in patients with Parkinson's. Together, our results provide that using OE-MSCs in neurodegenerative disorders might lead to better neural regeneration.

BCL-2 and PAX2 Expressions in EIN which Had Been Previously Diagnosed as Non-Atypical Hyperplasia.

The relationship between PAX2 and another anti-apoptotic gene, BCL-2, has been shown in a limited number of studies. The aims of this study are to investigate the value of PAX2 and BCL-2 expressions in lesions which have been defined as nonatypical hyperplasia in terms of detecting EIN and to evaluate the relations of these proteins in EIN. For this purpose, 108 cases of non-atypical endometrial hyperplasia diagnosed from 2006 to 2011 were re-evaluated. Immunohistochemical studies with PAX2 and BCL-2 were performed in 20 cases with EIN and 34 cases with benign hyperplasia. The mean BCL-2 immunohistochemistry scores of benign hyperplasia and EIN cases were 4.06 ± 1.04 and 4.63 ± 2.03, respectively. The mean BCL-2 score of EIN cases was significantly higher than benign hyperplasia (p = 0.021). The mean PAX2 scores of benign hyperplasia and EIN cases were 4.32 ± 1.07 and 2.19 ± 2.34, respectively. The mean PAX2 scores of EIN cases were significantly lower than benign hyperplasia (p = 0.001). BCL-2 expression was increased compared to normal endometrium in 66.7% of EIN cases, and PAX2 expression was decreased in 73.3%. Consistent with this, in 60% of cases, BCL-2 expression was increased compared to normal endometrium, while PAX2 expression was decreased. BCL-2 and PAX2 protein expression changes occur in early phases of endometrial tumorigenesis. These changes are often seen as a simultaneous increase in BCL-2 expression and decrease in PAX2 expression.

The Key Transcription Factor Expression in the Developing Vestibular and Auditory Sensory Organs: A Comprehensive Comparison of Spatial and Temporal Patterns.

Inner ear formation requires that a series of cell fate decisions and morphogenetic events occur in a precise temporal and spatial pattern. Previous studies have shown that transcription factors, including Pax2, Sox2, and Prox1, play important roles during the inner ear development. However, the temporospatial expression patterns among these transcription factors are poorly understood. In the current study, we present a comprehensive description of the temporal and spatial expression profiles of Pax2, Sox2, and Prox1 during auditory and vestibular sensory organ development in mice. Using immunohistochemical analyses, we show that Sox2 and Pax2 are both expressed in the prosensory cells (the developing hair cells), but Sox2 is later restricted to only the supporting cells of the organ of Corti. In the vestibular sensory organ, however, the Pax2 expression is localized in hair cells at postnatal day 7, while Sox2 is still expressed in both the hair cells and supporting cells at that time. Prox1 was transiently expressed in the presumptive hair cells and developing supporting cells, and lower Prox1 expression was observed in the vestibular sensory organ compared to the organ of Corti. The different expression patterns of these transcription factors in the developing auditory and vestibular sensory organs suggest that they play different roles in the development of the sensory epithelia and might help to shape the respective sensory structures.

PAX2 expression is correlated with better survival in tamoxifen-treated breast carcinoma patients.

PAX2 (paired box gene 2) is a transcription factor, which is involved in both cell proliferation and carcinogenesis. This study aimed to investigate PAX2 expression in tamoxifen resistant (TAM-R) and tamoxifen sensitive (TAM-S) breast carcinoma patients and analyze its correlation with clinicopathological characteristics and survival. Immunohistochemical analysis was performed to evaluate PAX2 protein expression in 36 TAM-R and 36 TAM-S formalin-fixed paraffin-embedded (FFPE) breast tumor tissues. Data analysis indicated that PAX2 expression was significantly higher in TAM-S group in comparison to TAM-R (P = 0.014). Overexpression of PAX2 was significantly correlated with perineural invasion (PNI) (P = 0.025). Kaplan-Meier survival analysis showed significant association between high expression of PAX2 and better disease-free survival (P < 0.001) and also overall survival (P = 0.031). Multivariate cox regression analysis demonstrated that patients with increased expression of PAX2 have a trend toward improved disease free survival (OR = 0.065, 95% CI: 0.009-0.476; P = 0.007) and overall survival (OR = 0.147, 95% CI: 0.020-1.105; P = 0.062). Our data suggested that high expression of PAX2 could be associated with better survival in estrogen receptor positive tamoxifen-treated breast carcinoma patients.

