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Fine-needle aspiration cytology (FNAC) is generally the initial sampling method for salivary gland neoplasms. The cytomorphologic features of acinic cell carcinoma (AciCC) of salivary gland can overlap with other neoplastic and nonneoplastic entities. AciCCs harbor a recurrent t(4;9) rearrangement with upregulation of nuclear receptor subfamily 4 group A member 3 (NR4A3). NR4A3 protein overexpression has been shown to be highly sensitive and specific for the diagnosis of AciCC in histologic specimens and cell block preparations. However, data on NR4A3 immunocytochemistry (ICC) on conventional smears or liquid-based cytology are limited.The authors identified 18 FNAC of histologically proven AciCC cases between 2013 and 2019. FNAC samples of diagnostic mimickers were likewise retrieved and included in the study cohort for comparison. The NOR1/NR4A3 mouse monoclonal antibody was applied directly to FNAC slides using a standard ICC technique.The cohort included ethanol-fixed Papanicolaou-stained cytologic smears and liquid-based preparations from 18 AciCC, one secretory carcinoma, four mucoepidermoid carcinomas, four salivary duct carcinomas, five pleomorphic adenomas (PA), five Warthin tumors, five oncocytomas, one oncocytic hyperplasia, and five nonneoplastic salivary gland cases. Strong nuclear staining for NR4A3 was present in all AciCC, weak nuclear staining was present in one PA, and all other non-AciCC were negative (sensitivity, 100%; specificity, 97%).NR4A3 ICC can be used directly on FNAC conventional smears and liquid-based cytology to reliably distinguish AciCC from its mimickers. This marker may be useful in cases where a cell block preparation is unavailable or inadequate.

BACKGROUND The guidelines published by the Papanicolaou Society of Cytopathology (PSC) intend to unify the reporting language in pancreaticobiliary specimens and improve communication between cytopathologists and clinicians. The six categories in the system will determine the best management for patients. However, there is limited evidence regarding the risk of malignancy (ROM) associated with each category. METHODS A retrospective search was performed for pancreaticobiliary fine-needle aspiration (FNA) reports with corresponding surgical follow-up. Cases were reclassified according to the PSC. The ROM, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each category. RESULTS A total of 297 cases were identified and reclassified as: 30 nondiagnostic (category I), 45 negative for malignancy (II), 20 atypical (III), 42 neoplastic: other (IVB), 19 suspicious for malignancy (V), and 141 malignant (VI). The absolute ROM was 10% for category I, 8.9% for category II, 60% for category III, 4.8% for category IV when the neoplasms were not characterized as malignant, and 100% when categorized as malignant; 100% for category V, and 95.7% for category VI. Sensitivity, specificity, positive predictive value, and negative predictive value for neoplasia and malignancy, including categories IV to VI, were 96.6%, 88.4%, 97.5%, and 84.4%, respectively. CONCLUSIONS The categories developed by the PSC stratify the ROM. Aspirates designated as categories V and VI had the highest ROM. Our rate of atypical category complies with the recommended rate of

Background and purpose Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Targeting Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a promising strategy for chronic inflammatory diseases. We investigated the vasculoprotective role of suppressor of cytokine signalling-1 (SOCS1), the negative JAK/STAT regulator, in experimental AAA. Experimental approach A synthetic, cell permeable peptide (S1) mimic of SOCS1 kinase inhibitory domain to suppress STAT activation was evaluated in the well-established mouse model of elastase-induced AAA by monitoring changes in aortic diameter, cellular composition, and gene expression in abdominal aorta. S1 function was further evaluated in cultured vascular smooth muscle cells (VSMC) and macrophages exposed to elastase or elastin-derived peptides. Key results S1 peptide prevented AAA development, evidenced by reduced incidence of AAA, aortic dilation and elastin degradation, partial restoration of medial VSMC, and decreased inflammatory cells and oxidative stress in AAA tissue. Mechanistically, S1 suppressed STAT1/3 activation in aorta, downregulated cytokines and metalloproteinases, and altered the expression of cell differentiation markers by favouring anti-inflammatory M2 macrophage and contractile VSMC phenotypes. In vitro, S1 suppressed the expression of inflammatory and oxidative genes, reduced cell migration, and reversed the phenotypic switch of macrophages and VSMC. By contrast, SOCS1 silencing promoted inflammatory response. Conclusion and implications This preclinical study demonstrates the therapeutic potential of SOCS1-derived peptide to halt AAA progression by suppressing JAK/STAT-mediated inflammation and aortic dilation. S1 peptide may therefore be a valuable option for the treatment of AAA.

