Generation of an induced pluripotent stem cell line (KNIHi001-A) by reprogramming peripheral blood mononuclear cells isolated from a patient with Parkinson's disease.

Parkinson's disease is a degenerative brain disorder characterized by dopamine neuronal degeneration and dopamine transporter loss. In this study, we generated an induced pluripotent stem cell (iPSC) line, KNIHi001-A, from the peripheral blood mononuclear cells (PBMCs) of a 76-year-old man with Parkinson's disease. The non-integrating Sendai virus was used to reprogram iPSCs. iPSCs exhibit pluripotent markers, a normal karyotype, viral clearance, and the ability to differentiate into the three germ layers.

Tubular dentin formation by TGF-ß/BMP signaling in dental epithelial cells.

OBJECTIVES: This study aimed to identify formation of tubular dentin induced by transforming growth factor-ß (TGF-ß) and bone morphogenic protein (BMP) signaling pathway in dental epithelial cells. METHODS: We collected conditioned medium (CM) of rTGF-ß1/rBMP-2-treated HAT-7 and treated to MDPC-23 cells. The expression levels of odontoblast differentiation markers, KLF4, DMP1, and DSP were evaluated by real-time PCR and Western blot analysis. To evaluate whether CM of rTGF-ß1/rBMP-2 induces tubular dentin formation, we made a beagle dog tooth defect model. RESULTS: Here, we show that Cpne7 is regulated by Smad4-dependent TGF-ß1/BMP2 signaling pathway in dental epithelial cells. CM of rTGF-ß1/rBMP-2 treated HAT-7 or rCPNE7 raises the expression levels of KLF4, DMP1, and DSP in MDPC-23 cells. When rTGF-ß1 or rBMP-2 is directly treated to MDPC-23 cells, however, expression levels of Cpne7-regulated genes remain unchanged. In a beagle dog defect model, application of rTGF-ß1/BMP2-treated CM resulted in tubular tertiary dentin mixed with osteodentin at cavity-prepared sites, while rTGF-ß1 group exhibited homogenous osteodentin. CONCLUSIONS: Taken together, Smad4-dependent TGF-ß1/BMP2 signaling regulates Cpne7 in dental epithelial cells, and CPNE7 protein secreted from pre-ameloblasts mediates odontoblast differentiation via epithelial-mesenchymal interaction.

Screening of Mood Symptoms Using MMPI-2-RF Scales: An Application of Machine Learning Techniques.

(1) Background: The MMPI-2-RF is the most widely used and most researched test among the tools for assessing psychopathology, and previous studies have established its validity. Mood disorders are the most common mental disorders worldwide; they present difficulties in early detection, go undiagnosed in many cases, and have a poor prognosis. (2) Methods: We analyzed a total of 8645 participants. We used the PHQ-9 to evaluate depressive symptoms and the MDQ to evaluate hypomanic symptoms. We used the 10 MMPI-2 Restructured Form scales and 23 Specific Problems scales for the MMPI-2-RF as predictors. We performed machine learning analysis using the k-nearest neighbor classification, linear discriminant analysis, and random forest classification. (3) Results: Through the machine learning technique, depressive symptoms were predicted with an AUC of 0.634-0.767, and the corresponding value range for hypomanic symptoms was 0.770-0.840. When using RCd to predict depressive symptoms, the AUC was 0.807, but this value was 0.840 when using linear discriminant classification. When predicting hypomanic symptoms with RC9, the AUC was 0.704, but this value was 0.767 when using the linear discriminant method. (4) Conclusions: Using machine learning analysis, we defined that participants' mood symptoms could be classified and predicted better than when using the Restructured Clinical scales.

Detecting suicidal risk using MMPI-2 based on machine learning algorithm.

