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Abstract Background Renal medullary carcinoma is one of the rarest malignancies arising from the kidney. Despite various aggressive therapeutic regimens, mortality remains significantly high (95%) with a median overall survival of 5 months. Furthermore, the scarcity of this malignancy renders randomized clinical trials impossible. We examined the expression of programmed death ligand 1 (PD-L1) in two new renal medullary carcinoma cases, investigated their responses to the PD-L1 inhibitor nivolumab and explored the predictive role of the rate of PD-L1 expression in such response. Case presentation Two African-American patients (male and female) with sickle cell trait who presented to our center with hematuria and flank pain were diagnosed with metastatic renal medullary carcinoma. PD-L1 was expressed at rate of 25% and 60% in patient 1 and 2 respectively. Following nephrectomy, they were started on nivolumab. Patient 1 initially responded to the treatment with regression of metastatic lesions. However, following this early response, patient 1 who has been receiving nivolumab for more than 15 months, was noted to have a disease progression. Patient 2 had disease progression after 3 months of nivolumab therapy. Conclusions Although PD-L1 is expressed in these patients with renal medullary carcinoma, response to nivolumab was only observed in patient 1 whose tumor has the lowest rate of PD-L1 expression. This may suggest that in RMC, response to PD-L1 inhibition therapy may not correlate with the rate of PD-L1 expression.

Background: Breast cancer genome sequencing projects, performed by the genome sequencing centers in the U.S., Canada, and the U.K., are elucidating the somatic mutations and other genomic alterations that occur in human breast cancer. These studies recently identified somatic HER2 mutations in breast cancers lacking HER2 gene amplification. Results: Compilation of data from seven sequencing studies documented 22 patients with somatic HER2 mutations. These mutations clustered in three regions. The first cluster was at amino acid (aa) 309-310 (exon 8), located in the extracellular domain. These aa residues form part of the HER2 dimerization interface. The second cluster was at aa 755-781, located in the kinase domain (exons 19-20). This was the most common location for HER2 mutations, with 17 out of 22 patients having somatic mutations here. The third region was at aa 835-896, also in the kinase domain (exons 21-22). Using multiple experimental approaches (cell line experiments, in vitro kinase assays, protein structure modeling, and xenograft experiments), we tested seven of these HER2 mutations and showed that 4 of them are activating mutations that are sensitive to lapatinib and trastuzumab. Another 2 mutations were found to be lapatinib resistant and we determined their sensitivity to neratinib, canertinib, and gefitinib. Conclusions: These findings biologically validate somatic HER2 mutations as good targets for breast cancer treatment, but the appropriate choice of targeted drug is dependent on the precise mutation present. This study is among the first to functionally characterize mutations identified by breast cancer genome sequencing. A prospective, multi-institutional clinical trial has been launched to screen for HER2 mutation positive patients and determine the clinical outcome of treatment with HER2 targeted drugs. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) participate in almost all disorders, including cancer. Many factors, including aging, a high-fat diet, a stressful lifestyle, smoking, infection, genetic mutations, etc., lead to elevated levels of ROS. Prostate cancer, the most prevalent type of cancer in senior American men and the second leading cause of cancer mortality in American men, results from chronic oxidative stress. The doubled incident rate as well as the doubled mortality numbers of prostate cancer have persisted in African Americans in comparison with Caucasian Americans and other racial groups, indicating a prostate cancer disparity in African American men. In this review, we mainly focus on the latest findings on ROS in prostate cancer development and progression within the last five years to update our understanding in this area, as several comprehensive literature reviews addressing oxidative stress and/or inflammation in prostate cancer before 2020 are available. In addition to other known factors such as socioeconomic disadvantage, cultural mistrust of the health care system, etc. that are long-existing in the African American group, we also summarize the latest evidence that demonstrated high systemic oxidative stress and inflammation in African Americans for their potential contribution to the racial prostate cancer disparity in this population.

