Digital Commons Network^™

Critical Role Of Leucine-Valine Change In Distinct Low Ph Requirements For Membrane Fusion Between Two Related Retrovirus Envelopes, Marceline Côté, Yi-Min Zheng, Kun Li, Shi-Hua Xiang, Lorraine M. Albritton, Shan-Lu Liu

Nebraska Center for Virology: Faculty Publications

Many viruses use a pH-dependent pathway for fusion with host cell membrane, the mechanism of which is still poorly understood. Here we report that a subtle leucine (Leu)-valine (Val) change at position 501 in the envelope glycoproteins (Envs) of two related retroviruses, jaagsiekte sheep retro-virus (JSRV) and enzootic nasal tumor virus (ENTV), is responsible for their distinct low pH requirements for membrane fusion and infection. The Leu and Val residues are predicted to reside within the C-terminal heptad repeat (HR2) region of JSRV and ENTV Envs, particularly proximal to the hairpin turn of the putative six-helix bundle (6HB). Substitution of …

Hiv-1 Effects On Neuropsychological Performance In A Resource-Limited Country, Zambia, Gabriel Holguin, Mwanza Banda, Elizabeth J. Willen, Costantine Malama, Kaseya O. Chiyenu, Victor C. Mudenda, Charles Wood

Nebraska Center for Virology: Faculty Publications

Zambia has substantially been affected by the HIV/AIDS epidemic with prevalence rates at 14% in a population estimated at 12 million. Yet, the extent of HIV-associated neurocognitive disorders (HAND) in this population remains to be clearly understood. A series of culturally appropriate neuropsychological (NP) assessments [International HIV Dementia Scale (IHDS), Color Trails Test 1 and 2, Grooved pegboard Test, and Time Gait Test] were used to test the effects of HIV on NP performance of HIV seropositive and seronegative individuals. Twenty-two percent HIV positive individuals ARV naïve met the criteria for IHDS-defined NP impairment. Gender significantly influenced the performance on …

Characterization Of Species C Human Adenovirus Serotype 6 (Ad6), Eric A. Weaver, Reeti Khare, Mathew L. Hillestad, Donna Palmer, Philip Ng, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Adenovirus serotype (Ad5) is the most studied Ad. Ad1, 2, and 6 are also members of species C Ad and are presumed to have biologies similar to Ad5. In this work, we have compared the ability of Ad1, 2, 5, and 6 to infect liver and muscle after intravenous and intramuscular injection. We found that Ad6 was surprisingly the most potent at liver gene delivery and that Ad1 and Ad2 were markedly weaker than Ad5 and 6. To understand these differences, we sequenced the Ad6 genome. This revealed that the Ad6 fiber protein is surprisingly three shaft repeats shorter than …

Generation Of A Kupffer Cell-Evading Adenovirus For Systemic And Liver-Directed Gene Transfer, Reeti Khare, Shannon M. May, Francesco Vetrini, Eric A. Weaver, Donna Palmer, Amanda Rosewell, Nathan Grove, Philip Ng, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to …

Molecular Bases Of Cutaneous And Uveal Melanomas, Sudeep Gaudi, Jane L. Messina

Pathology and Cell Biology Faculty Publications

Intensive research in recent years has begun to unlock the mysteries surrounding the molecular pathogenesis of melanoma, the deadliest of skin cancers. The high-penetrance, low-frequency susceptibility gene CDKN2A produces tumor suppressor proteins that function in concert with p53 and retinoblastoma protein to thwart melanomagenesis. Aberrant CDKN2A gene products have been implicated in a great many cases of familial cutaneous melanoma. Sporadic cases, on the other hand, often involve constitutive signal transduction along the mitogen-activated protein kinase (MAPK) pathway, with particular focus falling upon mutated RAS and RAF protooncogenes. The proliferative effects of the MAPK pathway may be complemented by the …

