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61.
Kimura disease is a rare form of chronic inflammatory disorder involving subcutaneous tissue, predominantly in the head and neck region and frequently associated with regional lymphadenopathy and/or salivary gland involvement. We present a case of Kimura disease in a 28-year-old male which showed florid squamous metaplasia in the salivary gland ducts and salivary duct inclusions in the intraparotid nodes besides the usual features of Kimura disease. The squamous metaplasia was extensive enough to pose a diagnostic dilemma. We describe this case to highlight the rare histological finding of florid squamous metaplasia in Kimura disease and its diagnostic implications. 相似文献
62.
Ronald T. Toth Samantha E. Pace Brittney J. Mills Sangeeta B. Joshi Reza Esfandiary C. Russell Middaugh David D. Weis David B. Volkin 《Journal of pharmaceutical sciences》2018,107(4):1009-1019
Antibodies are molecules that exhibit diverse conformational changes on different timescales, and there is ongoing interest to better understand the relationship between antibody conformational dynamics and storage stability. Physical stability data for an IgG4 monoclonal antibody (mAb-D) were gathered through traditional forced degradation (temperature and stirring stresses) and accelerated stability studies, in the presence of different additives and solution conditions, as measured by differential scanning calorimetry, size exclusion chromatography, and microflow imaging. The results were correlated with hydrogen exchange mass spectrometry (HX-MS) data gathered for mAb-D in the same formulations. Certain parameters of the HX-MS data, including hydrogen exchange in specific peptide segments in the CH2 domain, were found to correlate with stabilization and destabilization of additives on mAb-D during thermal stress. No such correlations between mAb physical stability and HX-MS readouts were observed under agitation stress. These results demonstrate that HX-MS can be set up as a streamlined methodology (using minimal material and focusing on key peptide segments at key time points) to screen excipients for their ability to physically stabilize mAbs. However, useful correlations between HX-MS and either accelerated or real-time stability studies will be dependent on a particular mAb's degradation pathway(s) and the type of stresses used. 相似文献
63.
Apurva S. More Ronald T. Toth Solomon Z. Okbazghi C. Russell Middaugh Sangeeta B. Joshi Thomas J. Tolbert David B. Volkin David D. Weis 《Journal of pharmaceutical sciences》2018,107(9):2315-2324
We have used hydrogen exchange–mass spectrometry to characterize local backbone flexibility of 4 well-defined IgG1-Fc glycoforms expressed and purified from Pichia pastoris, 2 of which were prepared using subsequent in vitro enzymatic treatments. Progressively decreasing the size of the N-linked N297 oligosaccharide from high mannose (Man8-Man12), to Man5, to GlcNAc, to nonglycosylated N297Q resulted in progressive increases in backbone flexibility. Comparison of these results with recently published physicochemical stability and Fcγ receptor binding data with the same set of glycoproteins provide improved insights into correlations between glycan structure and these pharmaceutical properties. Flexibility significantly increased upon glycan truncation in 2 potential aggregation-prone regions. In addition, a correlation was established between increased local backbone flexibility and increased deamidation at asparagine 315. Interestingly, the opposite trend was observed for oxidation of tryptophan 277 where faster oxidation correlated with decreased local backbone flexibility. Finally, a trend of increasing C'E glycopeptide loop flexibility with decreasing glycan size was observed that correlates with their FcγRIIIa receptor binding properties. These well-defined IgG1-Fc glycoforms serve as a useful model system to identify physicochemical stability and local backbone flexibility data sets potentially discriminating between various IgG glycoforms for potential applicability to future comparability or biosimilarity assessments. 相似文献
64.
Ashaben Patel Vineet Gupta John Hickey Nancy S. Nightlinger Richard S. Rogers Christine Siska Sangeeta B. Joshi Michael S. Seaman David B. Volkin Bruce A. Kerwin 《Journal of pharmaceutical sciences》2018,107(12):3032-3046
In this study, we investigated analytical challenges associated with the formulation of 2 anti-HIV broadly neutralizing antibodies (bnAbs), 3BNC117 and PGT121, both separately at 100 mg/mL and together at 50 mg/mL each. The bnAb formulations were characterized for relative solubility and conformational stability followed by accelerated and real-time stability studies. Although the bnAbs were stable during 4°C storage, incubation at 40°C differentiated their stability profiles. Specific concentration-dependent aggregation rates at 30°C and 40°C were measured by size exclusion chromatography for the individual bnAbs with the mixture showing intermediate behavior. Interestingly, although the relative ratio of the 2 bnAbs remained constant at 4°C, the ratio of 3BNC117 to PGT121 increased in the dimer that formed during storage at 40°C. A mass spectrometry-based multiattribute method, identified and quantified differences in modifications of the Fab regions for each bnAb within the mixture including clipping, oxidation, deamidation, and isomerization sites. Each bnAb showed slight differences in the levels and sites of lysine residue glycations. Together, these data demonstrate the ability to differentiate degradation products from individual antibodies within the bnAb mixture, and that degradation rates are influenced not only by the individual bnAb concentrations but also by the mixture concentration. 相似文献
65.