Introduction: Human papillomavirus virus-related oropharyngeal squamous cell carcinoma (HPV-OPSCC) comprises a significant portion of head and neck cancers. Several glucocorticoid-inducible proteins play important roles in pathogenesis of some cancers but their status and roles in HPV-OPSCC remain elusive; these include the glucocorticoid-induced leucine zipper (GILZ), Annexin-A1 and serum glucocorticoid-regulated kinase-1 (SGK-1)., Methods: We determined expression profiles of these proteins, using immunohistochemistry, in archived biopsy samples of patients diagnosed with HPV-OPSCC; samples of non-cancer oral lesions (e.g., hyperkeratosis) were used as controls., Results: GILZ staining was primarily confined to nuclei of all tissues but, in HPV-OPSCC specimens, neoplastic cells exhibiting mitosis displayed prominent cytoplasmic GILZ expression. On the other hand, nuclear, cytoplasmic and membranous Annexin-A1 staining was observed in suprabasal cell layers of control specimens. A noted feature of the HPV-OPSCC specimens was few clusters of matured and differentiated nonbasaloid cells that showed prominent nuclear and cytoplasmic Annexin-A1 staining while the remainder of the tumor mass was devoid of staining. Cytoplasmic and nuclear staining for SGK-1 was prominent for control than PV-OPSCC specimens while staining for phosphorylated SGK-1 (pSGK-1; active) was prominent for cell membrane and cytoplasm of control specimens but HPV-OPSCC specimens showed mild and patchy nuclear and cytoplasmic staining. Semi-quantitative analysis of GILZ immunostaining indicated increased staining area but similar normalized staining for HPV-OPSCC compared to control specimens. By contrast, staining area and normalized staining were reduced for other proteins in HPV-OPSCC than control specimens., Discussion: Our collective observations suggest differential cellular localization and expression of glucocorticoid-inducible proteins in HPV-OPSCC suggestive of different functional roles in pathogenesis of this condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Mozaffari, Abdelsayed, Emami and Kavuri.)

Introduction: Parathyroid carcinoma (PC) is an extremely rare entity, with a frequency of 0.005% of all malignancies. Most data related to this rare disease are limited to case series and a few database studies. We present a large database study that aims to investigate the demographic, clinical, and pathological factors, prognosis, and survival of PC. Methods: Data of parathyroid carcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) diagnosed between 1975 and 2016. Results: PC had a slightly higher incidence in men (52.2%, p < 0.005), the majority of cases affected Caucasians (75.4%, p < 0.005), and the mean age at diagnosis was 62 years. Histologically, 99.7% were adenocarcinomas not otherwise specified (p < 0.005), well-differentiated (p < 0.005), and 2−4 cm (p < 0.001) in size among the patients with available data. In cases with staging provided, most PC were organ-confined (36.8%, p < 0.001). Lymph nodes were positive in 25.2% of cases where lymph node status was reported. The main treatment modality was surgery (97.2%), followed by radiation alone (2%), and very few received chemotherapy alone (0.8%), p < 0.005. Five-year follow-up was available for 82.7% of the cases. Those who underwent surgery only or radiation alone had 5-year survivals of 83.8% and 72.2%, respectively (p < 0.037). Multivariable analysis identified tumor size >4 cm, age > 40 years, male sex, Caucasian race, distant spread, and poorly differentiated grade as independent risk factors for mortality (p < 0.001). Conclusion: PC is a very rare tumor mostly affecting Caucasian individuals in the fifth decade. Older age, poor histologic differentiation, and distant metastasis are associated with a worse prognosis. Surgical resection offers the best survival outcome. To better understand the pathogenesis and factors affecting survival, all PC patients should be enrolled in national and international registries.