Primary Colorectal Adenocarcinoma Metastatic To The Breast: Case Report And Review Of Nineteen Cases, Rodney E. Shackelford, Pushpa Allam-Nandyala, Marilyn M. Bui, John V. Kiluk, Nicole Nicosia Esposito

Pathology and Cell Biology Faculty Publications

Metastases to the breast from extramammary primaries are uncommon and account for 0.5–6% of all breast malignancies (Georgiannos et al., 2001, and Vizcaíno et al., 2001). Malignant melanoma, lymphoma, and lung and gastric carcinomas are the most frequently encountered nonmammary metastases to the breast in adults (Georgiannos et al., 2001, and Chaignaud et al., 1994). Primary colorectal adenocarcinoma (CRC) metastatic to the breast is extremely rare, with the medical literature having only 19 recorded cases. Typically CRC metastatic to the breast is indicative of widely disseminated disease and a poor prognosis. Here we present a case of poorly differentiated colon …

Pathology Of Breast Carcinoma: Diagnostic, Prognostic, And Therapeutic Issues And Challenges, Rohit Bhargava, Sunati Sahoo, Nicole Nicosia Esposito, Beiyun Chen

Pathology and Cell Biology Faculty Publications

No abstract provided.

Novel Molecular Markers Of Malignancy In Histologically Normal And Benign Breast, Aejaz Nasir, Dung-Tsa Chen, Mike Gruidl, Evita B. Henderson-Jackson, Chinnambally Venkataramu, Susan M. Mccarthy, Heyoung L. Mcbrid, Eleanor Harris, Nazanin Khakpour, Timothy J. Yeatman

Pathology and Cell Biology Faculty Publications

To detect the molecular changes of malignancy in histologically normal breast (HNB) tissues, we recently developed a novel 117-gene-malignancy-signature. Here we report validation of our leading malignancy-risk-genes, topoisomerase-2-alpha (TOP2A), minichromosome-maintenance-protein-2 (MCM2) and “budding-uninhibited-by-benzimidazoles-1-homolog-beta” (BUB1B) at the protein level. Using our 117-gene malignancy-signature, we classified 18 fresh-frozen HNB tissues from 18 adult female breast cancer patients into HNB-tissues with low-grade (HNB-LGMA; ) and high-grade molecular abnormality (HNB-HGMA; ). Archival sections of additional HNB tissues from these patients, and invasive ductal carcinoma (IDC) tissues from six other patients were immunostained for these biomarkers. TOP2A/MCM2 expression was assessed as staining index (%) and …

Ovarian Epithelial-Stromal Interactions: Role Of Interleukins 1 And 6, Kamisha T. Woolery, Patricia A. Kruk

Pathology and Cell Biology Faculty Publications

Ovarian epithelial cancer is the most lethal gynecologic malignancy. The high mortality is attributed to the fact that most cases typically present in late stage when ovarian cancer (OC) has already spread beyond the ovary. Ovarian epithelial cancer cells are shed into intraperitoneal ascites and easily disseminate throughout the peritoneal cavity with preferential metastasis to the omentum, peritoneum, and local organs. Understanding how ovarian epithelial cells interact with and modulate their microenvironment can provide insight into the molecular mechanism(s) involved with malignant transformation and progression which may eventually identify novel diagnostic, prognostic, and therapeutic targets. The objective of this paper …

Toward Personalized Cell Therapies: Autologous Menstrual Blood Cells For Stroke, Maria Carolina O. Rodrigues, Loren E. Glover, Nathan Weinbren, Jessica A. Rizzi, Kazutaka Shinozuka, Naoki Tajiri, Yuji Kaneko, Paul R. Sanberg, Julie G. Allickson, Nicole Kuzmin-Nichols, Svitlana Garbuzova-Davis, Julio Cesar Voltarelli, Eduardo Cruz, Cesar V. Borlongan