Minnesota Multiphasic Personality Inventory-2 (MMPI-2) is a widely used tool for early detection of psychological maladjustment and assessing the level of adaptation for a large group in clinical settings, schools, and corporations. This study aims to evaluate the utility of MMPI-2 in assessing suicidal risk using the results of MMPI-2 and suicidal risk evaluation. A total of 7,824 datasets collected from college students were analyzed. The MMPI-2-Resturcutred Clinical Scales (MMPI-2-RF) and the response results for each question of the Mini International Neuropsychiatric Interview (MINI) suicidality module were used. For statistical analysis, random forest and K-Nearest Neighbors (KNN) techniques were used with suicidal ideation and suicide attempt as dependent variables and 50 MMPI-2 scale scores as predictors. On applying the random forest method to suicidal ideation and suicidal attempts, the accuracy was 92.9% and 95%, respectively, and the Area Under the Curves (AUCs) were 0.844 and 0.851, respectively. When the KNN method was applied, the accuracy was 91.6% and 94.7%, respectively, and the AUCs were 0.722 and 0.639, respectively. The study confirmed that machine learning using MMPI-2 for a large group provides reliable accuracy in classifying and predicting the subject's suicidal ideation and past suicidal attempts.

Can the MMPI Predict Adult ADHD? An Approach Using Machine Learning Methods.

(1) Background: Adult attention-deficit/hyperactivity disorder (ADHD) symptoms cause various social difficulties due to attention deficit and impulsivity. In addition, in contrast to ADHD in childhood, ADHD in adulthood is difficult to diagnose due to mixed psychopathologies. This study aimed to determine whether it is possible to predict ADHD symptoms in adults using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) with machine learning (ML) techniques; (2) Methods: Data collected from 5726 college students were analyzed. The MMPI-2-Restructured Form (MMPI-2-RF) was used, and ADHD symptoms in adults were evaluated using the Attention-Deficit/Hyperactivity Disorder Self-Report Scale (ASRS). For statistical analysis, three ML algorithms were used, i.e., K-nearest neighbors (KNN), linear discriminant analysis (LDA), and random forest, with the ASRS evaluation result as the dependent variable and the 50 MMPI-2-RF scales as predictors; (3) Results: When the KNN, LDA, and random forest techniques were applied, the accuracy was 93.1%, 91.2%, and 93.6%, respectively, and the area under the curve (AUC) was 0.722, 0.806, and 0.790, respectively. The AUC of the LDA method was the largest, with an excellent level of diagnostic accuracy; (4) Conclusions: ML using the MMPI-2 in a large group could provide reliable accuracy in screening for adult ADHD.

Is personality linked to season of birth?

The environment is a very significant factor in early childhood development. Season of birth (SOB) is a proxy viable for the environment to which the babies are exposed, thus also significant in early development. This study investigates the association between SOB and personality. A total 2,962 college students were included as study participants. The participants were classified into four seasonal groups based on their birth month and underwent a personality assessment using the Temperament and Character Inventory (TCI). Statistical analysis was performed using one-way analysis of variance (ANOVA) and multinomial logistic regression analysis. The male participants born in autumn scored high on the Disorderliness (NS4) subscale (ß = 0.055, P = 0.042) and the male participants born in summer and winter scored high on the Extravagance (NS3) subscale (summer: ß = 0.072, P = 0.01, winter: ß = 0.078, P = 0.003). The difference observed indicates a relationship between the SOB and temperament, especially NS. Our findings suggest that environmental factors may affect temperament in early development, although further research is likely needed to clarify the causality between them.

Which PHQ-9 Items Can Effectively Screen for Suicide? Machine Learning Approaches.

(1) Background: The Patient Health Questionnaire-9 (PHQ-9) is a tool that screens patients for depression in primary care settings. In this study, we evaluated the efficacy of PHQ-9 in evaluating suicidal ideation (2) Methods: A total of 8760 completed questionnaires collected from college students were analyzed. The PHQ-9 was scored in combination with and evaluated against four categories (PHQ-2, PHQ-8, PHQ-9, and PHQ-10). Suicidal ideations were evaluated using the Mini-International Neuropsychiatric Interview suicidality module. Analyses used suicide ideation as the dependent variable, and machine learning (ML) algorithms, k-nearest neighbors, linear discriminant analysis (LDA), and random forest. (3) Results: Random forest application using the nine items of the PHQ-9 revealed an excellent area under the curve with a value of 0.841, with 94.3% accuracy. The positive and negative predictive values were 84.95% (95% CI = 76.03-91.52) and 95.54% (95% CI = 94.42-96.48), respectively. (4) Conclusion: This study confirmed that ML algorithms using PHQ-9 in the primary care field are reliably accurate in screening individuals with suicidal ideation.