Publicly available gene expression datasets were analyzed to develop a chromophobe and oncocytoma related gene signature (COGS) to distinguish chRCC from RO. The datasets GSE11151, GSE19982, GSE2109, GSE8271 and GSE11024 were combined into a discovery dataset. The transcriptomic differences were identified with unsupervised learning in the discovery dataset (97.8% accuracy) with density based UMAP (DBU). The top 30 genes were identified by univariate gene expression analysis and ROC analysis, to create a gene signature called COGS. COGS, combined with DBU, was able to differentiate chRCC from RO in the discovery dataset with an accuracy of 97.8%. The classification accuracy of COGS was validated in an independent meta-dataset consisting of TCGA-KICH and GSE12090, where COGS could differentiate chRCC from RO with 100% accuracy. The differentially expressed genes were involved in carbohydrate metabolism, transcriptomic regulation by TP53, beta-catenin-dependent Wnt signaling, and cytokine (IL-4 and IL-13) signaling highly active in cancer cells. Using multiple datasets and machine learning, we constructed and validated COGS as a tool that can differentiate chRCC from RO and complement histology in routine clinical practice to distinguish these two tumors.

Recognition of ancient Korean-Chinese cursive character (Hanja) is a challenging problem mainly because of large number of classes, damaged cursive characters, various hand-writing styles, and similar confusable characters. They also suffer from lack of training data and class imbalance issues. To address these problems, we propose a unified Regularized Low-shot Attention Transfer with Imbalance τ-Normalizing (RELATIN) framework. This handles the problem with instance-poor classes using a novel low-shot regularizer that encourages the norm of the weight vectors for classes with few samples to be aligned to those of many-shot classes. To overcome the class imbalance problem, we incorporate a decoupled classifier to rectify the decision boundaries via classifier weight-scaling into the proposed low-shot regularizer framework. To address the limited training data issue, the proposed framework performs Jensen-Shannon divergence based data augmentation and incorporate an attention module that aligns the most attentive features of the pretrained network to a target network. We verify the proposed RELATIN framework using highly-imbalanced ancient cursive handwritten character datasets. The results suggest that (i) the extreme class imbalance has a detrimental effect on classification performance; (ii) the proposed low-shot regularizer aligns the norm of the classifier in favor of classes with few samples; (iii) weight-scaling of decoupled classifier for addressing class imbalance appeared to be dominant in all the other baseline conditions; (iv) further addition of the attention module attempts to select more representative features maps from base pretrained model; (v) the proposed (RELATIN) framework results in superior representations to address extreme class imbalance issue., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background/aims: The pathoetiology of functional dyspepsia remains unclear; one mechanism could be chemical gastropathy from chronic bile reflux. We aim to examine the association of bile reflux gastropathy with functional dyspepsia and identify predisposing factors., Methods: In a retrospective study, patients with functional dyspepsia (Rome III) who completed symptom assessment, esophagogastroduodenoscopy, and biopsies were categorized into 3 groups; bile gastropathy (BG), non-bile gastropathy (NBG), and no gastropathy (NG). Demographics, symptoms, endoscopy, and motility data were compared between groups. Multivariate analysis identified clinical factors associated with BG., Results: Of 262 patients (77.5% female), 90 had BG, 121 had NBG, and 51 had NG. Baseline demographics were similar, however, patients with BG reported significantly more severe abdominal pain than NBG or NG groups ( P = 0.018). Gastric erythema was significantly more common in BG vs NBG groups ( P < 0.001). Cholecystectomy was significantly associated (OR, 6.6; P = 0.003) with the presence of gastropathy in BG compared to NBG or NG group. Patients with cholecystectomy had significantly more severe abdominal pain ( P < 0.05), gastric erythema ( P < 0.03), and gastritis ( P < 0.05), and were more likely to be prescribed narcotic medications ( P < 0.004) than patients without cholecystectomy., Conclusion: s Bile reflux gastropathy is associated with functional dyspepsia and causes more severe symptoms. Cholecystectomy predisposes to BG and abnormal pain, and could contribute to the pathogenesis of functional dyspepsia.