Neurosurgery and Brain Repair Faculty Publications

Cell therapy has been established as an important field of research with considerable progress in the last years. At the same time, the progressive aging of the population has highlighted the importance of discovering therapeutic alternatives for diseases of high incidence and disability, such as stroke. Menstrual blood is a recently discovered source of stem cells with potential relevance for the treatment of stroke. Migration to the infarct site, modulation of the inflammatory reaction, secretion of neurotrophic factors, and possible differentiation warrant these cells as therapeutic tools. We here propose the use of autologous menstrual blood cells in the restorative …

Provider-Related Barriers To Accessing Emergency Contraception In Developing Countries: A Literature Review, Katherine Williams

Reproductive Health

This systematic literature review aims to identify and describe existing provider-related barriers to accessing emergency contraception (EC) in developing countries, as well as the prevalence of these barriers and documented research programs to address them. Findings from this review will contribute to specific recommendations on provider attitudes and behaviors related to emergency contraception and inform the development of a global advocacy strategy to increase access to the method.

Circulating Anti-Plac1 Antibodies During Pregnancy And In Women With Reproductive Failure: A Preliminary Analysis, Anne C. Kotto-Kome, Celso Silva, Valerie Whiteman, Xiaoyuan Kong, Michael E. Fant

Pediatrics Faculty Publications

The aims of this study were to determine the prevalence of anti-PLAC1 antibodies in normal pregnant women and in women with infertility or recurrent pregnancy loss (RPL). Secondary outcomes were the development of complications associated with anti-PLAC1 seropositivity and the rate of seroconversion during pregnancy. Sera from 103 healthy pregnant women and 45 women with unexplained infertility or RPL were analyzed by ELISA. The prevalence of anti-PLAC1 antibodies was 2% in healthy pregnant women and 4.5% in women with unexplained infertility or RPL (𝑃 = 0 . 3 5 5). There was no detectable association of seropositivity with increased risk …

Late-Presenting Left-Sided Morgagni Congenital Diaphragmatic Hernia In A 9-Year-Old Male, Jennifer M. Kim, Marisa Couluris, Bruce M. Schnapf

Pediatrics Faculty Publications

Congenital diaphragmatic hernias are common, primarily occurring through the foramen of Bochdalek. However, in contrast, defects through the foramen of Morgagni are much more rare. When late presentations occur, patients may be asymptomatic or may be critically ill with respiratory and gastrointestinal symptoms. In this paper, we present a 9-year-old male who presented with recurrent, vague abdominal pain, and a previously normal abdominal CT scan. Initial investigation via an abdominal radiograph demonstrated an unexpected left lower lobe abnormality. Further evaluation and management revealed this abnormality to be an unusual left-sided congenital diaphragmatic hernia that appeared through the retrosternal foramen of …

Population Pharmacokinetic (Pk) And Pharmacodynamic (Pd) Modeling Of Ticarcillin‐Clavulanate In Pediatric Cf Patients, Jeffery T. Zobell, Chris Stockmann, D. C. Young, Jared Cash, Catherine M.T. Sherwin, Michael G. Spigarelli, Barbara A. Chatfield, Krow Ampofo

Pediatrics Faculty Publications

No abstract provided.

The Mechanosensory Role Of Primary Cilia In Vascular Hypertension, Surya M. Nauli, Xingjian Jin, Beerend P. Hierck

Pharmacy Faculty Articles and Research

Local regulation of vascular tone plays an important role in cardiovascular control of blood pressure. Aside from chemical or hormonal regulations, this local homeostasis is highly regulated by fluid-shear stress. It was previously unclear how vascular endothelial cells were able to sense fluid-shear stress. The cellular functions of mechanosensory cilia within vascular system have emerged recently. In particular, hypertension is insidious and remains a continuous problem that evolves during the course of polycystic kidney disease (PKD). The basic and clinical perspectives on primary cilia are discussed with regard to the pathogenesis of hypertension in PKD.

