Preclinical Safety Evaluation of HIV-1 gp120 Responsive Microbicide Delivery System in C57BL/6 Female Mice.

Many novel vaginal/rectal microbicide formulations failed clinically due to safety concerns, indicating the need for the early investigation of lead microbicide formulations. In this study, the preclinical safety of an HIV-1 gp120 and mannose responsive microbicide delivery system (MRP) is evaluated in C57BL/6 mice. MRP was engineered through the layer-by-layer coating of calcium carbonate (CaCO3) with Canavalia ensiformis lectin (Con A) and glycogen. MRP mean particle diameter and zeta potential were 857.8 ± 93.1 nm and 2.37 ± 4.12 mV, respectively. Tenofovir (TFV) encapsulation and loading efficiencies in MRP were 70.1% and 16.3% w/w, respectively. When exposed to HIV-1 rgp120 (25 µg/mL), MRP released a significant amount of TFV (∼5-fold higher) in vaginal and seminal fluid mixture compared to the control (pre-exposure) level (∼59 µg/mL) in vaginal fluid alone. Unlike the positive control treated groups (e.g., nonoxynol-9), no significant histological damages and CD45+ cells infiltration were observed in the vaginal and major reproductive organ epithelial layers. This was probably due to MRP biocompatibility and its isosmolality (304.33 ± 0.58 mOsm/kg). Furthermore, compared to negative controls, there was no statistically significant increase in pro-inflammatory cytokines such as IL1α, Ilß, IL7, IP10, and TNFα. Collectively, these data suggest that MRP is a relatively safe nanotemplate for HIV-1 gp120 stimuli responsive vaginal microbicide delivery system.

Evidence of BRAF V600E in indeterminate cell tumor and interdigitating dendritic cell sarcoma.

BRAF V600E mutations have been reported in several histiocytic and dendritic cell neoplasms. In this case series, we report BRAF V600E-positive histiocytic and dendritic cell neoplasms in association with lymphomas and lymphoid proliferations. This is a review of cases with immunohistochemistry for BRAF V600E, with additional immunohistochemistry to categorize tumors. We report the first case of BRAF V600E-positive indeterminate cell tumor in association with angioimmunoblastic T-cell lymphoma. We also report a case of BRAF V600E-positive interdigitating dendritic cell sarcoma in a patient with positive B-cell polymerase chain reaction. It is unclear if these neoplasms developed as transdifferentiation of lymphoid neoplasms or if they developed independently. These cases illustrate the expanding spectrum of BRAF V600E-positive histiocytic and dendritic cell tumors and suggest that attention should be paid to lymphomas for possible coincident presentation of these disorders.

Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways.

The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17ß-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in protection against oxidative DNA damage was increased in Res- and Res + E2-treated mammary tissues. Resveratrol also prevented E2-mediated inhibition of detoxification genes AOX1 and FMO1. Inhibition of E2-mediated alterations in NRF2 promoter methylation and expression of NRF2 targeting miR-93 after Res treatment indicated Res-mediated epigenetic regulation of NRF2 during E2-induced breast carcinogenesis. Resveratrol treatment also induced apoptosis and inhibited E2-mediated increase in DNA damage in mammary tissues. Increased apoptosis and decreased DNA damage, cell migration, colony and mammosphere formation in Res- and Res + E2-treated MCF-10A cells suggested a protective role of Res against E2-induced mammary carcinogenesis. Small-interfering RNA-mediated silencing of NRF2 inhibited Res-mediated preventive effects on the colony and mammosphere formation. Taken together, these results suggest that Res inhibits E2-induced breast carcinogenesis via induction of NRF2-mediated protective pathways.

Ganglioneuroma presenting as a paraesophageal mass lesion diagnosed by endoscopic ultrasound-guided fine needle aspiration cytology: a case report.

BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration is a well-established modality in detection and diagnosis of mediastinal lesions. Ganglioneuroma is a benign, rare, soft tissue neoplasm arising from sympathetic ganglion cells, and complete surgical resection is considered to be curative. Ganglioneuroma in a surgical specimen is a straightforward diagnosis; however, due to the infrequent occurrence of this entity, diagnosis by fine needle aspiration is more challenging. CASE: A case of paraesophageal ganglioneuroma was diagnosed by endoscopic ultrasound-guided fine needle aspiration. A 75-year-old man with a history of adenocarcinoma of the lung was noted to have a mediastinal mass on chest computed tomography. Upper endosonography identified a 40x17-mm mass extrinsic to the thoracic esophagus. An endoscopic ultrasound-guided fine needle aspiration of the mass revealed intermingled fragments of spindle cells and ganglion cells admixed within a fibromyxoid stroma. Immunohistochemistry showed that both the spindle and ganglion cell components were positive for S-100 protein and negative for pancytokeratin. This immunohistochemical profile established both the neurogenic origin of the spindle and ganglion cells. CONCLUSION: Our case represents 1 of the few reported cases of ganglioneuroma diagnosed by fine needle aspiration cytology and the second case diagnosed under endoscopic ultrasound guidance.