The nanoscale protein architecture of the kinetochore plays an integral role in specifying the mechanisms underlying its functions in chromosome segregation. However, defining this architecture in human cells remains challenging because of the large size and compositional complexity of the kinetochore. Here, we use Förster resonance energy transfer to reveal the architecture of individual kinetochore-microtubule attachments in human cells. We find that the microtubule-binding domains of the Ndc80 complex cluster at the microtubule plus end. This clustering occurs only after microtubule attachment, and it increases proportionally with centromeric tension. Surprisingly, Ndc80 complex clustering is independent of the organization and number of its centromeric receptors. Moreover, this clustering is similar in yeast and human kinetochores despite significant differences in their centromeric organizations. These and other data suggest that the microtubule-binding interface of the human kinetochore behaves like a flexible "lawn" despite being nucleated by repeating biochemical subunits., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Poor prognosis of patients with muscle-invasive bladder cancer that often metastasizes drives the need for discovery of molecular determinants of bladder cancer progression. Chondroitin sulfate proteoglycans, including CD44, regulate cancer progression; however, the identity of a chondroitinase (Chase) that cleaves chondroitin sulfate from proteoglycans is unknown. HYAL-4 is an understudied gene suspected to encode a Chase, with no known biological function. We evaluated HYAL-4 expression and its role in bladder cancer., Experimental Design: In clinical specimens, HYAL-4 wild-type (Wt) and V1 expression was evaluated by RT-qPCR, IHC, and/or immunoblotting; a novel assay measured Chase activity. Wt and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for stem cell phenotype, invasive signature and tumorigenesis, and metastasis in four xenograft models, including orthotopic bladder., Results: HYAL-4 expression, specifically a novel splice variant (V1), was elevated in bladder tumors; Wt expression was barely detectable. V1 encoded a truncated 349 amino acid protein that was secreted. In bladder cancer tissues, V1 levels associated with metastasis and cancer-specific survival with high efficacy and encoded Chase activity. V1 cleaved chondroitin-6-sulfate from CD44, increasing CD44 secretion. V1 induced stem cell phenotype, motility/invasion, and an invasive signature. CD44 knockdown abrogated these phenotypes. V1-expressing urothelial cells developed angiogenic, muscle-invasive tumors. V1-expressing bladder cancer cells formed tumors at low density and formed metastatic bladder tumors when implanted orthotopically., Conclusions: Our study discovered the first naturally-occurring eukaryotic/human Chase and connected it to disease pathology, specifically cancer. V1-Chase is a driver of malignant bladder cancer and potential predictor of outcome in patients with bladder cancer., (©2020 American Association for Cancer Research.)