Background Abdominal aortic aneurysm (AAA), a degenerative vascular pathology characterized by permanent dilation of the aorta, is considered a chronic inflammatory disease involving innate/adaptive immunity. However, the functional role of antibody‐dependent immune response against antigens present in the damaged vessel remains unresolved. We hypothesized that engagement of immunoglobulin G (IgG) Fc receptors (FcγR) by immune complexes (IC) in the aortic wall contributes to AAA development. We therefore evaluated FcγR expression in AAA lesions and analysed whether inhibition of FcγR signaling molecules (γ‐chain and Syk kinase) influences AAA formation in mice. Methods FcγR gene/protein expression was assessed in human and mouse AAA tissues. Experimental AAA was induced by aortic elastase perfusion in wild‐type (WT) mice and γ‐chain knockout (γKO) mice (devoid of activating FcγR) in combination with macrophage adoptive transfer or Syk inhibitor treatment. To verify the mechanisms of FcγR in vitro, vascular smooth muscle cells (VSMC) and macrophages were stimulated with IgG IC. Results FcγR overexpression was detected in adventitia and media layers of human and mouse AAA. Elastase‐perfused γKO mice exhibited a decrease in AAA incidence, aortic dilation, elastin degradation, and VSMC loss. This was associated with (1) reduced infiltrating leukocytes and immune deposits in AAA lesions, (2) inflammatory genes and metalloproteinases downregulation, (3) redox balance restoration, and (4) converse phenotype of anti‐inflammatory macrophage M2 and contractile VSMC. Adoptive transfer of FcγR‐expressing macrophages aggravated aneurysm in γKO mice. In vitro, FcγR deficiency attenuated inflammatory gene expression, oxidative stress, and phenotypic switch triggered by IC. Additionally, Syk inhibition prevented IC‐mediated cell responses, reduced inflammation, and mitigated AAA formation. Conclusion Our findings provide insight into the role and mechanisms mediating IgG‐FcγR‐associated inflammation and aortic wall injury in AAA, which might represent therapeutic targets against AAA disease., Our work suggests a pathogenic role of IgG IC interaction with activating FcγR present in infiltrating and VSMC during AAA formation. These results support the investigation of novel immunotherapeutic strategies targeting FcγRs and/or downstream molecules to inhibit humoral immune damage in AAA

Background Fine-needle aspiration (FNA) of a neck mass is frequently the initial diagnostic procedure for patients with human papillomavirus-positive head and neck squamous cell carcinoma. By performing a p16 immunocytochemistry (ICC) stain on FNA material, the pathologist can help to direct the treating physician's search for the primary site and to select the proper management for the patient. There is currently no established threshold for the evaluation of p16 ICC in cytology samples. This study was aimed at establishing an optimal threshold for p16 ICC interpretation in cytology samples. Methods The pathology databases were searched for all neck-mass FNAs diagnosed as squamous cell carcinoma from January 2010 to March 2019. p16 ICC was performed on cytology smears, and the percentage and intensity of p16-positive cells were assessed. Receiver operating characteristic (ROC) curves were plotted to determine the best cutoff threshold for p16 positivity on cytology smears. Results p16 ICC was performed on 50 cytology smears. An analysis of 8 different thresholds (combinations of the percentage and intensity of the p16 stain) using ROC curves demonstrated the best threshold to be 50% p16 staining with a sensitivity of 74% and a specificity of 100%. Applying the threshold used for surgical specimens (70%) to cytology samples resulted in a low sensitivity (45%). Conclusions p16 ICC on cytology smears shows diminished staining in comparison with surgical samples. Using 50% staining as the cutoff to consider positivity for p16 in cytology smears is proposed to decrease false-negative results while maintaining specificity.

Marine environments face acute pressures from human impacts, often resulting in substantial changes in community structure. On the inshore Great Barrier Reef (GBR), palaeoecological studies show the collapse of the previously dominant coral Acropora from the impacts of degraded water quality associated with European colonization. Even more dramatic impacts can result in the replacement of corals by fleshy macroalgae on modern reefs, but their past distribution is unknown because they leave no fossil record. Here, we apply DNA metabarcoding and high-throughput sequencing of the 18S rDNA gene on palaeoenvironmental DNA (aeDNA) derived from sediment cores at two sites on Pandora Reef (GBR), to enhance palaeoecological studies by incorporating key soft-bodied taxa, including macroalgae. We compared temporal trends in this aeDNA record with those of coral genera derived from macrofossils. Multivariate analysis of 12 eukaryotic groups from the aeDNA community showed wide variability over the past 750 years. The occurrence of brown macroalgae was negatively correlated only with the dominant coral at both sites. The occurrence of coralline and green macroalgae was positively correlated with only the dominant coral at one of the sites, where we also observed a significant association between the whole coral community and the occurrence of each of the three macroalgae groups. Our results demonstrate that reef sediments can provide a valuable archive for understanding the past distribution and occurrence of important soft-bodied reef dwellers. Combining information from fossils and aeDNA provides an enhanced understanding of temporal changes of reefs ecosystems at decadal to millennial timescales.