Taurine Protects against Postischemic Brain Injury via the Antioxidant Activity of Taurine Chloramine.

Taurine is ubiquitously distributed in mammalian tissues and is highly concentrated in the heart, brain, and leukocytes. Taurine exerts neuroprotective effects in various central nervous system diseases and can suppress infarct formation in stroke. Taurine reacts with myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) to produce taurine chloramine (Tau-Cl). We investigated the neuroprotective effects of taurine using a rat middle cerebral artery occlusion (MCAO) model and BV2 microglial cells. Although intranasal administration of taurine (0.5 mg/kg) had no protective effects, the same dose of Tau-Cl significantly reduced infarct volume and ameliorated neurological deficits and promoted motor function, indicating a robust neuroprotective effect of Tau-Cl. There was neutrophil infiltration in the post-MCAO brains, and the MPO produced by infiltrating neutrophils might be involved in the taurine to Tau-Cl conversion. Tau-Cl significantly increased the levels of antioxidant enzymes glutamate-cysteine ligase, heme oxygenase-1, NADPH:quinone oxidoreductase 1, and peroxiredoxin-1 in BV2 cells, whereas taurine slightly increased some of them. Antioxidant enzyme levels were increased in the post-MCAO brains, and Tau-Cl further increased the level of MCAO-induced antioxidant enzymes. These results suggest that the neutrophils infiltrate the area of ischemic injury area, where taurine is converted to Tau-Cl, thus protecting from brain injury by scavenging toxic HOCl and increasing antioxidant enzyme expression.

Overlimiting Current in Nonuniform Arrays of Microchannels: Recirculating Flow and Anticrystallization.

Overlimiting current (OLC) through electrolytes interfaced with perm-selective membranes has been extensively researched for understanding fundamental nano-electrokinetics and developing efficient engineering applications. This work studies how a network of microchannels in a nonuniform array, which mimics a natural pore configuration, can contribute to OLC. Here, micro/nanofluidic devices are fabricated with arrays of parallel microchannels with nonuniform size distributions, which are faced with a perm-selective membrane. All cases maintain the same surface and bulk conduction to allow probing of the sensitivity only by the nonuniformity. Rigorous experimental and theoretical investigation demonstrates that overlimiting conductance has a maximum value depending on the nonuniformity. Furthermore, in operando visualization reveals that the nonuniform arrays induce flow loops across the microchannel network enhancing advective transport. This recirculating flow eliminates local salt accumulations so that it can effectively suppress undesirable salt crystallization. Therefore, these results can significantly advance not only the fundamental understanding of the driving mechanism of the OLC but also the design rule of electrochemical membrane applications.

The relationship between circadian typology and lifetime experiences of hypomanic symptoms.

Circadian rhythms have been known to be associated with bipolar disorders. There are many cases in which hypomanic symptoms are not recognized as indicators of an illness. This study aimed to determine the correlation between the experience of lifetime hypomanic symptoms and circadian typology of university students. A total of 8,562 university students participated in the study. The participants completed the Composite Scale of Morningness (CSM) for circadian typology and Mood Disorder Questionnaire (MDQ). Chi-square test and analysis of variance were performed, and the post-hoc result was computed using the FDR adjusted p-values. Overall, the MDQ score was higher in the evening-type group. There was no significant difference between the intermediate-type group and morning-type group for male students. In the evening-type group, the positive response rate was significantly higher for 10 out of 13 items in the MDQ. The evening-type group was more likely to experience hypomanic symptoms. This study showed that circadian and seasonal characteristics related to circadian typology are associated with lifetime hypomanic symptoms. Hence, further investigation is needed to determine the eveningness trait, as it could be a trait marker of bipolar spectrum disorder.