Multimodal emotion understanding enables AI systems to interpret human emotions. With accelerated video surge, emotion understanding remains challenging due to inherent data ambiguity and diversity of video content. Although deep learning has made a considerable progress in big data feature learning, they are viewed as deterministic models used in a "black-box" manner which does not have capabilities to represent inherent ambiguities with data. Since the possibility theory of fuzzy logic focuses on knowledge representation and reasoning under uncertainty, we intend to incorporate the concepts of fuzzy logic into deep learning framework. This paper presents a novel convolutional neuro-fuzzy network, which is an integration of convolutional neural networks in fuzzy logic domain to extract high-level emotion features from text, audio, and visual modalities. The feature sets extracted by fuzzy convolutional layers are compared with those of convolutional neural networks at the same level using t-distributed Stochastic Neighbor Embedding. This paper demonstrates a multimodal emotion understanding framework with an adaptive neural fuzzy inference system that can generate new rules to classify emotions. For emotion understanding of movie clips, we concatenate audio, visual, and text features extracted using the proposed convolutional neuro-fuzzy network to train adaptive neural fuzzy inference system. In this paper, we go one step further to explain how deep learning arrives at a conclusion that can guide us to an interpretable AI. To identify which visual/text/audio aspects are important for emotion understanding, we use direct linear non-Gaussian additive model to explain the relevance in terms of causal relationships between features of deep hidden layers. The critical features extracted are input to the proposed multimodal framework to achieve higher accuracy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: The objective of this study was to determine the performance characteristics of the Tush brush (TB) compared with a saline moistened Dacron swab (DS) as anal cytology sampling devices., Materials and Methods: TB and DS anal cytology tests were randomly collected from 146 patients presenting for anal cytology. High-resolution anoscopy and biopsies were obtained as indicated. Sensitivity and specificity as well as rates of satisfactory specimens were determined for each method using the areas under the receiver operating characteristic curve (AUCROC) and McNemar's test, respectively. Perceived discomfort of each device was determined using a visual analog scale and compared using a paired t test., Results: The adjudicated AUCROC, sensitivity, and specificity were greater, but not significantly different, for the brush (0.63, 85.5, and 40.0, respectively) compared with the swab (0.50, 79.6, and 33.3, respectively) when the anal biopsy results were considered the criterion standard. In the 1 subject diagnosed with anal cancer, the swab cytology result was normal, but the brush result was abnormal. Specimen adequacy was 95.2% for the brush and 93.2% for the swab. Mean discomfort (visual analog scale) scores were swab 28.5 mm versus brush 35.6 mm (p = .0003) with both scores within the minimal to moderate discomfort range., Conclusions: Anal cytology AUCROC, sensitivity, and specificity in detecting anal neoplasia were greater using the TB when compared with the DS. A novel anal cytology sampling device designed specifically to increase the detection of anal neoplasia would be clinically beneficial.

Docetaxel resistance remains a major obstacle in the treatment of prostate cancer bone metastasis. In this study, we demonstrate that the dopamine D2 receptor (DRD2) agonist bromocriptine effectively enhances docetaxel efficacy and suppresses skeletal growth of prostate cancer in preclinical models. DRD2 is ubiquitously expressed in prostate cancer cell lines and significantly reduced in prostate cancer tissues with high Gleason score. Bromocriptine has weak to moderate cytotoxicity in prostate cancer cells, but effectively induces cell-cycle arrest. At the molecular level, bromocriptine inhibits the expression of c-Myc, E2F-1, and survivin and increases the expression of p53, p21, and p27. Intriguingly, bromocriptine markedly reduces androgen receptor levels, partially through Hsp90-mediated protein degradation. The combination of bromocriptine and docetaxel demonstrates enhanced in vitro cytotoxicity in prostate cancer cells and significantly retards the skeletal growth of C4-2-Luc tumors in mice. Collectively, these results provide the first experimental evidence for repurposing bromocriptine as an effective adjunct therapy to enhance docetaxel efficacy in prostate cancer. Mol Cancer Ther; 17(9); 1859-70. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Introduction: Napsin A is a diagnostic marker for pulmonary adenocarcinoma and a useful alternative to thyroid transcription factor 1 (TTF-1). TTF-1 also stains pulmonary small cell carcinoma (SCCA). Napsin A expression in SCCAs is not as established as it is in non-SCCAs. We analyzed napsin A and TTF-1 expression in 36 previously confirmed cytologic cases of pulmonary SCCA. Ours is currently the largest cytologic series of such cases examined for napsin A expression., Materials and Methods: Thirty-six patients, (20 men, 16 women), age 43-87 years, mean 57 years, had primary or metastatic pulmonary SCCA diagnosed by fine-needle aspiration biopsies of mediastinum (n = 5); liver (n = 3); subcutaneous nodule (n = 1); lung (n = 6); and axillary, cervical, and mediastinal lymph nodes (n = 20), as well as a pleural effusion (n = 1). Napsin A and TTF-1 expression was tested. Also, previous expression (or lack thereof) with immunocytochemical stains pancytokeratin and neuroendocrine markers (synaptophysin, chromogranin, and cluster of differentiation marker CD56) were noted., Results: All cases of pulmonary SCCA were positive for pancytokeratin. TTF-1 was positive in 35 of 36 cases (97%), and napsin A was negative in all 36 cases (100%). All 36 cases expressed ≥ 1 neuroendocrine marker, including the TTF-1 negative case., Conclusions: This study showed napsin A was negative in all pulmonary SCCAs. This stain may prove to be a useful exclusionary marker in distinguishing pulmonary SCCA from other poorly differentiated lung carcinomas with similar morphologic features, especially those with concomitant TTF-1 expression., (Copyright © 2014 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Treating testicular cancer with adjuvant radiation has been associated with a number of second malignancies affecting the genitourinary tract and retroperitoneal structures; however, there have been few reported cases of cutaneous second malignancies. We report the case of a man who developed stage IV squamous cell carcinoma (SCC) of a condyloma after orchiectomy and adjuvant radiation for testicular cancer. We also review relevant literature available to date. A 55-year-old Caucasian man presented to the hospital with a large growth at the right groin which had grown into his right thigh preventing ambulation. His past medical history was significant for right testicular cancer of unknown pathology treated with orchiectomy and adjuvant radiation twenty years ago. Punch biopsy of the lesion revealed superficially invasive squamous cell carcinoma. He underwent excision of the growth with subsequent Cisplatin, radiation boost, and Paclitaxel regimens. Despite an aggressive treatment regimen and an initial good response, the patient's cancer progressed requiring palliative care. It is unclear whether or not therapeutic radiation in this case promoted the conversion of the patient's condyloma to a malignant lesion. Further studies are required at this time to clarify the clinical implications of these findings.