Thiazolyl N-Benzyl-Substituted Acetamide Derivatives: Synthesis, Src Kinase Inhibitory And Anticancer Activities, Asal Fallah-Tafti, Alireza Foroumadi, Rakesh Tiwari, Amir Nasrolahi Shirazi, David G. Hangauer, Yahao Bu, Tahmineh Akbarzadeh, Keykavous Parang, Abbas Shafiee

Pharmacy Faculty Articles and Research

KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure-activity relationship, a number of N-benzyl substituted (2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI50 values of 1.34 μM and 2.30 M in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. …

Mentorship Programs For Faculty Development In Academic General Pediatric Divisions, Jennifer Takagishi, Sharon Dabrow

Pediatrics Faculty Publications

Introduction. Mentoring relationships have been shown to support academicians in areas of research, work/life balance, and promotion. Methods. General pediatric division chiefs accessed an electronic survey asking about mentorship relationships, their ability to create a mentorship program, and resources needed. Results. Dyadic mentorship programs were available at 53% of divisions. Peer mentorship programs were available at 27% of divisions. Overall, 84% of chiefs believed that dyadic mentorship would benefit their faculty. 91% of chiefs believed that peer mentorship would benefit their faculty. Chiefs were interested in starting peer (57%) or dyadic (55%) mentorship programs. Few divisions had …

Mesalamine-Induced Myocarditis And Coronary Vasculitis In A Pediatric Ulcerative Colitis Patient: A Case Report, Elimarys Perez-Colon, Gul H. Dadlani, Ivan Wilmot, Michelle Miller

Pediatrics Faculty Publications

Mesalamine-containing products are often a first-line treatment for ulcerative colitis. Severe adverse reactions to these products, including cardiovascular toxicity, are rarely seen in pediatric patients. We present a case of a 16-year-old boy with ulcerative colitis treated with Asacol, a mesalamine-containing product, who developed sudden onset chest pain after four weeks on therapy. Serial electrocardiograms showed nonspecific ST segment changes, an echocardiogram showed mildly decreased left ventricular systolic function with mild to moderate left ventricular dilation and coronary ectasia, and his troponins were elevated. Following Asacol discontinuation, his chest pain resolved, troponins were trending towards normal, left ventricular systolic function …

Isoniazid-Induced Severe Hepatotoxicity: An Infrequent But Preventable Cause Of Liver Failure In Children Treated For Latent Tuberculosis Infection, Dan Desrochers, Regino P. González-Peralta, Daniel T. Mcclenathan, Michael J. Wilsey Jr, Allah Haafiz

Pediatrics Faculty Publications

Isoniazid (INH) monotherapy has gained widespread acceptance as an efficacious therapy for latent tuberculosis infection (LTBI) especially in low-prevalence settings. Although INH related hepatotoxicity is well recognized, progression to severe liver dysfunction requiring care at a transplant center remains unpredictable. We report the management of a five year-old girl who developed progressive liver failure due to INH prophylaxis. This highlights the potential severity of INH related hepatic injury and underscores the significance of vigilant clinical monitoring throughout the duration of the therapy in children.

Polyethylenimine-Conjugated Gold Nanoparticles: Gene Transfer Potential And Low Toxicity In The Cornea, Ajay Sharma, Ashish Tandon, Jonathan C. K. Tovey, Rangan Gupta, J. David Robertson, Jennifer A. Fortune, Alexander M. Klibanov, John W. Cowden, Frank G. Rieger, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

This study examined the gene transfer efficiency and toxicity of 2-kDa polyethylenimine conjugated to gold nanoparticles (PEI2-GNP) in the human cornea in vitro and rabbit cornea in vivo. PEI2-GNP with nitrogen-to-phosphorus (N/P) ratios of up to 180 exhibited significant transgene delivery in the human cornea without altering the viability or phenotype of these cells. Similarly, PEI2-GNP applied to corneal tissues collected after 12 h, 72 h, or 7 days exhibited appreciable gold uptake throughout the rabbit stroma with gradual clearance of GNP over time. Transmission electron microscopy detected GNP in the keratocytes and the extracellular matrix of the rabbit corneas. …

A Ten-Year Review Of Neonatal Bloodstream Infections In A Tertiary Private Hospital In Kenya, Ruchika Kohli-Kochhar, Geoffrey Omuse, Gunturu Revathi

Pathology, East Africa

Introduction: Neonatal mortality in developing countries is usually due to an infectious cause. The gold standard of investigation in developing countries is a positive blood culture. It is important to know the aetiology of neonatal bloodstream infections so that empiric treatment can be effective.

