Neena Mirani

Oncogene‐induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions

In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction‐induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene‐induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans.

An outbreak of Fusarium keratitis associated with contact lens use in the northeastern United States.

Purpose: To report an outbreak of Fusarium keratitis in contact lens (CL) wearers in the northeastern United States. Methods: Over a 41-month period, all cases with culture-proven corneal ulceration secondary to Fusarium at 2 tertiary care eye centers were identified through the microbiology departments of each institution, and a retrospective review of charts was performed. Statistical analyses were performed to evaluate a possible association of Fusarium keratitis with specific CL and CL solution brands. Results: Fifteen cases of Fusarium keratitis were reported at the 2 tertiary centers between July 2005 and May 2006 (16.4 cases/yr) compared with 6 cases over the previous 30 months from January 2003 to June 2005 (2.4 cases/yr). All 15 of the more recent cases were CL users, and none had a history of trauma. All 15 patients claimed use of ReNu brand contact lens solution when they developed keratitis. Twelve (80.0%) of 15 patients were Acuvue soft contact lens users. Ten (66.7%) of 15 patients used tap water to rinse their contact lens cases. Six (40.0%) of 15 cases have thus far required corneal transplantation. Conclusions: The incidence of corneal ulceration secondary to Fusarium has increased sevenfold over the reported 11-month period at 2 tertiary eye care centers in the northeastern United States compared with the previous 30 months. There seems to be an association between the recent outbreak of Fusarium keratitis among CL users and the use of ReNu contact lens solution. Medical treatment of Fusarium keratitis may be ineffective, and emergent penetrating keratoplasty (PKP) may be required in some patients. CL users and their physicians should reconsider the risks of CL use and discuss proper lens care techniques.

Loss of interferon regulatory factor 5 (IRF5) expression in human ductal carcinoma correlates with disease stage and contributes to metastasis

IntroductionNew signaling pathways of the interleukin (IL) family, interferons (IFN) and interferon regulatory factors (IRF) have recently been found within tumor microenvironments and in metastatic sites. Some of these cytokines stimulate while others inhibit breast cancer proliferation and/or invasion. IRFs, a family of nine mammalian transcription factors, have multiple biologic functions that when dysregulated may contribute to tumorigenesis; most well-known are their roles in regulating/initiating host immunity. Some IRF family members have been implicated in tumorigenesis yet little is still known of their expression in primary human tumors or their role(s) in disease development/progression. IRF5 is one of the newer family members to be studied and has been shown to be a critical mediator of host immunity and the cellular response to DNA damage. Here, we examined the expression of IRF5 in primary breast tissue and determined how loss of expression may contribute to breast cancer development and/or progression.MethodsFormalin-fixed paraffin-embedded archival breast tissue specimens from patients with atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) were examined for their expression of IRF1 and IRF5. Knockdown or overexpression of IRF5 in MCF-10A, MCF-7 and MDA-MB-231 mammary epithelial cell lines was used to examine the role of IRF5 in growth inhibition, invasion and tumorigenesis.ResultsAnalysis of IRF expression in human breast tissues revealed the unique down-regulation of IRF5 in patients with different grades of DCIS and IDC as compared to IRF1; loss of IRF5 preceded that of IRF1 and correlated with increased invasiveness. Overexpression of IRF5 in breast cancer cells inhibited in vitro and in vivo cell growth and sensitized them to DNA damage. Complementary experiments with IRF5 siRNAs made normal mammary epithelial cells resistant to DNA damage. By 3-D culture, IRF5 overexpression reverted MDA-MB-231 to normal acini-like structures; cells overexpressing IRF5 had decreased CXCR4 expression and were insensitive to SDF-1/CXCL12-induced migration. These findings were confirmed by CXCR4 promoter reporter assays.ConclusionsIRF5 is an important tumor suppressor that regulates multiple cellular processes involved in the conversion of normal mammary epithelial cells to tumor epithelial cells with metastatic potential.