P21-activated kinases (Paks) are major effectors downstream of the small Rho family of GTPases. Among the six isoforms, Pak1 is the most ubiquitous and the best characterized member. Previous studies have shown that inhibition of Pak6, which is predominantly present in the prostate compared with other tissues, inhibits prostate tumor growth in vivo. Even though Pak1 has been identified in normal prostatic epithelial cells and cancer cells, its specific role in the development of prostate cancer remains unclear. We report here that highly invasive prostate cancer cells express significantly higher levels of Pak1 protein compared with non-invasive prostate cancer cells. Furthermore, prostate tumor tissues and prostate cancer metastasized to lungs showed a higher expression of Pak1 compared with normal tissues. Interestingly, Pak6 protein expression levels did not change with the invasive/metastatic potential of the cancer cells or tumors. Although inhibition of Pak1, and not Pak6, resulted in impaired PC3 cell migration, the effects of Pak1 knockdown on transendothelial migration (microinvasion), tumor growth, and tumor angiogenesis was higher compared with Pak6 knockdown. Finally, gene array data revealed reduced expression of matrix metalloproteinase 9 with the ablation of either Pak1 or Pak6 gene expression in PC3 cells, whereas protein levels of TGFβ was elevated significantly with specific modulation of Pak1 activity or ablation of the Pak1 gene. Our observations suggest that although some level of functional redundancy exists between Pak1 and Pak6 in prostate cancer cells, targeting Pak1 is a potential option for the management of prostate tumor growth, microinvasion, and metastasis.

Background: Ki-67 proliferation index was recently incorporated in the grading of neuroendocrine neoplasms (NENs) of the gastrointestinal tract (GIT) and pancreas. These are now divided into well-differentiated neuroendocrine tumors (WDNETs, grades 1 and 2) and poorly differentiated neuroendocrine carcinomas (grade 3). While Ki-67 is an established proliferation marker in NENs, phosphohistone H3 (PHH3), a newer marker of mitotic activity, is not., Methods: We determined Ki-67 and PHH3 indices on cytologic samples from WDNETs of the GIT and pancreas using an automated cellular imaging system (ACIS®)., Results: There was a strong correlation between Ki-67 and PHH3 indices generated by ACIS on cytologic samples. However, in some cases the two stains caused conflicting grades within the same tumor., Conclusion: Both antibodies stain cells in different phases of the cell cycle which may cause discordant grades, thus affecting patient management and prognostication. Ki-67 staining is stronger than PHH3, making 'hot spots' easier to identify on ACIS. Ki-67 is more ideal than PHH3 for staining NENs, especially in tumors with borderline grades. Because PHH3 generates lower mitotic indices it should not be used as a proliferation marker in NENs until its expression has been further characterized.