A Paradigm Shift in Nuclear Chromatin Interpretation: From Qualitative Intuitive Recognition to Quantitative Texture Analysis of Breast Cancer Cell Nuclei.

Assessing the pattern of nuclear chromatin is essential for pathological investigations. However, the interpretation of nuclear pattern is subjective. In this study, we performed the texture analysis of nuclear chromatin in breast cancer samples to determine the nuclear pleomorphism score thereof. We used three different algorithms for extracting high-level texture features: the gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), and gray-level size zone matrix (GLSZM). Using these algorithms, 12 GLCM, 11 GLRLM, and 16 GLSZM features were extracted from three scores of breast carcinoma (Scores 1-3). Classification accuracy was assessed using the support vector machine (SVM) and k-nearest neighbor (KNN) classification models. Three features of GLCM, 11 of GLRLM, and 12 of GLSZM were consistent across the three nuclear pleomorphism scores of breast cancer. Comparing Scores 1 and 3, the GLSZM feature large zone high gray-level emphasis showed the largest difference among breast cancer nuclear scores among all features of the three algorithms. The SVM and KNN classifiers showed favorable results for all three algorithms. A multiclass classification was performed to compare and distinguish between the scores of breast cancer. Texture features of nuclear chromatin can provide useful information for nuclear scoring. However, further validation of the correlations of histopathologic features, and standardization of the texture analysis process, are required to achieve better classification results. © 2021 The Authors. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.

Notch1-mediated inflammation is associated with endothelial dysfunction in human brain microvascular endothelial cells upon particulate matter exposure.

Exposure to atmospheric particulate matter (PM) is an emerging risk factor for the pathogenesis of several diseases in humans, including cerebrovascular diseases. However, the mechanisms underlying PM-induced endothelial dysfunction are currently unclear. In this study, we examined how PM leads to endothelial dysfunction in human brain microvascular endothelial cells (HBMECs). We demonstrated that PM10 exposure (up to 25 µg/mL) increase Notch1 cleavage, and it regulates endothelial dysfunction through NICD-mediated inflammation and senescence. PM10-induced NICD signaling causes increased expression of interleukin-1 beta (IL-1ß) and enhances characteristics of cellular senescence, which leads to increased endothelial permeability in HBMECs. Knockdown of Notch1 by siRNA blocks PM10-induced endothelial dysfunction via the suppression of inflammation and senescence. Furthermore, we found that Notch1-mediated inflammation accelerates endothelial senescence, which eventually leads to endothelial dysfunction. Altogether, our data suggest that Notch1 and NICD are potential target regulators for the prevention of cerebrovascular endothelial dysfunction induced by ambient air pollutants such as PM.

Adenosine Triphosphate Accumulated Following Cerebral Ischemia Induces Neutrophil Extracellular Trap Formation.

In ischemic stroke, neutrophils infiltrate damaged brain tissue immediately following the ischemic insult and aggravate inflammation via various mechanisms which include neutrophil extracellular traps (NETs) formation. In the present study, we showed that adenosine triphosphate (ATP), a DAMP molecule, accumulates in the brain and induces NETosis in brain parenchyma and in circulating neutrophils (PMNs) isolated from a murine model of stroke induced by middle cerebral artery occlusion (MCAO). Expression of peptidylarginine deiminase-4 (PAD4), which induces citrullination of histones H3 (CitH3) and initiates NETosis, was significantly enhanced in brain parenchyma and blood PMNs following MCAO. ATP or BzATP (a prototypic P2X7R agonist) significantly enhanced the inductions of PAD4 and CitH3 in a P2X7R-dependent manner and intracellular Ca2+ influx, PKCα activation, and NADPH oxidase-dependent reactive oxygen species (ROS) production play critical roles in this ATP-P2X7R-mediated NETosis. In our MCAO animal model, NETosis was markedly suppressed by treatment with apyrase, an enzyme hydrolyzing ATP, but enhanced by co-treatment of BzATP, confirming ATP-P2X7R-mediated NETosis. Since ATP not only induced NETosis but was also extruded after NETosis, our results indicate that ATP accumulated in the ischemic brain induces NETosis, mediating a cross-talk linking NETosis with neuronal damage that might aggravate inflammation and brain damage.

