Publications by authors named "Benjamin Tweel"

8 Publications

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P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model.

J Virol 2019 01 10;93(1). Epub 2018 Dec 10.

Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. An human tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1β) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation. Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.
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http://dx.doi.org/10.1128/JVI.01186-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288349PMC
January 2019

Quality Indicators: Measurement and Predictors in Head and Neck Cancer Free Flap Patients.

Otolaryngol Head Neck Surg 2018 02 2;158(2):265-272. Epub 2018 Jan 2.

2 Department of Otolaryngology-Head & Neck Surgery, Division of Head & Neck Oncology, Ohio State University, James Cancer Centre and Solove Research Institute, Columbus, Ohio, USA.

Objective To determine the predictors of length of stay (LOS), readmission within 30 days, and unplanned return to the operating room (OR) within 30 days in head and neck free flap patients. Study Design Case series with chart review. Setting Tertiary academic cancer hospital. Subjects and Methods All head and neck free flap patients at The Ohio State University (OSU, 2006-2012) were assessed. Multivariable logistic regression to assess the impact of patient factors, flap and wound factors, and intraoperative factors on the aforementioned quality metric outcomes. Results In total, 515 patients were identified, of whom 66% had oral cavity cancers, 33% had recurrent tumors, and 28% underwent primary radiotherapy. Of the patients, 31.5% had a LOS greater than 9 days, predicted by longer operative time, oral cavity and pharyngeal tumor sites, blood transfusion, diabetes mellitus, and any complication. A total of 12.6% of patients were readmitted within 30 days predicted by absent OSU preoperative assessment clinic attendance and any complication, and 14.8% of patients had an unplanned OR return predicted by advanced age. Conclusions When assessing quality metrics, adjustment for the complexity involved in managing patients with head and neck cancer with a high comorbidity index, clean contaminated wounds, and a high degree of primary radiotherapy is important. Patients seen in a preoperative assessment clinic had a lower risk of readmission postoperatively, and this should be recommended for all head and neck free flap patients. Quality improvement projects should focus on predictors and prevention of complications as this was the number one predictor of both increased length of stay and readmission.
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http://dx.doi.org/10.1177/0194599817742373DOI Listing
February 2018

Wound breakdown after middle cranial fossa craniotomy: an unusual complication after rhytidectomy.

Laryngoscope 2014 Feb 22;124(2):554-7. Epub 2013 Oct 22.

Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, U.S.A.

Wound complications after middle cranial fossa craniotomy are rare. We describe a patient who underwent a left middle fossa craniotomy for resection of a small internal auditory canal tumor with subsequent development of wound breakdown and infection 1 week postoperatively. Prompting of the patient elicited a history of bilateral rhytidectomies. Wound debridement, hyperbaric oxygen therapy, dermal regeneration template placement, and prolonged antibiotic treatment were performed. Complete secondary intention healing occurred with an acceptable cosmetic outcome. Prior rhytidectomy scars must be identified and incorporated into the surgical planning prior to performing middle fossa craniotomy incisions.
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http://dx.doi.org/10.1002/lary.24078DOI Listing
February 2014

Loss of PTEN expression is associated with poor prognosis in patients with intraductal papillary mucinous neoplasms of the pancreas.

Clin Cancer Res 2013 Dec 16;19(24):6830-41. Epub 2013 Oct 16.

Authors' Affiliations: Herbert Irving Comprehensive Cancer Center; Departments of Pathology, Surgery, and Otolaryngology/Head and Neck Surgery; Institute for Cancer Genetics, Columbia University Medical Center; and The Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.

Purpose: Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMN). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) dysregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. We investigated the dysregulation of the PI3K signaling pathway in IPMN and its clinical implication.

Experimental Design: Thirty-six IPMN specimens were examined by novel mutant-enriched sequencing methods for hot-spot mutations in the PIK3CA and AKT1 genes. PIK3CA and AKT1 gene amplifications and loss of heterozygosity at the PTEN locus were also evaluated. In addition, the expression levels of PDPK1/PDK1, PTEN, and Ki67 were analyzed by immunohistochemistry.

Results: Three cases carrying the E17K mutation in the AKT1 gene and one case harboring the H1047R mutation in the PIK3CA gene were detected among the 36 cases. PDK1 was significantly overexpressed in the high-grade IPMN versus low-grade IPMN (P = 0.034) and in pancreatic and intestinal-type of IPMN versus gastric-type of IPMN (P = 0.020). Loss of PTEN expression was strongly associated with presence of invasive carcinoma and poor survival in these IPMN patients (P = 0.014).