Clear cell sarcoma of soft tissue metastatic to the ovaries: a heretofore unreported occurrence.

Clear cell sarcoma of soft tissue (CCSST) is a rare soft tissue neoplasm with marked variable tumor progression and prognosis. Although morphologically similar to malignant melanoma, CCSST can be distinguished by the presence of a t(12; 22)(q13; q12) and/or associated EWSR1-ATF1 chimeric gene. CCSST has an affinity for the extremities and is capable of metastasizing to a wide variety of sites including bone, lung, and lymph nodes and rarely to skin, liver, heart, muscle, and brain. Metastases have been known to occur as late as 29 years after initial presentation. We report a case of a 33-year-old woman who presented with bilateral ovarian cystic tumors, ascites, and pulmonary nodules. Her past medical history was significant for clear cell sarcoma of the left foot 2 years earlier. Bilateral salpingo-oophorectomy was performed and the light microscopic and immunohistochemical findings coupled with the detection of an EWSR1 rearrangement by fluorescence in situ hybridization were compatible with a diagnosis of CCSST metastases to the ovaries. To the best of our knowledge, this is the first reported case of CCSST metastatic to the ovaries.

Ultrasound-guided fine needle aspiration cytology diagnosis of a foregut cyst in the thyroid: a case report.

BACKGROUND: Foregut cysts represent abnormal budding of the tracheobronchial anlage during embryogenesis. They occur most commonly in the mediastinum and pulmonary parenchyma and very seldom in the neck. CASE: A 42-year-old woman developed neck swelling and discomfort. An ultrasound scan showed a cystic nodule with a thick wall extending from the left lower pole of the thyroid gland. The material obtained from fine needle aspiration of the cyst demonstrated numerous detached ciliated tufts (DCTs) in a background of amorphous debris and degenerated cells. A diagnosis of ciliated cell remnants or DCTs consistent with a foregut cyst was made. CONCLUSION: Although this entity is rare, awareness of its occurrence in the thyroid gland may prevent unnecessary surgery.

Metastatic merkel cell carcinoma of the pancreas mimicking primary pancreatic endocrine tumor diagnosed by endoscopic ultrasound-guided fine needle aspiration cytology: a case report.

BACKGROUND: Merkel cell carcinoma (MCC) is a relatively infrequent, rapidly progressive and often fatal cutaneous malignancy exhibiting neuroendocrine differentiation. It has a penchant for local recurrence and distant metastasis to various sites, including regional lymph nodes, distant skin, lung, liver, testis and other rare organs, such as the pancreas. There are only 4 cases of MCC metastatic to the pancreas reported in the English-language literature, and they were all diagnosed by histology from pancreatic resection. CASE: A 79-year-old woman with a large pancreatic tail mass underwent endoscopic ultrasound guided fine needle aspiration (EUS-FNA). She had a history of MCC of the upper extremity with wide local excision 15 months earlier. Metastatic MCC was diagnosed based on the cytomorphology, characteristic immunohistochemical staining pattern, clinical history and comparison of the morphology with that of the primary tumor. CONCLUSION: The cytomorphology and immunohistochemical profile of this neoplasm mimicked a pancreatic endocrine tumor. We discuss the diagnostic pitfalls and differential diagnoses of the metastatic pancreatic MCC, highlighting the importance of thorough clinical history, attention to cytologic detail and corroborating immunohirtochemistry in arriving at the correct diagns. This is the first case ofa metastatic pancreatic MCC diagnosed by EUS-FNA cytology.

Papillary glioneuronal tumor: a case report and review of the literature.

