ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology.

Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5-KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology.

Multilocular cystic nephroma: A clinical case.

OBJECTIVE: To describe the clinical presentation, preoperative diagnostic possibilities, and treatment of cystic nephroma. METHODS: We describe a case of cystic nephroma in an adult male and show that, both in our patient and in the literature, a definitive diagnosis can only be obtained postoperatively, even when there is a reasonable clinical suspicion. CONCLUSIONS: Cystic nephroma is rare, and some authors consider it a questionable entity. However, it should be distinguished from renal cystic neoplasms, which can resemble the condition.

ERK5/BMK1 is a novel target of the tumor suppressor VHL: implication in clear cell renal carcinoma.

Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas.

Alopecia syphilitica with detection of Treponema pallidum in the hair follicle.

Alopecia is one of the clinical manifestations of secondary syphilis. It is uncommon for hair loss to be the sole or predominant manifestation, as hair loss is the chief clinical and histologic differential diagnosis of alopecia areata. The main difference between these two entities is the detection of Treponema pallidum in syphilis. We present the case of a 24-year-old Hispanic man, human immunodeficiency virus seropositive in treatment, with tiny patches of non-cicatricial alopecia in the parieto-occipital regions of his scalp. The patient denied previous history of genital or other skin lesions. A biopsy from an alopecic patch was performed which showed an inflammatory non-scarring alopecia with a discrete lymphocytic type inflammatory infiltrate localized in the peribulbar region. There was lymphocyte exocytosis into the matrix, associated with vacuolar degeneration, and scattered apoptotic cells were observed. Plasma cells were scattered. Immunohistochemical studies showed the presence of T. pallidum limited to the peribulbar region and penetrating into the follicle matrix. To the authors' knowledge, this is the first time that spirochetes have been shown in the hair follicle in alopecia syphilitica, suggesting that the spirochetes may be pathogenetic and responsible for the alopecia.

Polymorphous low-grade adenocarcinoma of the palate: report of cases.

OBJECTIVE: Polymorphous low-grade adenocarcinoma (PLGA) is a rare tumor that mostly affects minor salivary glands. The purpose of this study is to report six new cases followed-up during a long period. We also review the literature concerning clinical, histological and immunohistochemical features, as well as the proper management. METHODS: Malignant tumors of the salivary glands diagnosed in our department from 1990 to 1999 were reviewed. A total of 66 cases were registered. Six of these cases were diagnosed as PLGA. All cases satisfied the histopathological criteria for this entity, and at least 3 years follow-up was available. RESULTS: In the six cases the primary location was the mucosa of the palate. Hard palate was affected in 83.3% of the cases. There were no cases of extraoral PLGA in our series. Tumors were ulcerated in a 16.6% of the cases, and exofitic in the other 86.4%. Histologically, it was observed a tumoral proliferation of round clusters of uniform cells with round-to-oval clear nuclei and small nucleoli. All the cases underwent surgical management with local excision with surgical margins, five of them with bone extirpation associated. No recurrence was observed in four cases, whereas the remaining two cases showed recurrence in the follow-up. In one of the patients, lococervical recurrence appeared 12 months after the surgery, and this patient died after a few months. The remaining patients have been followed-up for 11, 7, 4 and 3 years postoperatively, with no evidence of recurrence. CONCLUSION: Our results for a long follow-up period support the idea for a low grade of malignancy and good prognosis of this tumor, but the appearance of recurrences many years after the surgery must induce us to be very careful and systematic with the follow-up.

Melanoma of the oral mucosa. Clinical cases and review of the literature.

The appearance of primary melanomas of the oral mucosa is uncommon. The aggressiveness of this entity and the absence of any standardized treatment protocol make the prognostic unfortunate. The difficulty to obtain free surgical margins, the elevated tendency to invade in depth and the early haematogenous metastasis have been referred as features which may explain its bad prognosis, even in comparison with cutaneous melanoma. However, no large clinical series exist and actually, clinical cases are the main source of information. Due to the absence of any treatment modality which may substantially increase long-term survival, we suggest the use of resective surgery with wide margins and early diagnosis by means of biopsy for suspicious melanotic-pigmented lesions. In this work we present 2 new cases of primary melanoma of the oral mucosa, with a follow-up period of 72 and 12 months respectively, and we make a review of the literature in relation with this rare entity.