Identifying organisms that play an important role in maintaining ecosystem function is a key aspect of resilience‐based management. For Australia's Great Barrier Reef (GBR), we found that the recovery ability of shallow exposed fore‐reefs is more than 14 times higher when tabular Acropora are present. The disproportionate role that tabular Acropora play appears to be driven by a combination of traits including high recruitment, high growth rate and, importantly, large maximum colony sizes. Despite this key role, tabular Acropora are highly sensitive to most pressures. We compile evidence suggesting that if tabular corals were to decline or disappear on the GBR, the potential for reef recovery on exposed fore‐reefs would be considerably slowed. We then consider the merits of placing special emphasis on the protection of tabular Acropora within the management of the GBR. Importantly, we recognise that an analysis of costs and benefits of such recognition is vital before any change is implemented. Actions might include targeted crown‐of‐thorns starfish control, anchoring restrictions and protection for tabular corals on reefs identified as essential for their larval dispersal. In addition, targeted communications about the critical importance of these highly recognisable corals may boost community support and participation in their protection.

Background Frailty is a major age-associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6-P dehydrogenase (G6PD). The G6PD-overexpressing mouse (G6PD-Tg) is protected against metabolic stresses. Our aim was to examine whether this protection delays frailty. Methods Old wild-type (WT) and G6PD-Tg mice were evaluated longitudinally in terms of frailty. Indirect calorimetry, transcriptomic profile, and different skeletal muscle quality markers and muscle regenerative capacity were also investigated. Results The percentage of frail mice was significantly lower in the G6PD-Tg than in the WT genotype, especially in 26-month-old mice where 50% of the WT were frail vs. only 13% of the Tg ones (P < 0.001). Skeletal muscle transcriptomic analysis showed an up-regulation of respiratory chain and oxidative phosphorylation (P = 0.009) as well as glutathione metabolism (P = 0.035) pathways in the G6PD-Tg mice. Accordingly, the Tg animals exhibited an increase in reduced glutathione (34.5%, P < 0.01) and a decrease on its oxidized form (-69%, P < 0.05) and in lipid peroxidation (4-HNE: -20.5%, P < 0.05). The G6PD-Tg mice also showed reduced apoptosis (BAX/Bcl2: -25.5%, P < 0.05; and Bcl-xL: -20.5%, P < 0.05), lower levels of the intramuscular adipocyte marker FABP4 (-54.7%, P < 0.05), and increased markers of mitochondrial content (COX IV: 89.7%, P < 0.05; Grp75: 37.8%, P < 0.05) and mitochondrial OXPHOS complexes (CII: 81.25%, P < 0.01; CIII: 52.5%, P < 0.01; and CV: 37.2%, P < 0.05). Energy expenditure (-4.29%, P < 0.001) and the respiratory exchange ratio were lower (-13.4%, P < 0.0001) while the locomotor activity was higher (43.4%, P < 0.0001) in the 20-month-old Tg, indicating a major energetic advantage in these mice. Short-term exercise training in young C57BL76J mice induced a robust activation of G6PD in skeletal muscle (203.4%, P < 0.05), similar to that achieved in the G6PD-Tg mice (142.3%, P < 0.01). Conclusions Glucose 6-P dehydrogenase deficiency can be an underestimated risk factor for several human pathologies and even frailty. By overexpressing G6PD, we provide the first molecular model of robustness. Because G6PD is regulated by pharmacological and physiological interventions like exercise, our results provide molecular bases for interventions that by increasing G6PD will delay the onset of frailty.

Objectives We analyze the relationship between CD44, epidermal growth factor receptor (EGFR), and p16 expression in oral cavity and oropharyngeal cancers in a diverse population. We also describe whether particular patterns of staining are associated with progression-free survival and overall survival. Study Design Prospective study, single-blind to pathologist and laboratory technologist. Setting Hospital based. Subjects and Methods Immunohistochemistry, comprising gross staining and cellular expression, was performed and interpreted in a blinded fashion on 24 lip/oral cavity and 40 oropharyngeal cancer specimens collected between 2007 and 2012 from participants of a larger study. Information on overall survival and progression-free survival was obtained from medical records. Results Nineteen cases were clinically p16 positive, 16 of which were oropharyngeal. Oral cavity lesions were more likely to exhibit strong CD44 membrane staining ( P = .0002). Strong CD44 membrane and strong EGFR membrane and/or cytoplasmic staining were more common in p16-negative cancers ( P = .006). Peripheral/mixed gross p16 staining pattern was associated with worse survival than the universal staining on univariate and multivariate analyses ( P = .006, P = .030). This held true when combining gross and cellular localization for p16. For CD44, universal gross staining demonstrated poorer overall survival compared with the peripheral/mixed group ( P = .039). CD44 peripheral/mixed group alone and when combined with universal p16 demonstrated the best survival on multivariate analysis ( P = .010). Conclusion In a diverse population, systematic analysis applying p16, CD44, and EGFR gross staining and cellular localization on immunohistochemistry demonstrates distinct patterns that may have prognostic potential exceeding current methods. Larger studies are warranted to investigate these findings further.