Papillary glioneuronal tumor is a recently described central nervous system neoplasm that almost always occurs adjacent to the lateral ventricle. We present a case of this rare entity, representing the 21st case of this lesion, which exhibits a mixed astrocytic and neuronal differentiation. This case was an incidental finding in a young woman who presented secondary to a traumatic injury to the left eye. Histologic evaluation after surgical removal showed a cystic tumor consisting of 2 distinct components: a unique pseudopapillary architecture admixed with foci of solid areas. The pseudopapillae were composed of thick hyalinized vessels enclosed by a single layer of glial fibrillary acid protein-positive astrocytes and variously sized synaptophysin-positive and chromogranin-negative neuronal cells in the interpapillary regions. Abundant Rosenthal fibers, foci of calcification, areas of hemosiderin deposition, gliosis, areas of vascular proliferation associated with piloid gliosis, and chronic inflammatory infiltrate were identified. The combination of cytologic benignity, lack of necrosis, and low proliferative index as evidenced by immunohistochemistry using antibody to Ki-67 confirmed the low malignant potential of this tumor. Knowledge and precise classification of this entity are important to avoid unnecessary use of chemo- and/or radiotherapy for treatment.

Stimuli-sensitive thiolated hyaluronic acid based nanofibers: synthesis, preclinical safety and in vitro anti-HIV activity.

AIM: To develop a seminal enzyme bioresponsive, mucoadhesive nanofibers (NFs) as safe and effective nanocarriers for the prevention of HIV vaginal transmission. METHODS: A novel thiolated hyaluronic acid (HA-SH) polymer was synthesized to fabricate tenofovir (TFV)-loaded electrospun NFs (HA-SH-NFs) and characterized in vitro/in vivo. RESULTS: A triggered drug release (87% w/w) from the engineered HA-SH-NFs (mean diameter ∼75 nm) occured within 1 h under the influence of seminal hyaluronidase enzyme. HA-SH-NFs were noncytotoxic, induced no damage on the C57BL/6 mice genital-tract and other organs. No significant CD45 cell-infiltration and changes in cytokines level in cervicovaginal tissues were observed. HA-SH-NFs significantly enhanced both TFV retention and bioavailability in vaginal tissue compared with the 1% TFV-gel. The anti-HIV activity of TFV (on pseudotyped virus followed by luciferase assay) was not adversely affected by the electrospinning process. CONCLUSION: HA-SH-NFs developed in this study could potentially serve as a safe nanotemplate for topical intravaginal delivery of HIV/AIDS microbicides.

Conjunctival myxoma: a synopsis of a rare ocular tumor.

Conjunctival myxoma is an exceptionally rare, slow-growing, benign neoplasm of primitive mesenchyme origin. Forty-one cases of conjunctival myxoma from a literature review, including the authors' case, are listed. The usual clinical history is a painless mass appearing during months to years. Grossly, the tumor is a well-circumscribed, cystlike, gelatinous, yellow-to-pink, translucent-to-solid mass. Microscopically, the hypocellular tumor contains stellate- and spindle-shaped cells in a mucoid stroma with abundant hyaluronic acid mucopolysaccharides. Vimentin and α-smooth muscle actin highlight the spindle and stellate cells. S100 protein and desmin are negative for the tumor cells. Treatment is complete surgical excision, with no recurrence reported in the follow-up period. Notably, conjunctival myxoma may be associated with Carney complex, an autosomal-dominant disorder associated with skin pigmentation, endocrine abnormalities, and myxoma of the heart and eye. Physicians should appreciate this unique ocular tumor because of its potential association with Carney complex.

The usefulness of S100P, mesothelin, fascin, prostate stem cell antigen, and 14-3-3 sigma in diagnosing pancreatic adenocarcinoma in cytological specimens obtained by endoscopic ultrasound guided fine-needle aspiration.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the pancreas is an efficient and minimally invasive procedure for the diagnosis and staging of pancreatic adenocarcinoma. Because of some limitations of EUS-FNA in diagnosis of well-differentiated or early stage cancers, the purpose of this study is to assess the added benefit of immunohistochemistry. We studied five proteins overexpressed in pancreatic adenocarcinoma, namely, prostate stem cell antigen, fascin, 14-3-3 sigma, mesothelin and S100P utilizing immunohistochemistry on paraffin sections from cellblocks obtained by EUS-FNA. Sixty-two cases of EUS-FNA of the pancreas that had follow-up histological and/or clinical diagnosis and sufficient material in cell blocks were included. Using histological diagnosis and/or clinical outcome as the reference standard, EUS-FNA shows the highest sensitivity (95%) and specificity (91%) and is superior to any marker in this study. Among five antibodies, S100P reveals the best diagnostic characters showing 90% of sensitivity and 67% of specificity. Fascin shows high specificity (92%) but low sensitivity (38%). Mesothelin has a moderate sensitivity (74%) and low specificity (33%), PSCA and 14-3-3 show high sensitivity but zero specificity. S100P and mesothelin were useful in nine indeterminate cases. S100P correctly predicted six of seven cancers and one of one without cancer and mesothelin correctly diagnosed five of seven cancers and one of two noncancers in this group. EUS-FNA cytomorphology is superior to any of the immunohistochemical markers used in this study. Use of S100P and mesothelin in cytologically borderline cases can increase the diagnostic accuracy in this group.