Ying Wan John M. Hickey Christopher Bird Katey Witham Paul Fahey Angus Forster Sangeeta B. Joshi David B. Volkin 《Journal of pharmaceutical sciences》2018,107(6):1540-1551
The worldwide switch to inactivated polio vaccines (IPVs) is a key component of the overall strategy to achieve and maintain global polio eradication. To this end, new IPV vaccine delivery systems may enhance patient convenience and compliance. In this work, we examine Nanopatch? (a solid, polymer microprojection array) which offers potential advantages over standard needle/syringe administration including intradermal delivery and reduced antigen doses. Using trivalent IPV (tIPV) and a purpose-built evaporative dry-down system, candidate tIPV formulations were developed to stabilize tIPV during the drying process and on storage. Identifying conditions to minimize tIPV potency losses during rehydration and potency testing was a critical first step. Various classes and types of pharmaceutical excipients (~50 total) were then evaluated to mitigate potency losses (measured through D-antigen ELISAs for IPV1, IPV2, and IPV3) during drying and storage. Various concentrations and combinations of stabilizing additives were optimized in terms of tIPV potency retention, and 2 candidate tIPV formulations containing cyclodextrin and a reducing agent (e.g., glutathione), maintained ≥80% D-antigen potency during drying and subsequent storage for 4 weeks at 4°C, and ≥60% potency for 3 weeks at room temperature with the majority of losses occurring within the first day of storage. 相似文献
66.
Madhu Nagappa Parayil S. Bindu Sikandar Adwani Sangeeta K. Seshagiri Jitender Saini Sanjib Sinha Arun B. Taly 《Annals of Indian Academy of Neurology》2014,17(1):113-116
Abetalipoproteinemia is an uncommon cause of ataxia and retinitis pigmentosa (RP). Most of the neurological and ocular manifestations occur secondary to deficiency syndromes that is consequent to fat malabsorption from the small intestine. In this report, we have described the phenotype of a young adult female who manifested with recurrent diarrheal illness in her first decade, followed by anemia, RP, and neurological involvement with progressive deafness, cerebellar and sensory ataxia, and subclinical neuropathy in her second decade of life. While RP and sensory ataxia due to vitamin E deficiency are well-recognized features of abetalipoproteinemia, deafness is rarely described. In addition, we have highlighted the abnormal posterior column signal changes in the cervical cord in this patient. Early recognition avoids unnecessary investigations and has a potential to retard the disease progression by replacing some of the deficient vitamins. 相似文献
67.
Sobell LC Sobell MB Connors GJ Agrawal S 《Alcoholism, clinical and experimental research》2003,27(10):1661-1666
BACKGROUND: Although the number of alcohol treatment efficacy trials has mushroomed, there is no consensus on how best to measure outcomes. To advance the goal of establishing cross-trial consistency in measuring outcomes in clinical efficacy studies, the National Institute on Alcohol Abuse and Alcoholism convened a panel of experts and charged them with exploring, debating, and, ultimately, selecting a "sentinel" or "optimal" outcome measure to be used in future alcohol treatment studies. The goal of this article, one in a series of several presented at the National Institute on Alcohol Abuse and Alcoholism conference, is to discuss (1) the rationale underlying selection of an optimal outcome measure, (2) the necessary characteristics of an optimal outcome measure, (3) the utility of selecting an optimal measure, and (4) which drinking assessment methods could be used to collect data to portray the optimal outcome measure. METHODS: At a minimum, the criteria for an "optimal" measure include that it be psychometrically sound. In addition, it should have considerable currency in the field, thereby increasing its prospects for adoption. The measure should also be consistent with the concepts of greatest interest and relevance to the field (e.g., directly reflect the fundamental goal of alcohol treatment). In light of these highly desired features, percent of days heavy drinking was chosen at the conference as a practical and relevant measure of alcohol treatment outcome. CONCLUSIONS: Percent of days heavy drinking should be the optimal measure of alcohol treatment outcome. Currently, daily drinking estimation methods are the most useful for gathering data that can reflect the optimal measure. In addition, data gathered by daily drinking estimation methods can be used to study a variety of other outcome variables of interest to clinical researchers. 相似文献
68.
Prolactin (PRL) is a polypeptide hormone with a wide range of physiological functions, and is critical for female reproduction. PRL exerts its action by binding to membrane bound receptor isoforms broadly classified as the long form and the short form receptors. Both receptor isoforms are highly expressed in the ovary as well as in the uterus. Although signaling through the long form is believed to be more predominant, it remains unclear whether activation of this isoform alone is sufficient to support reproductive functions or whether both types of receptor are required. The generation of transgenic mice selectively expressing either the short or the long form of PRL receptor has provided insight into the differential signaling mechanisms and physiological functions of these receptors. This review describes the essential finding that both long and short receptor isoforms are crucial for ovarian functions and female fertility, and highlights novel mechanisms of action for these receptors. 相似文献
69.
70.
Gaurav Gupta Sachin Kumar Sangeeta Gupta K. B. Golhar Swapnil Deshpande 《The Indian journal of surgery》2014,76(4):319-320