The beneficial effects of exercise have been well recognized for over half a century. Dr Jeremy Morris's pioneering studies in the fifties showed a striking difference in cardiovascular disease between the drivers and conductors on the double-decker buses in London. These studies sparked off a vast amount of research on the effects of exercise in health, and the general consensus is that exercise contributes to improved outcomes and treatment for several diseases including osteoporosis, diabetes, depression and atherosclerosis. Evidence of the beneficial effects of exercise is reviewed here. One way of highlighting the impact of exercise on disease is to consider it from the perspective of good practice. However, the intensity, duration, frequency (dosage) and counter indications of the exercise should be taken into consideration to individually tailor the exercise programme. An important case of the beneficial effect of exercise is that of ageing. Ageing is characterized by a loss of homeostatic mechanisms, on many occasions leading to the development of frailty, and hence frailty is one of the major geriatric syndromes and exercise is very useful to mitigate, or at least delay, it. Since exercise is so effective in reducing frailty, we would like to propose that exercise be considered as a supplement to other treatments. People all over the world have been taking nutritional supplements in the hopes of improving their health. We would like to think of exercise as a physiological supplement not only for treating diseases, but also for improving healthy ageing.

Xanthine oxidase (XO), a free radical-generating enzyme, is involved in tissue damage produced during exhaustive exercise. Our aim was to test whether allopurinol, a powerful inhibitor of XO, may be effective in preventing exercise-induced tissue damage in soccer players. Twelve soccer players were randomized into two experimental groups. One received allopurinol, before a match of the premier Spanish Football League, and the other placebo. Allopurinol prevented the exercise-induced increase in all the markers of skeletal muscle damage analyzed: creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and myoglobin. Creatine kinase-MB isoenzyme and highly sensitive troponin T, specific biomarkers of myocardial injury, increased significantly in the placebo but not in the allopurinol-treated group after the football match. We also found that the exercise-induced lipid peroxidation, as reflected by malondialdehyde measurements, was prevented after allopurinol administration. However, inhibition of XO did not prevent the increment in the activity of alanine aminotransferase found after the match. No changes in the serum gamma glutamyltransferase activity was found after the match on either the placebo and the allopurinol groups. These two enzymes were determined as biomarkers of liver injury. Allopurinol represents an effective and inexpensive pharmacological agent to prevent tissue damage in soccer players.

The beneficial effects of regular exercise for the promotion of health and cure of diseases have been clearly shown. In this review, we would like to postulate the idea that exercise can be considered as a drug. Exercise causes a myriad of beneficial effects for health, including the promotion of health and lifespan, and these are reviewed in the first section of this paper. Then we deal with the dosing of exercise. As with many drugs, dosing is extremely important to get the beneficial effects of exercise. To this end, the organism adapts to exercise. We review the molecular signalling pathways involved in these adaptations because understanding them is of great importance to be able to prescribe exercise in an appropriate manner. Special attention must be paid to the psychological effects of exercise. These are so powerful that we would like to propose that exercise may be considered as a psychoactive drug. In moderate doses, it causes very pronounced relaxing effects on the majority of the population, but some persons may even become addicted to exercise. Finally, there may be some contraindications to exercise that arise when people are severely ill, and these are described in the final section of the review. Our general conclusion is that exercise is so effective that it should be considered as a drug, but that more attention should be paid to the dosing and to individual variations between patients.

Prevention and treatment of atherosclerosis is still a clinical challenge in the cardiovascular medicine. The classical belief that atherosclerotic lesion development solely depends on lipid deposition has been replaced by the current concept that activation of immune and inflammatory responses plays a central role in plaque initiation and progression. In this review we summarize studies on human and genetically modified animals describing a finite number of cellular and molecular mechanisms that underlie immunoinflammation in atherosclerotic plaques. We focus on the pro- and antiinflammatory mediators activated during atherogenesis and the intracellular signaling pathways regulating these events. Besides the advances on established pharmacological agents, we propose potential strategies for reduction/stabilization of atherosclerotic plaques based on the clinical data in inflammatory-associated pathologies and on the encouraging studies in experimental models of atherosclerosis. We emphasize the potential of such novel inhibitors comprising receptor antagonists, neutralizing antibodies, kinase inhibitors, peptide-based technologies, and chemicals as emerging antiinflammatory strategies for the treatment of atherosclerotic disease complications.

To determine the level of sentinel lymph node sectioning necessary to accurately detect nodal micrometastasis.Cross-sectional.Tertiary care university medical center.Fine sections of oral squamous cell carcinoma sentinel lymph nodes previously sectioned at 2-mm intervals in a prospective clinical trial were reexamined. The results yielded from prior hematoxylin and eosin and immunohistochemical staining were compared with results following exhaustive serial sectioning at 150-µm intervals using identical staining methods. These experimental findings were compared with pathologic results of immediate completion selective neck dissection, previously recorded prospectively.Reexamination of 35 sentinel nodes at 150-µm intervals has not revealed any missed micrometastatic disease at 2-mm intervals used initially. Both comparisons of 150-µm sectioning analysis to the original 2-mm section samples and to the neck dissection pathology reports demonstrate a 100% negative predictive value.These data suggest that sentinel lymph node sectioning at 2-mm intervals for oral carcinoma using hematoxylin and eosin staining and then immunohistochemical analysis maximizes efficiency, accuracy, and expenditure for the detection of micrometastasis.