Diagnostic Utility of Pax8, Pax2, and NGFR Immunohistochemical Expression in Pediatric Renal Tumors.

Pediatric renal tumors (PRT) with small round blue or spindle cell morphology can be diagnostically challenging and only a limited number of immunohistochemical markers have been documented to help in the diagnosis: paired box (Pax) 2 and nerve growth factor receptor (NGFR) positivity have been demonstrated in Wilms tumor (WT) and clear cell sarcoma of the kidney (CCSK), respectively. However, the immunohistochemical expression of these markers in other PRT remains unknown. This study investigated Pax8, Pax2, and NGFR immunophenotype in a large series of PRT. Pax8 and Pax2 showed an identical staining pattern, and were expressed in all (100%) WT while most CCSK were negative. All congenital mesoblastic nephromas, metanephric stromal tumors, primitive neuroectodermal tumors, desmoplastic small round blue cell tumors, most rhabdoid tumors, and synovial sarcomas were negative for Pax8. NGFR was expressed in 96% of CCSK (diffuse expression in 91%). Only a minority of WT stained for NGFR: 16% showed expression in the blastemal and 25% in the mesenchymal components. NGFR expression was noted in synovial sarcomas (67%, with diffuse expression seen in only 1 case, 8%), rhabdoid tumors (19%), cellular congenital mesoblastic nephromas (13%) and metanephric stromal tumors (12.5%). Primitive neuroectodermal tumors and desmoplastic small round blue cell tumors were negative for NGFR. In conclusion, Pax8/Pax2 and NGFR are sensitive markers for the diagnosis of WT and CCSK, respectively. However, their specificity is limited by variable reactivity within a subset of other renal neoplasms.

HNF1B controls epithelial organization and cell polarity during ureteric bud branching and collecting duct morphogenesis.

Kidney development depends crucially on proper ureteric bud branching giving rise to the entire collecting duct system. The transcription factor HNF1B is required for the early steps of ureteric bud branching, yet the molecular and cellular events regulated by HNF1B are poorly understood. We report that specific removal of Hnf1b from the ureteric bud leads to defective cell-cell contacts and apicobasal polarity during the early branching events. High-resolution ex vivo imaging combined with a membranous fluorescent reporter strategy show decreased mutant cell rearrangements during mitosis-associated cell dispersal and severe epithelial disorganization. Molecular analysis reveals downregulation of Gdnf-Ret pathway components and suggests that HNF1B acts both upstream and downstream of Ret signaling by directly regulating Gfra1 and Etv5 Subsequently, Hnf1b deletion leads to massively mispatterned ureteric tree network, defective collecting duct differentiation and disrupted tissue architecture, which leads to cystogenesis. Consistently, mRNA-seq analysis shows that the most impacted genes encode intrinsic cell-membrane components with transporter activity. Our study uncovers a fundamental and recurring role of HNF1B in epithelial organization during early ureteric bud branching and in further patterning and differentiation of the collecting duct system in mouse.

Down-regulation of PAX2 promotes in vitro differentiation of podocytes from human CD34+ cells.

Podocytes are major kidney cells that help in glomerular filtration and any damage or loss is a major event in the progression of kidney diseases. Understanding podocytes development will help in designing therapeutic strategies against these renal diseases. Therefore, in vitro generation of podocytes from adult hematopoietic CD34+ stem cells is explored in the present study. Apheretically, isolated human HSCs from peripheral blood showed the presence of CD34 surface glycoprotein through immunocytochemistry (ICC) and flowcytometry. Initially, these HSCs were induced with activin-A (10 ng/ml), retinoic acid (RA) (10 ng/ml) and bone morphogenic protein (BMP-7) (2.5 ng/ml) for 5 days. Transdifferentiation of HSCs to podocytes through intermediate mesoderm was studied with positive selection of Osr1+ cells. Subsequently, thus-obtained Osr1+ cells were induced further with activin-A (10 ng/ml), RA (10 ng/ml), BMP-7 (2.5 ng/ml), EGF (30 ng/ml) and bFGF (30 ng/ml) for 9 days. Distinct cobblestone morphological changes were observed on staining with Leishman's stain. Consequently, differentiated cells were immunopositive for anti-podocin, anti-synaptopodin and anti-GLEPP1 monoclonal antibodies. These cells showed expression of early podocyte markers PAX2 and Wt1 at day 3 followed by day 6 and mature podocyte markers NPHS1, SULT1B1, NPHS2 and Synaptopodin at day 9. Interestingly, on day 9, diminished expression of PAX2 was noted. Differentiated cells showed high tyrosine kinase activity signifying that phosphorylation controls slit diaphragm proteins. Synaptopodin regulates the integrity of cytoskeleton and cell motility of podocytes and this phenomenon was confirmed through scratch assay using agarose molds that showed high cell mobility and migration. These findings establish HSCs as ideal candidates for regenerative therapies of damaged podocytes.

