Herpes simplex virus-1 triggered hemophagocytic lymphohistiocytosis in a patient with granulomatosis with polyangiitis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, aggressive hyperinflammatory syndrome in which an inciting event triggers massive, uninhibited activation of T lymphocytes and macrophages. Although viral infections are the most common trigger of HLH, cases of HSV-1 induced HLH are rare in adults. We present the case and postmortem findings of a 27-year-old woman diagnosed with HLH in the setting of immunosuppression for the treatment of granulomatosis with polyangiitis (GPA). Autopsy revealed evidence of herpes simplex virus-1 (HSV-1) infection and no findings suggestive of GPA recurrence.

Herpes simplex virus-infected squamous cell carcinoma: a case report.

BACKGROUND: Herpes simplex virus (HSV)-1 is a highly prevalent, non-oncogenic virus that has higher morbidity in immunocompromised hosts. Its most common clinical manifestation is superficial ulceration of the integument or mucus membranes. CASE PRESENTATION: A 65-year-old woman with a history of acute myelogenous leukemia treated with allogenic peripheral blood stem cell transplant presented for resection of an ulcerated buccal squamous cell carcinoma. We report a case of HSV-1-infected malignant cells discovered on histopathological examination of the carcinoma specimen ultimately treated with valacyclovir. CONCLUSIONS: HSV-1 is not considered an oncogenic virus itself but may increase risk of malignant progression. Cancer cells are vulnerable to superimposed viral infections, including HSV-1, which likely led to the findings in this case.

Herpes simplex virus-1 triggered hemophagocytic lymphohistiocytosis in a patient with granulomatosis with polyangiitis

ABSTRACT Hemophagocytic lymphohistiocytosis (HLH) is a rare, aggressive hyperinflammatory syndrome in which an inciting event triggers massive, uninhibited activation of T lymphocytes and macrophages. Although viral infections are the most common trigger of HLH, cases of HSV-1 induced HLH are rare in adults. We present the case and postmortem findings of a 27-year-old woman diagnosed with HLH in the setting of immunosuppression for the treatment of granulomatosis with polyangiitis (GPA). Autopsy revealed evidence of herpes simplex virus-1 (HSV-1) infection and no findings suggestive of GPA recurrence.

Overexpression of hsa-miR-186 induces chromosomal instability in arsenic-exposed human keratinocytes.

The mechanism of arsenic-induced skin carcinogenesis is not yet fully understood. Chromosomal instability contributes to aneuploidy and is a driving force in carcinogenesis. Arsenic causes mitotic arrest and induces aneuploidy. hsa-miR-186 overexpression is associated with metastatic cancers as well as arsenic-induced squamous cell carcinoma and is reported to target several mitotic regulators. Decreased levels of these proteins can dysregulate chromatid segregation contributing to aneuploidy. This work investigates the potential aneuploidogenic role of hsa-miR-186 in arsenic carcinogenesis. Clones of immortalized human keratinocytes (HaCaT) stably transfected with a hsa-miR-186 expression or empty vector were isolated. Three clones with high and low hsa-miR-186 expression determined by RT-qPCR were selected for further analysis and cultured with 0 or 100 nM NaAsO2 for 8 weeks. Analysis of mitoses revealed that chromosome number and structural abnormalities increased in cells overexpressing hsa-miR-186 and were further increased by arsenite exposure. Double minutes were the dominant structural aberrations. The peak number of chromosomes also increased. Cells with >220 to >270 chromosomes appeared after 2 months in hsa-miR-186 overexpressing cells, indicating multiple rounds of endomitosis had occurred. The fraction of cells with increased chromosome number or structural abnormalities did not increase in passage matched control cells. Levels of selected target proteins were determined by western blot. Expression of BUB1, a predicted hsa-miR-186 target was suppressed in hsa-miR-186 overexpressing clones, but increased with arsenite exposure. CDC27 remained constant under all conditions. These results suggest that overexpression of miR-186 in arsenic exposed tissues likely induces aneuploidy contributing to arsenic-induced carcinogenesis.

miRNA expression profiles of premalignant and malignant arsenic-induced skin lesions.

Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59-172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors.

The effect of black raspberry extracts on MnSOD activity in protection against concanavalin A induced liver injury.

Inflammation and oxidative stress are the key events in carcinogenetic transformation. Black raspberries (BRB) have been demonstrated to have antioxidant, antiinflammatory and anticancer bioactivities. In this study, a concanavalin A induced hepatitis mouse model is used to examine the effect of BRB extract on hepatic injury. Three BRB extracts, including ethanol/H2O extracts (both anthocyanin-contained fraction and nonanthocyanin-contained fraction) and hexane extract were used. The alterations in hepatic histology, apoptosis, and oxidative stress were observed in the animals pretreated with BRB extracts and then challenged by concanavalin A. Results indicate that ethanol/H2O extracts can inhibit Con A induced liver injury. The hepatic protection by the ethanol/H2O BRB extracts is associated with decreases of lipid peroxidation and NDA oxidative damage. Importantly, the BRB extracts increase manganese superoxide dismutase (MnSOD) activity but not the CuZnSOD. The preservation of MnSOD by BRB extracts is associated with the protective action in the liver challenged by Con A. Ethanol/H2O BRB extracts function as antioxidants, thus demonstrating the critical role of oxidative stress in the Con A induced liver injury, and providing evidence that the protective effects of ethanol/H2O BRB extracts result, at least in part, from their antioxidant action.

Sodium arsenite and hyperthermia modulate cisplatin-DNA damage responses and enhance platinum accumulation in murine metastatic ovarian cancer xenograft after hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum (Pt) - resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER), decreased mismatch repair (MMR) and decreased platinum uptake. The objective of this study is to investigate how a novel combination of sodium arsenite (NaAsO2) and hyperthermia (43°C) affect mechanisms of cisplatin resistance in ovarian cancer. METHODS: We established a murine model of metastatic EOC by intraperitoneal injection of A2780/CP70 human ovarian cancer cells into nude mice. We developed a murine hyperthermic intraperitoneal chemotherapy model to treat the mice. Mice with peritoneal metastasis were perfused for 1 h with 3 mg/kg cisplatin ± 26 mg/kg NaAsO2 at 37 or 43°C. Tumors and tissues were collected at 0 and 24 h after treatment. RESULTS: Western blot analysis of p53 and key NER proteins (ERCC1, XPC and XPA) and MMR protein (MSH2) suggested that cisplatin induced p53, XPC and XPA and suppressed MSH2 consistent with resistant phenotype. Hyperthermia suppressed cisplatin-induced XPC and prevented the induction of XPA by cisplatin, but it had no effect on Pt uptake or retention in tumors. NaAsO2 prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO2 and hyperthermia decreased cisplatin-induced XPC 24 h after perfusion, maintained higher levels of MSH2 in tumors and significantly increased initial accumulation of Pt in tumors. ERCC1 levels were generally low except for NaAsO2 co-treatment with cisplatin. Systemic Pt and arsenic accumulation for all treatment conditions were in the order: kidney > liver = spleen > heart > brain and liver > kidney = spleen > heart > brain respectively. Metal levels generally decreased in systemic tissues within 24 h after treatment. CONCLUSION: NaAsO2 and/or hyperthermia have the potential to sensitize tumors to cisplatin by inhibiting NER, maintaining functional MMR and enhancing tumor platinum uptake.