Objective: To describe the cytologic findings in 6 adult variants of granuloma cell tumors (AGCTs) and 1 juvenile variant (JGCT), emphasizing differences between recurrent/metastatic (REC AGCT) and nonrecurrent tumors (NED AGC7)., Study Design: Imprints and fluids were evaluated for: hypercellularity, Call-Exner bodies (CEB), sheets, single cells/naked nuclei, nuclear grooves, single cell necrosis and established histologic criteria of atypia in AGCT (>3 mitoses, pleomorphism, hyperchromasia, prominent nucleoli)., Results: All AGCTs and JGCT showed hypercellularity, clusters, sheets, single cells and naked nuclei. CEBs and grooves were seen only in AGCTs. Fluids had less cellularity than imprints, fewer clusters, grooves, single cells/naked nuclei and no sheets, CEBs, necrosis or vacuoles. Hyperchromasia and nucleoli were more striking in JGCT than AGCTs. All REC AGCTs had cytoplasmic vacuoles, while NED AGCTs did not. Prominent nucleoli were 3 times more common in REC AGCTs than NED AGCTs. Increased mitoses and necrosis were seen in 1 REC AGCT., Conclusion: CEBs and grooves are not seen in JGCT. JGCT shows more striking cellular atypia than AGCT (REC AGCTs and NED AGCTs). When evaluating pelvic washes/ascitic fluid a high index of suspicion is necessary, as tumor cells can be overlooked. AGCTs showing cytoplasmic vacuoles, prominent nucleoli, mitoses and necrosis are suggestive of aggressive behavior, and that information should be conveyed in cytology reports.

Primary endothelial cells are fully resistant to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Here, we demonstrate that certain environmental conditions, such as exposure to the widespread allergen nickel, can dramatically increase the susceptibility of naturally resistant primary endothelial cells or keratinocytes to TRAIL-induced apoptosis. While nickel treatment increased surface expression of the apoptosis-inducing TRAIL receptors TRAIL-R1 and TRAIL-R2, it also up-regulated the apoptosis-deficient TRAIL-R4, suggesting that modulation of TRAIL receptor expression alone is unlikely to fully account for the dramatic sensitization effect of nickel. Further analysis of candidate mediators revealed that nickel strongly repressed c-FLIP at mRNA and protein levels. Accordingly, increased activation of Caspase-8 and Caspase-3 following nickel treatment was observed. Importantly, depletion of c-FLIP by RNA interference could largely recapitulate the effect of nickel and sensitize endothelial cells to TRAIL-dependent apoptosis in the absence of nickel pre-treatment. Conversely, ectopic expression of c-FLIP(L) largely protected nickel-treated cells from TRAIL-mediated apoptosis. Our data demonstrate that one key mechanism of sensitization of primary human endothelial cells or keratinocytes is transcriptional down-regulation of c-FLIP. We hypothesize that environmental factors, exemplified by the contact allergen nickel, strongly modulate death ligand sensitivity of endothelial cells and keratinocytes thus influencing vascular and epidermal function and integrity under physiological and pathophysiological conditions.