Pax2-Islet1 Transgenic Mice Are Hyperactive and Have Altered Cerebellar Foliation.

The programming of cell fate by transcription factors requires precise regulation of their time and level of expression. The LIM-homeodomain transcription factor Islet1 (Isl1) is involved in cell-fate specification of motor neurons, and it may play a similar role in the inner ear. In order to study its role in the regulation of vestibulo-motor development, we investigated a transgenic mouse expressing Isl1 under the Pax2 promoter control (Tg +/- ). The transgenic mice show altered level, time, and place of expression of Isl1 but are viable. However, Tg +/- mice exhibit hyperactivity, including circling behavior, and progressive age-related decline in hearing, which has been reported previously. Here, we describe the molecular and morphological changes in the cerebellum and vestibular system that may cause the hyperactivity of Tg +/- mice. The transgene altered the formation of folia in the cerebellum, the distribution of calretinin labeled unipolar brush cells, and reduced the size of the cerebellum, inferior colliculus, and saccule. Age-related progressive reduction of calbindin expression was detected in Purkinje cells in the transgenic cerebella. The hyperactivity of Tg +/- mice is reduced upon the administration of picrotoxin, a non-competitive channel blocker for the γ-aminobutyric acid (GABA) receptor chloride channels. This suggests that the overexpression of Isl1 significantly affects the functions of GABAergic neurons. We demonstrate that the overexpression of Isl1 affects the development and function of the cerebello-vestibular system, resulting in hyperactivity.

Overexpression of microRNA-497 suppresses cell proliferation and induces apoptosis through targeting paired box 2 in human ovarian cancer.

MicroRNAs are a class of endogenous, small non-coding RNAs which are tightly involved in evolution and progression of human cancers. MicroRNA-497 has been reported as tumor-suppressor in various human cancer. However, the role of miR-497 in ovarian cancer is still poorly known. We investigated the expression level and cellular function of miR-497 in human ovarian cancer. In this study, the expression of miR-497 in ovarian cancer tissues and SKOV3 cells was detected by quantitative reverse­transcription polymerase chain reaction (qRT-PCR). CCK-8 assay was used to analysis the cell proliferation. Transwell assay was performed to analysis cell migration and invasion. Cell apoptosis was evaluated by flow cytometry. Luciferase assay was performed to verify a putative target site of miR-497 in the 3'UTR of PAX2 mRNA. The results showed that miR-497 was markedly decreased in ovarian cancer tissues and SKOV3 cells. Moreover, overexpression of miR-497 in SKOV3 cells induced PAX2 protein expression and resulted in inhibition of cell proliferation, migration and invasion, and induction of cell apoptosis. In addition, we confirmed that PAX2 is a direct target gene of miR-497. Furthermore, Silencing of PAX2 by RNA interference suppressed cell proliferation and promoted cell apoptosis in vitro. Taken together, our study rationally present that miR-497 has a potential role as a useful diagnostic and therapeutic biomarker for human ovarian cancer.

Expression of PAX2 and PTEN Correlates to Therapy Response in Endometrial Hyperplasia.

AIM: To investigate if a levonorgestrel-impregnated intrauterine system (LNG-IUS) was more efficient compared to oral progestin in the clearance of the paired box 2 gene (PAX2) - and phosphatase and tensin homolog (PTEN)-null endometrial glands and assess the significance of PAX2- and PTEN-null glands as markers for therapy response in endometrial hyperplasia. PATIENTS AND METHODS: Immunohistochemical staining using antibodies against PAX2 and PTEN was performed in 141 pre- and post-treatment endometrial biopsies comparing the effect of LNG-IUS, 10 mg medroxyprogesterone acetate (MPA) taken continuously, or 10 mg MPA taken 10 days per cycle for six months. PAX2- and PTEN-null glands were investigated by light microscopy in pre-and post-treatment biopsies. RESULTS: Clearance of PAX2- and PTEN-null glands was significantly more efficient by LNG-IUS compared to oral MPA (p<0.000 and p=0.008, respectively) and significantly related to therapy response (p<0.000 and p=0.002, respectively).