Methodology: We conducted a retrospective clinical audit over ten years between January 2000 until December 2009, looking at the aetiology of both early and late onset neonatal sepsis. We analysed data from 152 (23%) patient isolates out of 662 suspected cases of neonatal sepsis.

Results: Our study revealed that Gram-positive organisms were the predominant cause of …

Malaria Rapid Testing By Community Health Workers Is Effective And Safe For Targeting Malaria Treatment: Randomised Cross-Over Trial In Tanzania, M. Mubi, A. Janson, M. Warsame, A. Martensson, K. Kallander, M.G. Petzold, B. Ngasala, G. Maganga, L.L. Gustafsson, A. Massele, G. Tomson, Zul Premji, A. Bjorkman

Pathology, East Africa

Background: Early diagnosis and prompt, effective treatment of uncomplicated malaria is critical to prevent severe disease, death and malaria transmission. We assessed the impact of rapid malaria diagnostic tests (RDTs) by community health workers (CHWs) on provision of artemisinin-based combination therapy (ACT) and health outcome in fever patients.

Methodology/Principal Findings: Twenty-two CHWs from five villages in Kibaha District, a high-malaria transmission area in Coast Region, Tanzania, were trained to manage uncomplicated malaria using RDT aided diagnosis or clinical diagnosis (CD) only. Each CHW was randomly assigned to use either RDT or CD the first week and thereafter alternating weekly. …

Pre-Referral Rectal Artesunate In Severe Malaria: Flawed Trial, K.F. Hirji, Zul Premji

Pathology, East Africa

Background:Immediate injectable treatment is essential for severe malaria. Otherwise, the afflicted risk lifelong impairment or death. In rural areas of Africa and Asia, appropriate care is often miles away. In 2009, Melba Gomes and her colleagues published the findings of a randomized, placebo-controlled trial of rectal artesunate for suspected severe malaria in such remote areas. Enrolling nearly 18,000 cases, the aim was to evaluate whether, as patients were in transit to a health facility, a pre-referral artesunate suppository blocked disease progression sufficiently to reduce these risks. The affirmative findings of this, the only trial on the issue thus far, …

Aggressive Embryonal Rhabdomyosarcoma Presenting As Schwanoma : A Case Report, Mohammad Sohail Awan, Montasir Junaid, Zain A. Sobani

Department of Radiology

Rhabdomyosarcomas (RMS) are thought to arise from pluripotent muscle cell precursors intended to form the bodyís future striated muscle. Due to the wide distribution of striated muscle across the body these tumors may appear anywhere and cause symptoms accordingly. Presenting symptoms are highly variable and based on the tumor size and location making clinical diagnosis difficult. The diagnosis of RMS is based on histological examination; however they express varying cytologic pictures representing the different stages of rhabdomyoblasts and their development into skeletal muscle presenting pictures from highly to poorly differentiated neoplasms. Therefore their histological diagnosis also requires the use of …

The State Of Emergency Care In The Republic Of Kenya, Benjamin Wachira, Ian Martin

Family Medicine, East Africa

Approximately 580,000 km2 in size, the Republic of Kenya is as big as Botswana but only half the size of countries like South Africa, Mali, and Angola. Kenya is comprised of eight provinces: Central, Coast, Eastern, Nairobi, North Eastern, Nyanza, Rift Valley, and Western. The 2009 census revealed a population of over 38 million people, with a population density of approximately 66 persons per square kilometre. Majority of the population (68%) lives in rural areas, as compared with the sub-Saharan African average of approximately 62%. With a gross domestic product (GDP) per capita of US $1,600 in 2010, Kenya is …

P-Dat: Lessons From Patients With Disabilities, Casey R. Bonaquist Do, Sweety Jain Md, Alex Garder

Department of Family Medicine

No abstract provided.