Lesions that contain abundant benign myoepithelial cells, including pleomorphic adenomas of salivary gland origin, may present a diagnostic challenge in fine-needle aspiration (FNA) specimens. Benign metastasizing pleomorphic adenoma is a rare neoplasm, in which the benign appearing pleomorphic adenoma, without any histological evidence of malignancy, metastasizes to distant sites including lung. In the absence of clinical history of a pre-existing myoepithelial neoplasm, the presence of myoepithelial cells in the lung or any other organs besides salivary glands may create diagnostic difficulty. Here we present the cytologic findings of such a metastatic tumor found in the lung FNA and pleural fluid specimens from a 64-year-old woman, with a history of local recurrent salivary gland pleomorphic adenomas, who presented with multiple bilateral pulmonary nodules and pleural effusion. The diagnosis of benign metastasizing pleomorphic adenoma was made based on clinical information and cytomorphology, and confirmed by immunocytochemistry.

Summary Vascular endothelial dysfunction occurs during the human aging process, and it is considered as a crucial event in the development of many vasculopathies. We investigated the underlying mechanisms of this process, particularly those related with oxidative stress and inflammation, in the vasculature of subjects aged 18‐ 91 years without cardiovascular disease or risk factors. In isolated mesenteric microvessels from these subjects, an age-dependent impairment of the endotheliumdependent relaxations to bradykinin was observed. Similar results were observed by plethysmography in the forearm blood flow in response to acetylcholine. In microvessels from subjects aged less than 60 years, most of the bradykinin-induced relaxation was due to nitric oxide release while the rest was sensitive to cyclooxygenase (COX) blockade. In microvessels from subjects older than 60 years, this COX-derived vasodilatation was lost but a COX-derived vasoconstriction occurred. Evidence for age-related vascular oxidant and inflammatory environment was observed, which could be related to the development of endothelial dysfunction. Indeed, aged microvessels showed superoxide anions (O2 ) ) and peroxynitrite (ONOO ) ) formation, enhancement of NADPH oxidase and inducible NO synthase expression. Pharmacological interference of COX, thromboxane A2 ⁄prostaglandin H2 receptor, O2 ) , ONOO ) , inducible NO synthase, and NADPH oxidase improved the age-related endothelial dysfunction. In situ vascular nuclear factor-jB activation was enhanced with age, which correlated with endothelial dysfunction. We conclude that the age-dependent endothelial dysfunction in human vessels is due to the combined effect of oxidative stress and vascular wall

Aim: To determine whether chronic physical training increases atrial and ventricular refractoriness in isolated rabbit heart. Methods: Trained rabbits were submitted to a protocol of treadmill running. The electrophysiological parameters of refractoriness investigated in an isolated heart preparation were: (1) atrial effective refractory period (AERP) and atrial functional refractory period and ventricular effective and functional refractory periods (VERP and VFRP) using the extrastimulus technique at four different pacing cycle lengths; (2) the dominant frequency (DF) of ventricular fibrillation (VF). A multi-electrode plaque containing 256 electrodes and a spectral method were used to obtain the mean, maximum and minimum DF of VF. Sinus cycle length of the isolated hearts was determined as an electrophysiological parameter of training. In vivo heart rate, myocardial heat shock proteins (HSP60) and inducible nitric oxide synthase were also determined in some animals as electrophysiological and biochemical markers of training respectively. Results: VERP and VFRP were longer in the trained group than in the control group. The mean DF of VF was lower in the trained group than in the control group. Despite the fact that training did not significantly modify the AERP, it tended to be longer in the trained group (P = 0.09). Conclusion: Training seems to increase the electrical stability of ventricular myocardium. As the electrophysiological modifications were exhibited in hearts not submitted to extrinsic nervous system or humoral influences, they are, at least in part, intrinsic modifications. These electrophysiological data also suggest that training could protect against reentrant ventricular arrhythmias.

BACKGROUND. Differentiating primary glandular from high-grade squamous intraepithelial lesions (HSIL) that involve endocervical glands is not an uncommon diagnostic problem in liquid-based gynecological cytology. Squamous and atypical glandular cell lesions may show similar cytomorphologic features. The aim of this study was to evaluate the use of p63 as a marker of basal and/or squamous cell derivation in this differential diagnosis. METHODS. Of 59,257 liquid-based cervicovaginal specimens collected over a 3-year period, 149 were diagnosed as atypical glandular cells of uncertain significance (AGUS) or adenocarcinoma and had histological follow-up. Ten cases (8AGUS and 2 adenocarcinomas) were proven to be high-grade dysplasia on cervical biopsies and the remaining cases represented glandular pathology. Slides from discrepant cases were stained with p63 antibody. In addition, the authors stained 25 control cases (10 adenocarcinomas, 10 HSIL, and 5 negative cervicovaginal specimens). RESULTS. In all 10 discrepant cases, the abnormal groups originally interpreted as glandular in origin showed a homogeneous strong nuclear staining for p63 that indicated their squamous origin. Nuclei of isolated HSIL cells and basal cells from atrophic smears were also positive for p63. Benign and malignant glandular cells were uniformly negative. Isolated metaplastic, intermediate, and superficial squamous cells were likewise negative for this antibody. CONCLUSIONS. p63 is a useful immunocytochemical marker for differentiating primary glandular pathology from HSIL in cervicovaginal specimens. It also detects isolated HSIL cells (“litigation cells”). This antibody is not expressed in AGUS, adenocarcinoma, or normal glandular cells. p63 stains basal cells and may be a diagnostic pitfall in atrophic cervicovaginal specimens. Cancer (Cancer Cytopathol) 2007 © 2006 American Cancer Society.