Preferential Propagation of Competent SIX2+ Nephronic Progenitors by LIF/ROCKi Treatment of the Metanephric Mesenchyme.

Understanding the mechanisms responsible for nephrogenic stem cell preservation and commitment is fundamental to harnessing the potential of the metanephric mesenchyme (MM) for nephron regeneration. Accordingly, we established a culture model that preferentially expands the MM SIX2+ progenitor pool using leukemia inhibitory factor (LIF), a Rho kinase inhibitor (ROCKi), and extracellular matrix. Passaged MM cells express the key stem cell regulators Six2 and Pax2 and remain competent to respond to WNT4 induction and form mature tubular epithelia and glomeruli. Mechanistically, LIF activates STAT, which binds to a Stat consensus sequence in the Six2 proximal promoter and sustains SIX2 levels. ROCKi, on the other hand, attenuates the LIF-induced differentiation activity of JNK. Concomitantly, the combination of LIF/ROCKi upregulates Slug expression and activates YAP, which maintains SIX2, PAX2, and SALL1. Using this novel model, our study underscores the pivotal roles of SIX2 and YAP in MM stem cell stability.

Dorsoventral patterning of the Xenopus eye involves differential temporal changes in the response of optic stalk and retinal progenitors to Hh signalling.

BACKGROUND: Hedgehog (Hh) signals are instrumental to the dorsoventral patterning of the vertebrate eye, promoting optic stalk and ventral retinal fates and repressing dorsal retinal identity. There has been limited analysis, however, of the critical window during which Hh molecules control eye polarity and of the temporal changes in the responsiveness of eye cells to these signals. RESULTS: In this study, we used pharmacological and molecular tools to perform stage-specific manipulations of Hh signalling in the developing Xenopus eye. In gain-of-function experiments, most of the eye was sensitive to ventralization when the Hh pathway was activated starting from gastrula/neurula stages. During optic vesicle stages, the dorsal eye became resistant to Hh-dependent ventralization, but this pathway could partially upregulate optic stalk markers within the retina. In loss-of-function assays, inhibition of Hh signalling starting from neurula stages caused expansion of the dorsal retina at the expense of the ventral retina and the optic stalk, while the effects of Hh inhibition during optic vesicle stages were limited to the reduction of optic stalk size. CONCLUSIONS: Our results suggest the existence of two competence windows during which the Hh pathway differentially controls patterning of the eye region. In the first window, between the neural plate and the optic vesicle stages, Hh signalling exerts a global influence on eye dorsoventral polarity, contributing to the specification of optic stalk, ventral retina and dorsal retinal domains. In the second window, between optic vesicle and optic cup stages, this pathway plays a more limited role in the maintenance of the optic stalk domain. We speculate that this temporal regulation is important to coordinate dorsoventral patterning with morphogenesis and differentiation processes during eye development.

Diagnostic utility of PAX2 and PAX5 in distinguishing non-small cell lung cancer from small cell lung cancer.

Lung cancer is the leading cause of cancer-related death in both men and women and consists of different histological types. Histopathological examination and accurate subtype diagnosis has become increasingly important in guiding patient management and, as such, is the most important currently available lung cancer "biomarker". In this study, we examined the expression of PAX2 and PAX5 by immunohistochemistry in 47 cases of lung cancer and 13 cases of pneumonia. The results demonstrated that PAX2 were detected in 82.8% (24/29) of NSCLC, 0% (0/18) of SCLC and 7.7% (1/13) of pneumonia, respectively; However, PAX5 were detected in 15/18 cases (83.3%) of SCLC, 6.8% (2/29) of NSCLC and 7.7% (1/13) of pneumonia. Further, the samples with lymphatic metastasis had remarkable higher positive PAX2 or PAX5 than that without metastases. Overall, our data indicated that PAX2 and PAX5 differentially expressed in NSCLC and SCLC. Thus, PAX2 and PAX5 are useful biomarker in the differential diagnosis of lung cancer.

Evaluation of PAX2 and PAX8 expression in salivary gland neoplasms.