Ninjurin 1 dodecamer peptide containing the N-terminal adhesion motif (N-NAM) exerts proangiogenic effects in HUVECs and in the postischemic brain.

Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is a cell adhesion molecule responsible for cell-to-cell interactions between immune cells and endothelial cells. In our previous paper, we have shown that Ninj1 plays an important role in the infiltration of neutrophils in the postischemic brain and that the dodecamer peptide harboring the Ninj1 N-terminal adhesion motif (N-NAM, Pro26-Asn37) inhibits infiltration of neutrophils in the postischemic brain and confers robust neuroprotective and anti-inflammatory effects. In the present study, we examinedt the pro-angiogenic effect of N-NAM using human umbilical vein endothelial cells (HUVECs) and rat MCAO (middle cerebral artery occlusion) model of stroke. We found that N-NAM promotes proliferation, migration, and tube formation of HUVECs and demonstrate that the suppression of endogenous Ninj1 is responsible for the N-NAM-mediated pro-angiogenic effects. Importantly, a pull-down assay revealed a direct binding between exogenously delivered N-NAM and endogenous Ninj1 and it is N-terminal adhesion motif dependent. In addition, N-NAM activated the Ang1-Tie2 and AKT signaling pathways in HUVECs, and blocking those signaling pathways with specific inhibitors suppressed N-NAM-induced tube formation, indicating critical roles of those signaling pathways in N-NAM-induced angiogenesis. Moreover, in a rat MCAO model, intranasal administration of N-NAM beginning 4 days post-MCAO (1.5 µg daily for 3 days) augmented angiogenesis in the penumbra of the ipsilateral hemisphere of the brain and significantly enhanced total vessel lengths, vessel densities, and pro-angiogenic marker expression. These results demonstrate that the 12-amino acid Ninj1 peptide, which contains the N-terminal adhesion motif of Ninj1, confers pro-angiogenic effects and suggest that those effects might contribute to its neuroprotective effects in the postischemic brain.

Altered COVID-19 receptor ACE2 expression in a higher risk group for cerebrovascular disease and ischemic stroke.

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.

Assessment of suicidal risk using Minnesota multiphasic personality inventory-2 restructured form.

BACKGROUND: Suicide is a major social issue, affected by both social and psychopathological factors. This study investigated suicide risk assessment using the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF). METHODS: Data were collected from 7824 college students using the MMPI-2-RF. The participants were classified into high-, moderate-, and low-risk for suicide groups based on their scores on the structured Mini-International Neuropsychiatric Interview (MINI) for comparative analysis. The relationships between scores on the Restructured Clinical (RC) Scales of the MMPI-2-RF and suicide risk level were investigated using a multiple logistic regression. RESULTS: Out of the 7824 participants, 964 (12.3%) were identified as being at risk of suicide. There were 553 participants considered low-risk, 312 moderate-risk, and 99 at high-risk. Suicide risk in the participants tended to increase as RC scale scores increased. Out of the nine RC scales, the Demoralization (RCd) and Negative Emotions (RC7) scale scores were highest across all risk groups. The results of a multiple logistic regression indicated that the Demoralization (RCd) scores were significantly elevated in all three suicide risk groups. Antisocial Behavior (RC4) and Aberrant Experiences (RC8) scale scores were significantly elevated for the low-risk group, whereas Somatic Complaints (RC1) scores were elevated for the moderate-risk group, and Somatic Complaints (RC1), Low Positive Emotions (RC2), Antisocial Behavior (RC4), and Ideas of Persecution (RC6) scale scores were elevated for the high-risk group. CONCLUSIONS: Compared to the healthy control group, all three suicide risk groups showed elevated scores on the RC Scales overall, suggesting that various psychopathological factors are involved in the etiology of suicide. More psychopathologic factors were found to influence suicide-related issues in the higher risk groups than lower risk groups, suggesting that more risk factors are involved in higher suicide risk groups. Compared to healthy controls, even the low-risk group showed a significant elevation in emotional factors and antisocial behaviors. While the healthy controls and those at risk of suicide differed significantly on both the Demoralization (RCd) and Negative Emotions (RC7) scales, only the Demoralization (RCd) scale appeared to be able to screen for high suicide risk.