Reactive oxygen or nitrogen species (RONS) are produced during exercise due, at least in part, to the activation of xanthine oxidase. When exercise is exhaustive they cause tissue damage; however, they may also act as signals inducing specific cellular adaptations to exercise. We have tested this hypothesis by studying the effects of allopurinol-induced inhibition of RONS production on cell signalling pathways in rats submitted to exhaustive exercise. Exercise caused an activation of mitogen-activated protein kinases (MAPKs: p38, ERK 1 and ERK 2), which in turn activated nuclear factor κB (NF-κB) in rat gastrocnemius muscle. This up-regulated the expression of important enzymes associated with cell defence (superoxide dismutase) and adaptation to exercise (eNOS and iNOS). All these changes were abolished when RONS production was prevented by allopurinol. Thus we report, for the first time, evidence that decreasing RONS formation prevents activation of important signalling pathways, predominantly the MAPK–NF-κB pathway; consequently the practice of taking antioxidants before exercise may have to be re-evaluated.

BACKGROUND In 1996, the National Cancer Institute (NCI) recommended five categories for the diagnosis of breast aspiration cytology: benign, atypical, suspicious, malignant, and unsatisfactory. The authors evaluated the usefulness of separating inconclusive diagnoses into the aforementioned atypical and suspicious categories. The current study examined the correlation between cytologic and histologic findings made in breast aspiration cytology specimens that were categorized in accordance with these NCI guidelines. METHODS From 1992 to 2000, 7727 breast aspirations were performed at the University of Miami/Jackson Memorial Medical Center (Miami, FL). Aspirates were classified using criteria similar to the NCI recommendations. Four hundred eighty-nine aspirates (6%) were classified as being cytologically ‘atypical’ or ‘suspicious’. Of those, 225 ‘atypical’ aspirates and 162 ‘suspicious’ aspirates had available histologic follow-up data and were included in the study. RESULTS Among the ‘atypical’ aspirates, 118 (52%) yielded malignant findings on histologic evaluation. Infiltrating ductal carcinoma (n = 87; 74%) was the most common malignant diagnosis, followed by infiltrating lobular carcinoma (n = 12; 10%). Among ‘suspicious’ aspirates, 135 (83%) yielded malignant findings on histologic analysis. The most common benign diagnosis in both ‘atypical’ and ‘suspicious’ aspirates was proliferative fibrocystic changes with or without atypia, followed by fibroadenoma. CONCLUSIONS Most aspirates that yielded suspicious findings on cytologic examination proved to be malignant, as did > 50% of aspirates that yielded atypical findings. Infiltrating lobular carcinoma commonly was underdiagnosed as being atypical on cytologic examination. Benign lesions with atypical or suspicious cytologic diagnoses included certain cases of atypical ductal hyperplasia. The authors concluded that the distinction between the atypical and suspicious categories, as recommended by the NCI, is not warranted. Therefore, they suggest the use of a single term, such as ‘equivocal’, to describe inconclusive diagnoses on breast fine-needle aspiration cytology. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society.

