Chk1 and the Host Cell DNA Damage Response as a Potential Antiviral Target in BK Polyomavirus Infection.

The human BK polyomavirus (BKPyV) is latent in the kidneys of most adults, but can be reactivated in immunosuppressed states, such as following renal transplantation. If left unchecked, BK polyomavirus nephropathy (PyVAN) and possible graft loss may result from viral destruction of tubular epithelial cells and interstitial fibrosis. When coupled with regular post-transplant screening, immunosuppression reduction has been effective in limiting BKPyV viremia and the development of PyVAN. Antiviral drugs that are safe and effective in combating BKPyV have not been identified but would be a benefit in complementing or replacing immunosuppression reduction. The present study explores inhibition of the host DNA damage response (DDR) as an antiviral strategy. Immunohistochemical and immunofluorescent analyses of PyVAN biopsies provide evidence for stimulation of a DDR in vivo. DDR pathways were also stimulated in vitro following BKPyV infection of low-passage human renal proximal tubule epithelial cells. The role of Chk1, a protein kinase known to be involved in the replication stress-induced DDR, was examined by inhibition with the small molecule LY2603618 and by siRNA-mediated knockdown. Inhibition of Chk1 resulted in decreased replication of BKPyV DNA and viral spread. Activation of mitotic pathways was associated with the reduction in BKPyV replication. Chk1 inhibitors that are found to be safe and effective in clinical trials for cancer should also be evaluated for antiviral activity against BKPyV.

Primary dural lymphoma: a novel concept of heterogeneous disease.

Spinal primary dural lymphoma (PDL) is uncommon with a total of 37 previous well-documented cases reported, including one diagnosed in the authors' institution. More recently we encountered an additional case of spinal PDL that, similarly to our previous case, was grade 1-2 follicular B-cell PDL. Our two cases were diagnosed over a 3-year interval in a 72-year-old female and a 74-year-old male, respectively. An exhaustive literature review on PDL was performed consequently to reveal that: (i) spinal and cerebral sites of involvement by PDL are constantly mutually exclusive; and (ii) unlike cerebral PDL, which is usually of marginal zone B-cell type, only two of the 38 cases of spinal PDL were diagnosed as such, diffuse large B-cell lymphoma being the most commonly encountered type in the spine. This divergence infers that, in contrast to the prevailing concept that PDL is a unique disease group, PDL appears to be rather heterogeneous with a difference in predilection of lymphoma type for the anatomical site of dural involvement. Such a site-specific lymphoma-type predilection phenomenon, well-recognized in other organ systems, has not been acknowledged in PDL. This report brings new insights into PDL, and may contribute to a better understanding of nervous system pathophysiology and lymphoma classification.

Fibrosis correlates with detailed histological analysis of human undescended testes.

OBJECTIVE: To evaluate whether semiquantitatively assessing the histological degree of fibrosis provides equivalent information to a detailed histological analysis of undescended testes in children. PATIENTS AND METHODS: We reviewed retrospectively the histological and clinical data from 86 consecutive orchidopexies. Biopsies fixed in Bouin's solution were evaluated histologically for tubular diameter, germ cell number and fibrosis. Fibrosis was assessed semiquantitatively by a pathologist reviewing sections stained with Masson's trichrome. The median (range) age of the patients was 1.9 (0.5-13.5) years, with 29 aged <1 year and 57 aged >1 year. RESULTS: There were 65 palpable and 21 impalpable testes; 62 were inguinal and 13 were intra-abdominal. Testicular biopsies showed smaller tubules and fewer germ cells in patients aged >1 year, but there were no significant differences based on the location of the testis on physical examination or at the time of operation. The amount of fibrosis correlated well with tubular diameter and germ cell counts. CONCLUSION: Fibrosis can be assessed easily and correlates well with more complex forms of histological evaluation of testicular health in children.

Cutaneous balloon cell dermatofibroma (fibrous histiocytoma).

Dermatofibroma (DF) or cutaneous fibrous histiocytoma is a common benign skin tumor that exhibits multiple, distinct histologic variants. Although clear cell DF has been described in the literature, balloon cell degeneration causing a clear cell DF phenotype has been not been reported to date. Herein, we describe the clinicopathologic findings of balloon cell DF arising on the heel of a 43-year-old man. Clinically, it presented as enlarging tan-white, ulcerated, firm 1.5 cm nodule, clinically suspected to be pyogenic granuloma. Excisional biopsy revealed a circumscribed fibrous tumor populated by mostly clear and spindle cells. A zonal arrangement separated the varied tumor cells where the most superficial, polypoid area showed large, clear polygonal balloon cells; the mid-dermal zone demonstrated a transition between balloon cells, epithelioid cells, and spindle cells; and the deep dermal zone had storiform arrangement of spindle cells, with the fascicles separated by coarse collagen bundles. A CD10+ > CD68+ > Factor XIIIa+ immunophenotype was identified with negative immunolabeling for S-100 protein, HMB-45, cytokeratin AE1/AE3, desmin, smooth muscle actin, lysozyme, and leukocyte common antigen (LCA). Ultrastructurally, the clear tumor cells were filled with multiple, empty, nonmembrane bound vacuoles of varying size. No recurrence has been described after complete excision and 7 months of follow up. DF with balloon cell change, likely secondary to persistent irritation, should be added to the differential diagnosis of cutaneous primary and metastatic neoplasms showing balloon cell degeneration such as balloon cell melanocytic nevi and renal cell carcinoma, respectively.

Apoptosis and proliferation in human undescended testes.

OBJECTIVE: To study apoptosis and proliferation in the testes of children with undescended testes; the degree to which undescended testes contributes to a patient's ultimate fertility is debatable, but undescended testes have fewer germ cells, and some have proposed that apoptosis is an important cause. PATIENTS AND METHODS: Testis biopsies were taken at the time of orchidopexy in a consecutive series of children undergoing surgical repair for undescended testes. Immunohistological techniques were used to detect apoptosis and proliferation, and the numbers of cells undergoing apoptosis or proliferation per 50 seminiferous tubules were recorded. RESULTS: Inguinal testes had less apoptosis than abdominal testes, with a mean (sd) of 0.71 (1.31) vs 1.63 (1.95) apoptotic cells per 50 seminiferous tubules (P < 0.02). Similarly, there was less apoptosis in children aged > 1 years than in children aged < 1 years (0.68 (1.40) vs 1.35 (1.56); P < 0.03). Proliferation was very limited in all cryptorchid testes. In contrast to cryptorchid testes, five autopsy controls had many more apoptotic cells, (10.60 (1.34) per 50 seminiferous tubules), and many more proliferating cells, (8.40 (6.43) per 50 seminiferous tubules). CONCLUSION: In contrast to animal studies, neither apoptosis nor proliferation was common in undescended testes from 6 months of age onward. However, apoptosis was more common in abdominal testes and in children aged < 1 year. It is likely that, if substantial apoptosis occurs in human undescended testes, it occurs before 6 months of age.