Respiratory Epithelial Adenomatoid Hamartomas and Chondroosseous Respiratory Epithelial Hamartomas of the Sinonasal Tract: A Case Series and Literature Review:

Background Respiratory epithelial adenomatoid hamartomas (REAH) and chondroosseous respiratory epithelial (CORE) hamartomas are rare sinonasal/nasopharyngeal lesions first characterized in 1995. Although REAH and CORE hamartomas are benign, nonneoplastic lesions, awareness and recognition of these lesions are important because they can be confused grossly and microscopically with more threatening sinonasal tumors. Methods This report presents two cases of REAH and one case of a CORE hamartoma. The literature regarding REAH and CORE hamartomas is reviewed, and their distinction from related entities of the sinonasal tract and nasopharynx is discussed. Conclusions Misdiagnosing REAH or CORE hamartoma as either inverted papilloma or adenocarcinoma may lead to far more aggressive surgical intervention then is necessary.

18F-FDG PET Evaluation of Sinonasal Papilloma

OBJECTIVE It has been suggested that (18)F-FDG uptake determined by PET can differentiate squamous cell carcinoma from benign sinonasal papilloma. We wish to present our experience with sinonasal papillomas and PET/CT to determine if the degree of FDG uptake is indicative of benign or malignant disease. CONCLUSION Benign sinonasal papilloma may be associated with intense FDG uptake on PET/CT. FDG PET/CT does not appear to reliably differentiate benign from malignant sinonasal papilloma.

Optic nerve sheath fenestration in cryptococcal meningitis

A patient with acquired immunodeficiency syndrome (AIDS) developed crytpococcal meningitis, complicated by papilledema and severe progressive visual loss despite medical therapy. Bilateral optic sheath fenestration resulted in significant improvement in vision and resolution of papilledema. Histopathologic evaluation of the optic nerve sheath demonstrated numerous cryptococci. Optic nerve sheath fenestration may be an effective treatment method when high intracranial pressure is contributing to visual loss, even in the presence of involvement of the optic nerve sheath by the fungus.

Actinomyces israelii endogenous endophthalmitis

Actinomyces species are anaerobic Gram-positive pleomorphic rods that are commensals of the oral flora and facultative pathogens.1 In ophthalmological practice, Actinomyces are typically associated with canaliculitis. Although these organisms have rarely been described as causative agents of postoperative endophthalmitis, they have not yet, to our knowledge, been associated with endogenous endophthalmitis.2 3 A 74-year-old woman with diabetes experienced acute unilateral visual loss one week after a dental procedure. Initial examination was remarkable for light perception vision and dense vitritis in the right eye. Despite two vitrectomies with intravitreal vancomycin and ceftazidime injections, and a course of oral steroids, the endophthalmitis progressed, leading to blindness in five months. Diagnostic work-up included microbiological and cytological evaluation of two vitreous biopsies, and systemic investigation for a source of metastatic endophthalmitis (including whole-body positron emission tomography/computed tomography …

Ameloblastoma presenting as a unilateral nasal obstruction

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Primary alveolar soft part sarcoma of fibula demonstrating ASPL–TFE3 fusion: a case report and review of the literature

Alveolar soft part sarcoma is a rare soft tissue tumor typically affecting young adults. These tumors are most often seen in the deep soft tissues of the extremities and patients generally present with advanced disease. Primary bone involvement is extremely rare and has only been reported in seven cases. This is the first case of alveolar soft part sarcoma in bone documenting the ASPL-TFE3 gene product. Herein, we report a rare presentation of alveolar soft part sarcoma presenting as a primary bone neoplasm involving the proximal fibula in a 41-year-old woman.

Sinonasal eosinophilic angiocentric fibrosis: a systematic review.

Eosinophilic angiocentric fibrosis (EAF) is a benign rare lesion of the upper respiratory mucosa. EAF most commonly presents with an obstructive nasal mass. Due to the rarity of EAF, case reports and case studies have predominated the literature. This systematic review discusses the demographics, clinical presentation, associated findings, management, and outcomes of this uncommon entity.