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Amit Agrawal

Publications and source records attributed to Amit Agrawal.

34 records · Page 2Linked to original sources
PubMed2005

Somatic acquisition and signaling of TGFBR1*6A in cancer.

CONTEXT: TGFBR1*6A is a common polymorphism of the type I transforming growth factor beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. OBJECTIVES: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. DESIGN, SETTING, AND PATIENTS: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. MAIN OUTCOME MEASURES: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation. RESULTS: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. CONCLUSIONS: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.

Activin Receptors, Type I↗
PubMed2005

The human D-glucuronyl C5-epimerase gene is transcriptionally activated through the beta-catenin-TCF4 pathway.

Heparan sulphate (HS) is a ubiquitous constituent of the extracellular matrix that is required for the biological activity of circulating soluble and insoluble extracellular ligands. GLCE (D-glucuronyl C5-epimerase), an enzyme responsible for the epimerization of D-glucuronic acid into L-iduronic acid of HS, endows the nascent polysaccharide chain with the ability to bind to growth factors and cytokines. In order to examine the mechanism of regulation of GLCE expression, the functional organization of the human GLCE gene promoter has been investigated. Studies utilizing stepwise deleted and site-directed mutagenized promoter constructs have shed light on the functional relevance of two cis-acting binding elements for the beta-catenin-TCF4 complex (where TCF4 stands for T-cell factor 4) that are located in the enhancer region of the promoter. The ability of the putative binding sequences to bind the beta-catenin-TCF4 complex has been confirmed through electrophoretic mobility-shift and supershift analyses. We have found that, in a set of human colon carcinoma cell lines, the expression of GLCE correlates with the degree of activation of the beta-catenin-TCF4 transactivation complex. Furthermore, the ectopic expression of beta-catenin-TCF4 in cells that constitutively express low levels of the transactivation complex produces a significant increase of GLCE transcript level and, at the same time, enhances the rate of D-glucuronic acid epimerization in HS. The data obtained are consistent with the idea that the beta-catenin-TCF4 transactivation pathway plays a major role in modulating GLCE expression, thus contributing to the regulation of HS biosynthesis and its structural organization.

Base Sequence↗
PubMed2005

Neurological manifestations of Hansen's disease and their management.

Hansen's disease is almost eliminated from developed countries but in developing countries of Africa, Asia and Latin America leprosy is still considered to be a public health problem. Mycobacterium leprae have the affinity for peripheral nerves and neuropathy is a cardinal manifestation of the disease. The nerve damage affects sensory, motor, and autonomic fibers resulting in the physical impairments and limitation of physical activities and social participation. Leprosy is a curable disease and treatment provided in the early stages will avert the disabilities. Approach to the neuritic leprosy depends on its clinical characteristics, nerve biopsy, and histological appearance of dermatological and neurological lesions. In this article we review the literature and discuss the pathology, clinical features, diagnosis and management of neurological manifestations of leprosy.

Bacterial Vaccines↗
PubMed2005

Ingestion of acidic foods mimics gastroesophageal reflux during pH monitoring.

Ingestion of acidic foods may produce artifactual drops in pH to < 4 that may be difficult to differentiate from a true acid reflux event. We aimed to evaluate intraesophageal pH changes during the ingestion of acidic food and describe the frequency and implications of acidic food ingestion on ambulatory pH monitoring. Ten normal volunteers (six females; mean age, 34) underwent combined impedance-pH testing with a pH electrode placed 5 cm above the lower esophageal sphincter. Each volunteer received 50 ml each of acidic foods in random order. Nadir and mean pH for 30 sec after ingestion of each substance were recorded. Subsequently 100 randomly selected reflux monitor diaries were reviewed, searching for ingestion of acidic foods, and 100 pH tracings were reviewed to evaluate the impact of including/excluding meal periods on percentage time pH < 4 and DeMeester scores. All foods produced abrupt drops to pH < 4, in 80% of cases exceeding 30 sec. During ambulatory pH monitoring 78% of patients recorded ingestion of at least 1 of the 10 tested substances during meals, the majority admitting ingesting carbonated beverages. Not excluding meal periods would have led to the misinterpretation of 6-16% of tracings, depending on the criteria used to identify abnormal acid exposure. We conclude that ingestion of acidic foods is frequent and carries the risk of overdiagnosing GERD. Current findings support the recommendations to carefully instruct patients to record all oral intake and to exclude meal periods from the analysis.