Dietary Flaxseed Oil Protects against Bleomycin-Induced Pulmonary Fibrosis in Rats.

Bleomycin, a widely used antineoplastic agent, has been associated with severe pulmonary toxicity, primarily fibrosis. Previous work has shown a reduction in bleomycin-induced lung pathology by long-chain omega-3 fatty acids. Treatment by short-chain omega-3 fatty acids, α-linolenic acid, found in dietary flaxseed oil may also reduce lung fibrosis, as previously evidenced in the kidney. To test this hypothesis, 72 rats were divided between diets receiving either 15% (w/w) flaxseed oil or 15% (w/w) corn oil (control). These groups were further divided to receive either bleomycin or vehicle (saline) via an oropharyngeal delivery, rather than the traditional intratracheal instillation. Lungs were harvested at 2, 7, and 21 days after bleomycin or saline treatment. Animals receiving flaxseed oil showed a delay in edema formation (P = 0.025) and a decrease in inflammatory cell infiltrate and vasculitis (P = 0.04 and 0.007, resp.). At days 7 and 21, bleomycin produced a reduction in pulmonary arterial lumen patency (P = 0.01), but not in rats that were treated with flaxseed oil. Bleomycin-treated rats receiving flaxseed oil had reduced pulmonary septal thickness (P = 0.01), signifying decreased fibrosis. Dietary flaxseed oil may prove beneficial against the side effects of this highly effective chemotherapeutic agent and its known toxic effects on the lung.

Placental Cryptococcus neoformans infection without neonatal disease: case report and review of the literature.

We report placental cryptococcosis in a woman with multidrug resistant human immunodeficiency virus (HIV) infection. She received antifungal therapy for cryptococcal meningitis prior to delivery. Cesarean section was performed with delivery of a single full-term male infant. There was no evidence of HIV or cryptococcal infection in the infant. The placenta grossly showed multiple white nodules. Microscopically, numerous encapsulated budding yeasts, morphologically consistent with cryptococci, were identified in the intervillous space and, to a lesser extent, in the chorionic villi. Cryptococcal infections are not uncommon, but only 2 cases of placental cryptococcosis have been reported. Our case is the 1st account documenting cryptococcal organisms within the chorionic villi, and yet there was no evidence of infection in the infant. Mother-to-fetal transmission of cryptococcal infection is not well defined. We review the literature and discuss its possible mechanisms.

Clear cell sarcoma of tendons and aponeuroses: a review.

Clear cell sarcoma of tendons and aponeuroses, also referred to as malignant melanoma of soft parts, is a rare malignancy derived from neural crest cells. It usually presents in the distal lower extremities of young adults, frequently attached to tendons or aponeuroses. It behaves like a high-grade soft tissue sarcoma and is associated with poor overall survival. Magnetic resonance imaging studies of the lesion reveal T1 hypointensity, T2 hyperintensity, and gadolinium uptake. Grossly, the tumor is usually circumscribed with a histologic pattern of uniform polygonal to fusiform cells with clear to pale eosinophilic cytoplasm divided into variably sized clusters by fibrous septa. Immunohistochemical studies in most cases show that the neoplastic cells are positive with HMB-45 and react with antibody against S100 protein. Most cases show a reciprocal cytogenetic translocation t(12;22)(q13;q12) that creates a unique chimeric fusion EWSR1/ATF1 gene transcript. Metastasis occurs mainly to regional lymph nodes and lungs. Poor prognostic indicators include a tumor size equal to or more than 5 cm, presence of metastasis, and necrosis. The mainstay of treatment is wide excision of the tumor. The use of sentinel lymph node biopsy may become an important procedure in detecting occult regional metastasis and guiding the extent of surgery. The beneficial effects of adjuvant chemotherapy and radiotherapy have not been fully evaluated. This article provides a short overview of the current knowledge of clear cell sarcoma of tendons and aponeuroses.