Background. Peptide sequence homology between the gene product of human MUC4 and rat sialomucin complex (SMC) has recently been reported. Each contains a mucin subunit with antiadhesive activity linked to the plasma membrane by means of a transmembrane subunit with two epidermal growth factor (EGF)–like domains that act as ligand for ErbB2. This study investigates MUC4 and ErbB2 receptor expression in major and minor salivary gland mucoepidermoid carcinoma and correlates patterns of expression with clinical outcomes. Methods. MUC4 antigens and ErbB2 receptor expression are localized by immunohistochemical studies that use archival formalin-fixed and paraffin-embedded tissue. Clinical outcomes are determined by retrospective chart review of all patients (n = 28) with available archived pathologic specimens at the University of Miami–affiliated hospitals treated between 1994 and 2000. Results. Median survival time was 24 months (range, 2–60 months) among the nine patients who died, whereas median follow-up time in the remaining 19 patients is 33.4 months (range, 4.7–73 months). A trend toward a reduction in MUC4 antigen expression in high-grade tumors (55% expression) compared with low-grade (91% expression) and intermediate-grade (100% expression) tumors is identified (chi square, p = .0975). Patients with tumors expressing MUC4 antigens are at reduced risk of death (hazard ratio [HR], 0.20; p = .0531). Adjustment for pathologic grade, T stage, and age results in a much higher risk of death for patients whose tumors do not express MUC4 antigens, although this does not meet statistical significance (HR, 26.6; p = .1). Analysis of recurrence adjusting for T stage reveals that patients whose tumors do not express MUC4 antigens are at increased risk of recurrence compared with patients whose tumor expresses MUC4 antigens (HR, 6.37; p = .03). ErbB2 receptor staining is noted in seven of 28 patients, with five of these seven showing 2+ and 3+ membrane-staining patterns. Adjustment for pathologic grade and age suggests that patients whose tumors express high levels of ErbB2 (2+, 3+) are at increased risk of death compared with patients with low or no expression of ErbB2 (HR, 2.29; p = .32). MUC4 antigen positivity is seen in two of the five cases with 2+ and 3+ staining for ErbB2. Conclusions. These findings suggest MUC4 antigen positivity is associated with reduced risk of death and reduced risk of recurrence and may identify a subset of patients with more favorable prognosis. Although limited by small sample size, analysis reveals ErbB2 overexpression is not consistently associated with MUC4 antigen positivity and might be associated with increased risk of death © 2004 Wiley Periodicals, Inc. Head Neck26: 353–364, 2004

Background. Lymphoscintigraphy and sentinel node biopsy (LS/SNB) is a minimally invasive technique that samples first-echelon lymph nodes to predict the need for more extensive neck dissection. Methods. We evaluated this technique in 18 oral cavity cancers, stages T1–T3, N0. Patients underwent CT and positron emission tomography (PET) of the neck, followed by LS/SNB, frozen section, immediate selective neck dissection, definitive histology, and immunoperoxidase staining for cytokeratin. Histopathology of the sentinel node was correlated with that of the neck specimen. Results. There were 10 true positives: 6 identified on frozen section; 2 on permanent histology; and 2 only on immunoperoxidase staining. In six, the sentinel node was the only positive node. There were seven true negatives and one false negative. Conclusions. Gross tumor replacement of lymph node architecture may obstruct and redirect lymphatic flow. Overall LS/SNB holds promise for oral cancer. © 2002 Wiley Periodicals, Inc. Head Neck 25: 000–000, 2003

BACKGROUND Adenocarcinomas are the most common epithelial malignancies in body cavity fluids. Subclassification of adenocarcinomas according to primary site can be a challenging task. Thyroid transcription factor 1 (TTF-1) is a nuclear transcription factor that is expressed in normal lung, in thyroid, and in their neoplasms. Because thyroid carcinomas rarely metastasize to the serosal surfaces, the authors used TTF-1 as a marker to distinguish adenocarcinomas of the lung from carcinomas of other organs. METHODS The authors studied 113 body cavity fluids (92 pleural fluid samples and 21 ascitic samples) from 113 patients with a diagnosis of adenocarcinoma on the basis of routine cytology. The primary sites of origin were confirmed clinically or histologically for all patients. There were 39 adenocarcinomas of the lung, 24 adenocarcinomas of the breast, 34 adenocarcinomas of the genitourinary tract, and 16 adenocarcinomas of the gastrointestinal tract. Archival Papanicolaou-stained, cytocentrifuged slides were used without destaining for immunocytochemistry with the monoclonal TTF-1 antibody using a commercial available method. RESULTS TTF-1 was expressed in 21 of 39 lung adenocarcinomas (54%). Intense nuclear staining was present in tumor cells that occurred in groups or in isolated form. In contrast, none of the other types of adenocarcinomas expressed TTF-1. CONCLUSIONS TTF-1 is a highly specific marker for adenocarcinomas of the lung in body cavity fluids. Immunocytochemistry using this antibody can be performed easily on archival Papanicolaou-stained, cytocentrifuged slides of fluid specimens. Cancer (Cancer Cytopathol) 2002;96:289–93. © 2002 American Cancer Society.

This study investigates MUC4 expression in normal squamous epithelia and squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT), and in salivary gland neoplasms.MUC4 antigens in tumor and adjacent normal tissue are localized by immunocytochemical studies. Fresh frozen tissues from surgical resection specimens are further analyzed by Western blot.MUC4 is identified by immunocytochemical staining throughout the normal UADT mucosa, in 34 of 40 primary UADT SCC, and in 11 of 12 metastatic cervical lymph nodes. A trend toward decreased MUC4 staining in moderately and poorly differentiated tumors is noted. Immunoblots show MUC4 in 4 of 5 SCC analyzed. Immunocytochemical staining of MUC4 in 13 major and minor salivary gland neoplasms reveal variable staining of normal and neoplastic tissue. MUC4 is demonstrated in immunoblots of normal parotid tissue and in the single parotid malignancy analyzed, but is not demonstrated in one minor salivary gland malignancy. These findings characterize normal UADT mucosal and salivary MUC4 expression, and MUC4 expression in SCC of the UADT and in salivary gland tumors.Correlation of MUC4 expression with clinical outcomes may establish MUC4 as a potential molecular prognostic marker for these tumors.