Adult↗
PubMed2005

Real-time detection of virus particles and viral protein expression with two-color nanoparticle probes.

Respiratory syncytial virus (RSV) mediates serious lower respiratory tract illness in infants and young children and is a significant pathogen of the elderly and immune compromised. Rapid and sensitive RSV diagnosis is important to infection control and efforts to develop antiviral drugs. Current RSV detection methods are limited by sensitivity and/or time required for detection. In this study, we show that antibody-conjugated nanoparticles rapidly and sensitively detect RSV and estimate relative levels of surface protein expression. A major development is use of dual-color quantum dots or fluorescence energy transfer nanobeads that can be simultaneously excited with a single light source.

Respiratory Syncytial Viruses↗
PubMed2004

Role of the physician versus the patient in the detection of recurrent disease following treatment for head and neck cancer.

OBJECTIVES/HYPOTHESIS: Objective evidence supporting current National Comprehensive Cancer Network guidelines regarding surveillance of patients treated for head and neck cancer is presently lacking. The study examines the relative role of current surveillance methods on disease detection in this patient population. STUDY DESIGN: Prospective nonrandomized study. METHODS: Clinical information was prospectively collected in a standardized format during 3645 encounters with patients with head and neck cancer over an 18-month period. Data pertaining to visit history, symptom history, patient findings, physician findings, and disease status for each encounter were reviewed. RESULTS: Of 3645 visits, disease recurrence or new primary tumor was documented in 180 encounters (5%). Salvage therapy was thought to be feasible in at least 65% of cases. Of these 180 recurrences or new primaries, there were 142 patients (79%) who had identified new symptoms or physical findings, or both, before the physician's examination. Most commonly reported was the presence of a neck mass (38%), progressive pain (27%), or other visible lesion or ulcer (14%). Patients with recurrence represented nearly 40% of all patients reporting new symptoms or findings (142 of 367). Conversely, recurrence was rare in the absence of reported symptoms or findings (1.2%). Surprisingly, despite patients reporting new symptoms or findings, physician evaluation most commonly occurred at the patient's routine surveillance visit rather than an earlier time point (104 of 142 [73%]). CONCLUSION: Self-diagnosis of recurrent or new primary disease is extremely common by virtue of symptoms or findings noted by patients before interaction with the clinician. However, presence of symptoms or findings did not motivate the patients to seek earlier medical attention. In the absence of such symptoms, physician diagnosis of recurrence is uncommon. Given the significant social and economic impact involved in surveillance of patients with head and neck cancer, further prospective study to optimize the method and frequency of this type of clinical activity is warranted and planned.

Head and Neck Neoplasms↗
PubMed2003

Evolutionary landscapes for the acquisition of new ligand recognition by RNA aptamers.