Background: Plasmablastic lymphoma (PBL) is a rare form of non-Hodgkin lymphoma that was once believed to occur primarily in the oral cavity of human immunodeficiency virus-positive individuals. Numerous extraoral sites have also been reported to date. To the authors' knowledge, however, only 3 reports in the literature describe its cytologic features. In the current study, the cytologic findings in 5 additional patients are reported, 3 of whom had concomitant second malignancies. The goal of the current study was to define the cytomorphologic features that may help to distinguish PBL from other mimics., Methods: Five cases were identified from the pathology files for which cytology was available. The presence of the following was evaluated: cellularity, plasmablastic cells, background necrosis (BN), single-cell necrosis (SCN), lymphoglandular bodies (LGB), tingible-body macrophages (TBM), 3-dimensional clusters/sheets, and cytoplasmic vacuoles., Results: The patients included 3 women and 2 men with an age range of 40 to 57 years. Two patients had the acquired immunodeficiency syndrome and 3 had second non-PBL related malignancies including endometrial carcinoma, lung adenocarcinoma, and small lymphocytic lymphoma. The most common cytologic features were hypercellularity (80%), plasmablastic cells (73%), SCN (73%), BN (87%), and LGB (66%). TBMs (33%) and clusters/sheets (47%) were the least common features., Conclusions: Although no 1 cytologic feature is diagnostic of PBL, a constellation of findings should raise suspicion. These include hypercellular specimens with abundant plasmablastic cells, LGB, SCN, and BN. However, although these findings may suggest PBL, a definitive diagnosis requires adjunctive studies including immunohistochemistry and flow cytometry. As with any lymphocyte-rich aspirate, additional material should be collected for these studies. Over-reliance on adjuvant studies is discouraged because the PBL immunophenotype is not considered standard., ((c) 2008 American Cancer Society.)

In most cell types, tumor necrosis factor (TNF) induces a transient activation of the JNK pathway. However, in NFkappaB-inhibited cells, TNF stimulates also a second sustained phase of JNK activation, which has been implicated in cell death induction. In the present study, we have analyzed the relationship of cell death induction, caspase activity, JNK, and NFkappaB stimulation in the context of TNF signaling in four different cellular systems. In all cases, NFkappaB inhibition enhanced TNF-induced cell death and primed most, but not all, cells for sustained JNK activation. The caspase inhibitor Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-fmk) and overexpression of the antiapoptotic proteins FLIP-L and Bcl2 differentially blocked transient and sustained JNK activation in NFkappaB-inhibited KB and HaCaT cells, indicating that the two phases of TNF-induced JNK activation occur at least in these cellular models by different pathways. Although the broad range caspase inhibitor Z-VAD-fmk and the antioxidant butylated hydroxyanisole interfered with TNF-induced cell death to a varying extent in a cell type-specific manner, inhibition of JNK signaling had no or only a very moderate effect. Notably, the JNK inhibitory effect of neither Z-VAD-fmk nor butylated hydroxyanisole was strictly correlated with the capability of these compounds to rescue cells from TNF-induced cell death. Thus, sustained JNK activation by TNF has no obligate role in TNF-induced cell death and is mediated by caspases and reactive oxygen species in a cell type-specific manner.

Background: Nephrotic syndrome (NS) is a stressful condition for children where oxidative damage would also influence the response of these patients to therapy., Methods: The present study was conducted in children with nephrotic syndrome during relapse and remission and in 10 age- and sex-matched healthy volunteers. Red cell glutathione (GSH), superoxide dismutase (SOD) and malondialdehyde (MDA) concentrations as well as plasma ceruloplasmin (CP) and vitamin E concentrations were analyzed in controls and in patients., Results: Erythrocyte superoxide dismutase concentrations were significantly increased in both the groups when compared to controls. Erythrocyte glutathione significantly decreased in nephrotic syndrome in remission along with plasma vitamin E concentrations in both the groups. A significant increase in plasma ceruloplasmin was observed in cases in remission. However, no significant change was observed in the concentrations of erythrocyte malondialdehyde., Conclusion: Thus, antioxidant concentrations change considerably, indicating a compensatory mechanism to cope up with increased pro-oxidant status in such cases., (Copyright 2002 Elsevier Science B.V.)