Tertiary Syphilis Masquerading as Oropharyngeal Cancer.

Syphilis is re-emerging in the United States. Treponema pallidum, the spirochete bacterium responsible for syphilis, has immunoevasive properties that facilitate pathogenesis and widespread tissue involvement. Host immune status, particularly the presence of HIV/AIDS, can influence the presentation and severity of the disease. Patients co-infected with HIV and syphilis may develop atypical lesions, including those involving the oropharynx. Any immunocompromised patient with tongue lesions and lymphadenopathy is presumed to have a wide differential diagnosis, and tissue sampling with histopathologic analysis is indicated. We present a patient with gumma of the tongue as the initial manifestation of tertiary syphilis.

Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer.

We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein), is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin loss in endocrine therapy-treated ER+ breast cancer. Neurofibromin-deficient ER+ breast cancer cells initially retain sensitivity to selective ER degraders (SERDs). However, Ras activation does play a role in acquired SERD resistance, which can be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER+ breast tumors.

Tributyltin chloride (TBT) induces RXRA down-regulation and lipid accumulation in human liver cells.

A subset of environmental chemicals acts as "obesogens" as they increase adipose mass and lipid content in livers of treated rodents. One of the most studied class of obesogens are the tin-containing chemicals that have as a central moiety tributyltin (TBT), which bind and activate two nuclear hormone receptors, Peroxisome Proliferator Activated Receptor Gamma (PPARG) and Retinoid X Receptor Alpha (RXRA), at nanomolar concentrations. Here, we have tested whether TBT chloride at such concentrations may affect the neutral lipid level in two cell line models of human liver. Indeed, using high content image analysis (HCA), TBT significantly increased neutral lipid content in a time- and concentration-dependent manner. Consistent with the observed increased lipid accumulation, RNA fluorescence in situ hybridization (RNA FISH) and RT-qPCR experiments revealed that TBT enhanced the steady-state mRNA levels of two key genes for de novo lipogenesis, the transcription factor SREBF1 and its downstream enzymatic target, FASN. Importantly, pre-treatment of cells with 2-deoxy-D-glucose reduced TBT-mediated lipid accumulation, thereby suggesting a role for active glycolysis during the process of lipid accumulation. As other RXRA binding ligands can promote RXRA protein turnover via the 26S proteasome, TBT was tested for such an effect in the two liver cell lines. We found that TBT, in a time- and dose-dependent manner, significantly reduced steady-state RXRA levels in a proteasome-dependent manner. While TBT promotes both RXRA protein turnover and lipid accumulation, we found no correlation between these two events at the single cell level, thereby suggesting an additional mechanism may be involved in TBT promotion of lipid accumulation, such as glycolysis.

Blood Loss and Visibility with Esmolol vs Labetalol in Endoscopic Sinus Surgery: A Randomized Clinical Trial.

OBJECTIVES: Improved intraoperative visibility during functional endoscopic sinus surgery (FESS) decreases the risk of serious orbital or skull base injuries. Esmolol and labetalol have been used to reduce bleeding and achieve better visibility, but it remains unclear which drug is more effective. This study aims to measure visibility scores and mucosal bleeding rates for esmolol and labetalol in FESS. METHODS: This is a 1-year randomized double-blind trial of adults undergoing FESS at a tertiary academic center. The inclusion criteria were as follows: age 18 or older; history of chronic rhinosinusitis (CRS) with or without nasal polyps; undergoing FESS for CRS; and American Society of Anesthesiologists (ASA) physical status 1 (healthy) or 2 (patient with mild systemic disease). The exclusion criteria were as follows: pregnancy; asthma, chronic obstructive pulmonary disease (COPD), bradycardia, heart failure, end-stage renal disease, cerebrovascular accident, diabetes mellitus; preoperative use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or beta-blockers; and body mass index (BMI) greater than 40 kg/m2. Patients received either dose-infused esmolol or intravenous push labetalol. The primary outcome was intraoperative visibility determined by surgeon using validated scoring systems (Boezaart, Wormald). The secondary outcome was hemodynamic control (rate of blood loss, average mean arterial pressure [MAP], average heart rate [HR]). Hypothesis of no difference between drugs formed before data collection. RESULTS: Of the 32 adults given drug (mean age = 50), 28 patients (13 esmolol and 15 labetalol) with complete data were included in the final analysis. There were no statistically significant differences between esmolol and labetalol in rate of blood loss (0.59 [0.28] vs 0.66 [0.37] mL/min, P = 0.62), average MAP (79.7 [7.5] vs 79.4 [7.7] mm Hg, P = .93), HR (72 [8.7] vs 68 [11.7] bpm, P = .26), or mean visibility scores for the Boezaart (3.1 [0.69] vs 3.1 [0.89], P = .85) and Wormald (6.1 [1.7] vs 5.9 [1.9], P = .72) grading scales. CONCLUSIONS: There were no significant differences between esmolol and labetalol in rate of blood loss, MAP control, HR, or surgical visibility in FESS. Either drug may be used, and other considerations (availability, cost) can dictate choice.

Preventing unnecessary tympanostomy tube placement in children.

OBJECTIVE: In 2013 the American Academy of Otolaryngology published tympanostomy tube guidelines for children; Action Statement 6 recommends against tube placement without middle ear effusion (MEE) at time of assessment. To date, little research has directly evaluated this recommendation in reducing the need for ear tubes. We evaluated the effectiveness of this recommendation and potential risk factors that influence the success of watchful waiting. METHODS: Retrospective chart review collecting demographics, daycare status, smoking exposure, and time of year of visit. Children aged 6 months to 12 years without MEE on presentation, but with 3 or more episodes of acute otitis media (AOM) in 6 months or 4 or more episodes in 12 months, were assigned to watchful waiting (WW) treatment. These patients were followed every 4 months or returned sooner with additional infections. Any continued AOM, or MEE on follow up leading to tube placement, defined WW failure. RESULTS: 123 patients met criteria, with 81 still in WW to date (66% success rate). 42 children failed WW and received tympanostomy tubes (34% failure rate). There were no statistically significant associations between age, race, gender, smoking exposure, daycare, or month of presentation between children who failed WW compared to children receiving tubes. CONCLUSIONS: Tympanostomy tube guidelines mitigate unnecessary tube placement in a majority of children with recurrent AOM without MEE. To our knowledge, this is the first study supporting the 2013 recommendations, with a 66% success rate. Additionally, no significant associations between modifying risk factors in those who failed watchful waiting were identified.

Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets.

Approximately 75% of breast cancers are estrogen receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10-40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERα proteins may offer new therapeutic targets for endocrine-resistant cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ERα LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ERα. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.