Conclusion: This is the first report of AKT1 mutations in IPMN. Our data indicate that oncogenic activation of the PI3K pathway can contribute to the progression of IPMN, in particular loss of PTEN expression. This finding suggests the potential employment of PI3K pathway-targeted therapies for IPMN patients. The incorporation of PTEN expression status in making surgical decisions may also benefit IPMN patients and should warrant further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0624DOI Listing
December 2013

Velopharyngeal incompetence as a complication of Grisel syndrome.

Otolaryngol Head Neck Surg 2013 Oct 24;149(4):645-6. Epub 2013 Jul 24.

Department of Otolaryngology-Head and Neck Surgery, The Ohio State University, Columbus, Ohio, USA.

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http://dx.doi.org/10.1177/0194599813496972DOI Listing
October 2013

Crystal structure of human mitochondrial acyl-CoA thioesterase (ACOT2).

Biochem Biophys Res Commun 2009 Aug 2;385(4):630-3. Epub 2009 Jun 2.

Department of Biological Sciences, Columbia University, New York, NY 10027, USA.

Acyl-CoA thioesterases (ACOTs) catalyze the hydrolysis of CoA esters to free CoA and carboxylic acids and have important functions in lipid metabolism and other cellular processes. Type I ACOTs are found only in animals and contain an alpha/beta hydrolase domain, through currently no structural information is available on any of these enzymes. We report here the crystal structure at 2.1A resolution of human mitochondrial ACOT2, a type I enzyme. The structure contains two domains, N and C domains. The C domain has the alpha/beta hydrolase fold, with the catalytic triad Ser294-His422-Asp388. The N domain contains a seven-stranded beta-sandwich, which has some distant structural homologs in other proteins. The active site is located in a large pocket at the interface between the two domains. The structural information has significant relevance for other type I ACOTs and related enzymes.
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http://dx.doi.org/10.1016/j.bbrc.2009.05.122DOI Listing
August 2009

Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186.

Structure 2004 Sep;12(9):1683-91

Department of Biological Sciences, Columbia University, New York, NY 10027, USA.

Acetyl-coenzyme A carboxylases (ACCs) are important targets for the development of therapeutic agents against obesity, diabetes, and other diseases. CP-640186 is a potent inhibitor of mammalian ACCs and can reduce body weight and improve insulin sensitivity in test animals. It is believed to target the carboxyltransferase (CT) domain of these enzymes. Here we report the crystal structure of the yeast CT domain in complex with CP-640186. The inhibitor is bound in the active site at the interface of a dimer of the CT domain. CP-640186 has tight interactions with the putative biotin binding site in the CT domain and demonstrates a distinct mode of inhibiting the CT activity as compared to the herbicides that inhibit plant ACCs. The affinity of inhibitors for the CT domain has been assessed using kinetic and fluorescence anisotropy binding studies. The structural information identifies three regions for drug binding in the active site of CT.
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http://dx.doi.org/10.1016/j.str.2004.07.009DOI Listing
September 2004

Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme-A carboxylase by haloxyfop and diclofop.

Proc Natl Acad Sci U S A 2004 Apr 12;101(16):5910-5. Epub 2004 Apr 12.

Department of Biological Sciences, Columbia University, New York, NY 10027, USA.

Acetyl-CoA carboxylases (ACCs) are crucial for the metabolism of fatty acids, making these enzymes important targets for the development of therapeutics against obesity, diabetes, and other diseases. The carboxyltransferase (CT) domain of ACC is the site of action of commercial herbicides, such as haloxyfop, diclofop, and sethoxydim. We have determined the crystal structures at up to 2.5-A resolution of the CT domain of yeast ACC in complex with the herbicide haloxyfop or diclofop. The inhibitors are bound in the active site, at the interface of the dimer of the CT domain. Unexpectedly, inhibitor binding requires large conformational changes for several residues in this interface, which create a highly conserved hydrophobic pocket that extends deeply into the core of the dimer. Two residues that affect herbicide sensitivity are located in this binding site, and mutation of these residues disrupts the structure of the domain. Other residues in the binding site are strictly conserved among the CT domains.
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http://dx.doi.org/10.1073/pnas.0400891101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC395897PMC
April 2004
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