Background. Insulin is an important regulator of serum sex hormone-binding globulin (SHBG) concentration which works by inhibiting its production in hepatocytes. Low SHBG level is associated with increased insulin resistance and hyperinsulinemia. Our purpose was to compare maternal serum SHBG level between normal and gestational diabetic pregnant women and to study the relationships between SHBG, SHBG/insulin and SHBG/glucose ratio and several endocrine, metabolic and clinical parameters.Methods. Serum SHBG concentrations were measured in 34 women with gestational diabetes and in 32 matched controls. Glucose, insulin, C-peptide, fructosamine, s-HCG, cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein A, apolipoprotein B, total and free T4, total and free estriol, T3 and IGF-1 were measured. Insulin sensitivity was estimated using the short insulin tolerance test.Results. SHBG, SHBG/insulinemia ratio and SHBG/glucose ratio were significantly lower in the diabetic group (309.54± 112...

Summary: Most human nephritis is caused by the deposition and/or formation of immune complexes in the glomerular region. Recently, it has been demonstrated that mesangial cells (MC) possess Fc receptors for IgG and IgA. In this work we demonstrate that catabolism of immune complexes occurs via Fc receptors. Mesangial cell incubation with IgA or IgG complexes induced cell proliferation and extracellular matrix synthesis, two key aspects of progressive renal diseases. These effects are in part due to the production of cytokines IL-6 and transforming growth factor-β (TGF-β), as specific antibodies decreased thymidine incorporation and fibronectin (FN) production. Fc receptor stimulation induced several intracellular signals involving phospholipase Cγ activation, inositol trisphosphate (IP3) formation, and Ca2+ mobilization. Furthermore, we observed activation of the transcription factor NF-κB, and increase in gene expression of monocyte chemoattractant protein-1 (MCP-1), proinflammatory cytokine participating in the recruitment of mononuclear cells, a phenomenon related to the onset and progression of renal injury. These responses depend on the Fc region of immunoglobulins because Fc fragments inhibited these effects. To observe whether this could be the case in vivo, rats with immune complex nephritis were treated with IgG Fc fragments. The administration of fragments significantly decreased proteinuria and morphological lesions. Our results show that MC activation through Fc receptors induces several intracellular responses, such as cell proliferation, synthesis of proinflammatory and profibrogenic cytokines, and accumulation of matrix proteins. • Modulation of immune complex—MC interaction by in vivo Fc fragments administration could represent a new approach in the glomerulonephritis treatment.

A case of metastatic medullary thyroid carcinoma (MTC) to the liver of a patient with multiple endocrine neoplasia (MEN) Type IIb was suggested by percutaneous fine-needle aspiration cytology and confirmed by histology and immunohistochemistry. The cytologic presentation of this unusual thyroid cancer in liver has not been previously reported. We report such a case and discuss its differential diagnosis from other metastatic tumors of the liver.

Objective: 1) Histopathologically characterize glomus jugulare paragangliomas preoperatively embolized with ethylene vinyl alcohol copolymer (EVAC). 2) Describe histopathological differences between glomus jugulare paragangliomas preoperatively embolized with polyvinyl alcohol (PVA) and EVAC.Method: Case series of glomus jugulare paragangliomas preoperatively embolized with EVAC. The tumors were subsequently resected at a tertiary care center between 2003 and 2010. Patient demographic and clinical data were collected, and histopathological analysis of the preoperatively embolized tumors was performed.Results: Glomus jugulare paragangliomas embolized with EVAC demonstrated 100% or near 100% occlusion of arterial vessels by histopathological analysis, whereas in previous studies PVA demonstrated a significantly lower percentage of embolization. Even when resection was performed several months after embolization, there was no revascularization of EVAC embolized vessels, whereas PVA embolized vessels have dem...

For development of new cardiotonic agents a series of 5-aryl-3,4-dihydropyridin-2(1H)-ones, related to amrinone have been prepared from methylquinolines, 2-arylacetic acid or 3-arylethanones by direct aminomethylenation and subsequent condensation-cyclization with malonamide and cyanacetamide in classic basic media or phase-transfer catalysis, in good to excellent yields. Preliminary pharmacological assays have shown that these compounds, especially 5h and 5i, have a remarkable cardiotonic effect and present a selective inhibition of PDE-III/PDE-I isolated from cat heart.

For development of new cardiotonic agents a series of 5-aryl-3,4-dihydropyridin-2(1H)-ones, related to amrinone have been prepared from methylquinolines, 2-arylacetic acid or 3-arylethanones by direct aminomethylenation and subsequent condensation-cyclization with malonamide and cyanacetamide in classic basic media or phase-transfer catalysis, in good to excellent yields. Preliminary pharmacological assays have shown that these compounds, especially 5h and 5i, have a remarkable cardiotonic effect and present a selective inhibition of PDE-III/PDE-I isolated from cat heart.