PAX2 and PAX8 are transcription factors involved in embryogenesis that have been utilized as immunohistochemical indicators of tumor origin. Specifically, PAX2 is a marker of neoplasms of renal and müllerian origin, while PAX8 is expressed by renal, müllerian, and thyroid tumors. While studies examining these transcription factors in a variety of tumors have been published, data regarding their expression in salivary gland neoplasms are limited. The goal of this study was to assess expression of PAX2 and PAX8 in a large cohort of salivary gland tumors. Utilizing tissue microarrays, samples of normal salivary glands (n = 68) and benign and malignant salivary gland neoplasms (n = 442) were evaluated for nuclear immunoreactivity with PAX2 and PAX8. No expression was observed with either marker in the normal salivary glands, and PAX8 was negative in all neoplasms. Focal expression of PAX2 was observed in one example each of oncocytoma and acinic cell carcinoma. These results indicate that evaluation of PAX2 and/or PAX8 expression would be valuable in differentiating primary salivary gland tumors from metastases known to express PAX2 and/or PAX8.

Mesonephric carcinosarcoma involving uterine cervix and vagina: report of 2 cases with immunohistochemical positivity For PAX2, PAX8, and GATA-3.

Mesonephric carcinomas are rare tumors predominantly arising in the uterine cervix from mesonephric remnants. Although the tumor has classic morphologic features, some cases can mimic Müllerian adenocarcinoma and be misdiagnosed, especially those with significant ductal pattern. Moreover, there is an overlap in immunohistochemical results with endometrial and endocervical carcinomas. In this study, we report 2 cases of mesonephric carcinosarcoma, originally diagnosed as Müllerian carcinomas, 1 presenting in the vagina; review immunohistochemical results including positivity for GATA-3, not previously reported and comment on the proposed panel of PAX8, p16, and estrogen receptors as discriminators of Müllerian adenocarcinoma (endocervical or endometrial) versus mesonephric carcinoma.

Cell atavistic transition: Paired box 2 re-expression occurs in mature tubular epithelial cells during acute kidney injury and is regulated by Angiotensin II.

The regeneration of tubular epithelial cells (TECs) after acute kidney injury (AKI) is crucial for the recovery of renal structure and function. The mechanism by which quiescent TECs re-obtain a potential to regenerate remains unknown. In this study, we observed a transient re-expression of embryonic gene Paired box 2 (Pax2) in adult rat TECs in vivo during ischemia-reperfusion induced AKI and most Pax2 positive TECs co-expressed kidney injury molecule-1 (KIM-1), a tubular injury marker. The re-expression of Pax2 was accompanied by increased levels of intrarenal Angiotensin II, which is a crucial injury factor of AKI. Furthermore, we also found a temporary re-expression of Pax2 in NRK-52E cells under the stimulation of Angiotensin II. This stimulatory effect could be blocked by PD123319 (Angiotensin II type 2 receptor (AT2R) inhibitor) and AG490 (Janus Kinase 2 (JAK2) inhibitor). As Pax2 is essential for the phenotypic conversion from mesenchymal stem cells to TECs during kidney development, we proposed that the re-expression of Pax2 in mature TECs may be an indicator of "atavistic" transition which mimics but reverses the processes of development of TECs. This could be proved by that a progenitor marker, CD24, was also found to be transiently expressed shortly after the expression of Pax2 in NRK-52E cells stimulated with Angiotensin II. The expression of CD24 was also suppressed by PD123319 and AG490. Moreover, knockdown of Pax2 by RNA interference could significantly reduce the expression of CD24 in NRK-52E cells stimulated with Angiotension II. Those findings suggest that mature TECs can trans-differentiate into progenitor-like cells by "atavistic transition", which may participate in the recovery of tissue structure and Pax2 may play a pivotal role in this process. That might have important implications for further understanding of tubular regeneration after injury.

The potential signal pathway between PAX2 and CD2AP in the renal interstitial fibrosis disease.