Targeted Identification Of Metastasis-Associated Cell-Surface Sialoglycoproteins In Prostate Cancer, Lifang Yang, Julius O. Nyalwidhe, Sigi Guo, Richard R. Drake, O. John Semmes

Bioelectrics Publications

Covalent attachment of carbohydrates to proteins is one of the most common post-translational modifications. At the cell surface, sugar moieties of glycoproteins contribute to molecular recognition events involved in cancer metastasis. We have combined glycan metabolic labeling with mass spectrometry analysis to identify and characterize metastasis-associated cell surface sialoglycoproteins. Our model system used syngeneic prostate cancer cell lines derived from PC3 (N2, nonmetastatic, and ML2, highly metastatic). The metabolic incorporation of AC₄ManNAz and subsequent specific labeling of cell surface sialylation was confirmed by flow cytometry and confocal microscopy. Affinity isolation of the modified sialic-acid containing cell surface proteins …

Should Histologic Grade Be Incorporated Into The Tnm Classification System For Small (T1, T2) Node-Negative Breast Adenocarcinomas?, Matthew Purdom, Michael L. Cibull, Terry D. Stratton, Luis M. Samayoa, Edward Romond, Patrick C. Mcgrath, Rouzan G. Karabakhtsian

Pathology and Laboratory Medicine Faculty Publications

Prognosis of invasive ductal carcinoma (IDC) strongly correlates with tumor grade as determined by Nottingham combined histologic grade. While reporting grade as low grade/favorable (G1), intermediate grade/moderately favorable (G2), and high grade/unfavorable (G3) is recommended by American Joint Committee on Cancer (AJCC) staging system, existing TNM (Primary Tumor/Regional Lymph Nodes/Distant Metastasis) classification does not directly incorporate these data. For large tumors (T3, T4), significance of histologic grade may be clinically moot as those are nearly always candidates for adjuvant therapy. However, for small (T1, T2) node-negative (N0) tumors, grade may be clinically relevant in influencing treatment decisions, but data on …

Spinal Cord Protection: Lessons Learned From Endovascular Repair, Jennifer N Dulin, Meredith L Moore, Kevin W Gates, Joanna H Queen, Raymond J Grill

Faculty, Staff and Student Publications

There is a high incidence of infertility in males following traumatic spinal cord injury (SCI). Quality of semen is frequently poor in these patients, but the pathophysiological mechanism(s) causing this are not known. Blood-testis barrier (BTB) integrity following SCI has not previously been examined. The objective of this study was to characterize the effects of spinal contusion injury on the BTB in the rat. 63 adult, male Sprague Dawley rats received SCI (n = 28), laminectomy only (n = 7) or served as uninjured, age-matched controls (n = 28). Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), BTB permeability to the …

Combination Of Dasatinib And Curcumin Eliminates Chemo-Resistant Colon Cancer Cells, Jyoti Nautiyal, Shailender S. Kanwar, Yingjie Yu, Adhip Pn Majumdar

Wayne State University Associated BioMed Central Scholarship

Abstract

Metastatic colorectal cancer remains a serious health concern with poor patient survival. Although 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) is the standard therapy for colorectal cancer, it has met with limited success. Recurrence of the tumor after chemotherapy could partly be explained by the enrichment of the chemo-resistant sub-population of cancer stem cells (CSCs) that possess the ability for self-renewal and differentiation into different lineages in the tumor. Therefore development of therapeutic strategies that target CSCs for successful treatment of this malignancy is warranted. The current investigation was undertaken to examine the effectiveness of the combination therapy of …