The evolution of ligand specificity underlies many important problems in biology, from the appearance of drug resistant pathogens to the re-engineering of substrate specificity in enzymes. In studying biomolecules, however, the contributions of macromolecular sequence to binding specificity can be obscured by other selection pressures critical to bioactivity. Evolution of ligand specificity in vitro--unconstrained by confounding biological factors--is addressed here using variants of three flavin-binding RNA aptamers. Mutagenized pools based on the three aptamers were combined and allowed to compete during in vitro selection for GMP-binding activity. The sequences of the resulting selection isolates were diverse, even though most were derived from the same flavin-binding parent. Individual GMP aptamers differed from the parental flavin aptamers by 7 to 26 mutations (20 to 57% overall change). Acquisition of GMP recognition coincided with the loss of FAD (flavin-adenine dinucleotide) recognition in all isolates, despite the absence of a counter-selection to remove FAD-binding RNAs. To examine more precisely the proximity of these two activities within a defined sequence space, the complete set of all intermediate sequences between an FAD-binding aptamer and a GMP-binding aptamer were synthesized and assayed for activity. For this set of sequences, we observe a portion of a neutral network for FAD-binding function separated from GMP-binding function by a distance of three mutations. Furthermore, enzymatic probing of these aptamers revealed gross structural remodeling of the RNA coincident with the switch in ligand recognition. The capacity for neutral drift along an FAD-binding network in such close approach to RNAs with GMP-binding activity illustrates the degree of phenotypic buffering available to a set of closely related RNA sequences--defined as the set's functional tolerance for point mutations--and supports neutral evolutionary theory by demonstrating the facility with which a new phenotype becomes accessible as that buffering threshold is crossed.

Base Sequence↗
PubMed2003

Mucoepidermoid carcinoma of the lacrimal sac.

Mucoepidermoid carcinoma of the lacrimal sac is a rare entity. We report a case of mucoepidermoid carcinoma arising in the lacrimal sac of a 30-year-old man who presented with an inner canthal mass. To our knowledge this is the first example of the cytopathology of this neoplasm in this anatomic site.

Adult↗
PubMed2002

Multimodal intensification therapy for previously untreated advanced resectable squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx.

BACKGROUND: An intensified treatment regimen for previously untreated Stage III and IV resectable oral cavity, oropharyngeal, or hypopharyngeal squamous cell carcinoma was analyzed to assess disease control, patient compliance, and toxicity. METHODS: Forty three patients with previously untreated, advanced, resectable squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx were enrolled in a prospective Phase II institutional clinical trial at a tertiary care comprehensive cancer center. This regimen was a continuum of multimodal treatment in a contracted time interval. It included preoperative slightly accelerated hyperfractionated radiotherapy with concurrent cisplatin, followed immediately with surgery and intraoperative radiotherapy, and completed with early postoperative weekly paclitaxel (beginning on Day 6 after surgery), two additional cisplatin cycles, and concurrent once daily radiotherapy beginning on Day 28 after surgery. RESULTS: The current trial was designed to reduce the toxicity of the systemic therapy while maintaining or improving locoregional/distant disease control and patient compliance. There were 43 patients enrolled, and the range of time at risk was 2.6 to 24.7 months (median, 14.6 months). Of the 43 registered patients, 43 were evaluable. The locoregional (100%) and systemic (93%) disease control rates were excellent, with low rates of patient noncompliance (21%) and reduced levels of toxicity. CONCLUSIONS: An intensive treatment regimen that improves disease control and treatment compliance is clearly feasible for this patient population. Future plans include modifications to continue to reduce toxicity and expansion to a multi-center Phase II trial to determine if the single institutional results can be duplicated.

Adult↗
PubMedDate not supplied

Osteochondroma of the sacrum with a correlative radiographic and histological evaluation.

Primary benign sacral tumors are rare representing only 1-4% of solitary exostoses and constituting 4% of all solitary spinal tumor. The tumor usually comes to attention in childhood or adolescence. The treatment of symptomatic lesions is resection. We present here a case of a sacral osteochondroma with characteristic histological and radiological features in an adolescent presenting with radicular pain.

Adolescent↗
PubMedDate not supplied

Ulnar nerve abscess and relapse in a patient with indeterminate leprosy 1 year after completion of multidrug therapy.

The introduction of multidrug therapy has efficiently controlled leprosy in developing countries. However, Mycobacterium laprae may survive and cause relapse despite adequate treatment with antileprosy drugs. Relapse may be characterized by a combination of new signs or symptoms and presence of acid-fast bacilli on skin or nerve biopsy samples. We report a case of a child in whom ulnar abscess developed 12 months after successful completion of multidrug therapy with clinical and histopathological evidence of relapse.

Abscess↗