Paired box gene 2 (PAX2) can regulate tissue development and cellular differentiation, and it is associated with renal diseases. CD2-associated protein (CD2AP) is an adaptor protein involving in a variety of physiological and disease processes. Renal interstitial fibrosis (RIF) is a hallmark of common progressive chronic diseases which lead to renal failure. This study was performed to investigate whether there was a potential signal pathway between PAX2 and CD2AP in RIF rats induced by unilateral ureteral obstruction (UUO). Eighty Wistar male rats were divided into two groups randomly: sham operation group (SHO) and model group subjected to UUO (GU), n = 40. The model was established by left ureteral ligation. Renal tissues were collected at 14 d and 28 d after surgery. RIF index, cell apoptosis index, protein expression of PAX2, CD2AP, transforming growth factor-ßl (TGF-ß1), collagen-IV (Col-IV), fibronectin (FN) in renal interstitium and renal tissue, and mRNA expression of PAX2, CD2AP, and TGF-ß1 in renal tissue were detected. Compared with that in the SHO group, the PAX2 and CD2AP expressions (mRNA and protein) were significantly increased (p < 0.01). Protein expressions of TGF-ß1, Col-IV, and FN, and RIF index or cell apoptosis index in the GU group were markedly elevated than those in the SHO group (all p < 0.01). PAX2 or CD2AP was positively correlated with TGF-ß1, Col-IV, and FN, and RIF index or cell apoptosis index (all p < 0.05). Furthermore, PAX2 was positively correlated with CD2AP (p < 0.05). In conclusion, the expression of PAX2 or CD2AP was increased in RIF rats, and PAX2 was positively correlated with CD2AP. There might be a potential signaling pathway between PAX2 and CD2AP in RIF disease. Further research is needed to determine the association in RIF disease.

Mdm2 is required for maintenance of the nephrogenic niche.

The balance between nephron progenitor cell (NPC) renewal, survival and differentiation ultimately determines nephron endowment and thus susceptibile to chronic kidney disease and hypertension. Embryos lacking the p53-E3 ubiquitin ligase, Murine double minute 2 (Mdm2), die secondary to p53-mediated apoptosis and growth arrest, demonstrating the absolute requirement of Mdm2 in embryogenesis. Although Mdm2 is required in the maintenance of hematopoietic stem cells, its role in renewal and differentiation of stem/progenitor cells during kidney organogenesis is not well defined. Here we examine the role of the Mdm2-p53 pathway in NPC renewal and fate in mice. The Six2-GFP::Cre(tg/+) mediated inactivation of Mdm2 in the NPC (NPC(Mdm)2(-/-)) results in perinatal lethality. NPC(Mdm)2(-/-) neonates have hypo-dysplastic kidneys, patchy depletion of the nephrogenic zone and pockets of superficially placed, ectopic, well-differentiated proximal tubules. NPC(Mdm2-/-) metanephroi exhibit thinning of the progenitor GFP(+)/Six2(+) population and a marked reduction or loss of progenitor markers Amphiphysin, Cited1, Sall1 and Pax2. This is accompanied by aberrant accumulation of phospho-γH2AX and p53, and elevated apoptosis together with reduced cell proliferation. E13.5-E15.5 NPC(Mdm2-/-) kidneys show reduced expression of Eya1, Pax2 and Bmp7 while the few surviving nephron precursors maintain expression of Wnt4, Lhx1, Pax2, and Pax8. Lineage fate analysis and section immunofluorescence revealed that NPC(Mdm2-/-) kidneys have severely reduced renal parenchyma embedded in an expanded stroma. Six2-GFP::Cre(tg/+); Mdm2(f/f) mice bred into a p53 null background ensures survival of the GFP-positive, self-renewing progenitor mesenchyme and therefore restores normal renal development and postnatal survival of mice. In conclusion, the Mdm2-p53 pathway is essential to the maintenance of the nephron progenitor niche.

PAX2 and PAX8: useful markers for metastatic effusions.

OBJECTIVE: It was the aim of this study to determine the utility of PAX2 and PAX8 in cytology effusions with metastatic tumor. STUDY DESIGN: PAX2 and PAX8 immunohistochemical staining was performed on cell blocks of 89 pleural, pericardial and peritoneal effusions with benign diagnoses (18 cases), or secondary to renal cell carcinoma (RCC; 9 cases), müllerian carcinoma (21 cases) or non-müllerian carcinoma (41 cases). RESULTS: PAX2 stained 0% (0/18) of controls, 100% (8/8) of RCCs, 35% (7/20) of müllerian carcinomas, and 2% (1/41) of non-müllerian carcinomas. PAX8 stained 6% (1/18) of control cases, 100% (9/9) of RCC cases, 100% (20/20) of müllerian carcinomas, and 5% (2/41) of non-müllerian carcinomas. PAX2 was 35% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. PAX8 was 100% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. CONCLUSIONS: PAX8 is more sensitive than PAX2 for metastatic effusions from müllerian carcinomas (100 vs. 35%), while also having a higher intensity of staining than PAX2. However, PAX2 and PAX8 are both highly sensitive and specific for RCCs. PAX2 and PAX8 are valuable diagnostic markers for metastatic müllerian carcinomas and RCCs in effusion cytology. PAX8 is superior for carcinomas of müllerian origin.