Multivariate discriminant analysis for branching classification of colonic tubular adenoma glands.

BACKGROUND: Many morphologic findings of histology can be translated into mathematically computerized data, and identifying important parameters is primarily pathologists' task as users. Shape-specific parameters based on computational geometry properties of glands can be used in the field of pathology. We evaluated the diagnostic utility of three shape-specific parameters: the chord intersection ratio, convexity ratio, and maximum concave area ratio for branching classification of glands. METHODS: Seven cases of tubular adenoma were studied. After image analysis, segmented neoplastic glands were classified into nonbranching, mild branching, and moderate branching. Using image analysis formulae for the three shape-specific parameters, we compared the values of the parameters with the branching classification results for colonic tubular adenoma. RESULTS: Multivariate discriminant analysis was used to classify the branching groups. Classification accuracies of nonbranching, mild branching, and moderate branching group based on the three shape-specific parameters were 98, 94, and 95%, respectively. More branching growth exhibited a higher chord intersection ratio and maximum concave area ratio but lower convexity ratio. We found a statistically significant difference in chord intersection ratio, maximum concave area ratio, and convexity ratio between mild, moderate, and nonbranching groups. Among the three features, the chord intersection ratio was the most significant parameter. CONCLUSIONS: Shape-based parameters of chord intersection ratio, convexity ratio, and maximum concave area ratio are valid assessment parameters for irregular branching structures. For the understanding of spatial relationships of histology, the holistic geometric approach using shape-based parameters can be useful.

Osteopontin heptamer peptide containing the RGD motif enhances the phagocytic function of microglia.

Osteopontin (OPN) is a phosphorylated glycoprotein expressed in various tissues, including brain, and mediates a wide range of cellular activities. In our previous studies, we reported recombinant OPN and RGD and SLAY-containing OPN-peptide icosamer (OPNpt20) exhibited robust neuroprotective activities in an animal model of transient focal ischemia, and attributed these effects to the anti-inflammatory, pro-angiogenic, and phagocytic functions of OPNpt20. In the present study, we truncated OPNpt20 to 13 or 7 amino acid peptides containing RGD (R) and/or SLAY (S) motif (OPNpt13RS, OPNpt7R, OPNpt7RS, and OPNpt7S) and their cell motility and migration inducing activities were examined in BV2 cells (a microglia cell line). All four peptides significantly enhanced BV2 cell motility and migration, but OPNpt7R, an RGD-containing 7-amino-acid OPN peptide (VPNGRGD), was found to be most potent and its potency was comparable to OPNpt20. Phagocytic activity and F-actin polymerization were also significantly enhanced in OPNpt7R-treated BV2 cells. Importantly, studies using two mutant peptides (OPNpt7R-RAA and OPNpt7R-RAD, wherein RGD in OPNpt7R was replaced with RAA or RAD, respectively) revealed that all these effects of OPNpt7R, motility, migration, F-actin polymerization, and phagocytosis induction, were RGD-dependent. Furthermore, the Erk, Fak, and Akt signaling pathways appeared to be involved in the induction of phagocytic activity by OPNpt7R. Co-treating cells with OPNpt7R and D98059 or wortmannin (pharmacological inhibitors of Erk and Akt, respectively) significantly suppressed OPNpt7R-mediated phagocytosis induction. These results indicate the RGD-containing OPN heptamer OPNpt7R triggers microglial motility, migration, and phagocytic activity and that the RGD motif plays a critical role in these activities.

Comparative pathologic analysis of mediastinal B-cell lymphomas: selective expression of p63 but no GATA3 optimally differentiates primary mediastinal large B-cell lymphoma from classic Hodgkin lymphoma.

BACKGROUND: Interpretation of mediastinal biopsy is often challenging even for experienced pathologists especially when a hematolymphoid neoplasm is suspected. Primary mediastinal large B-cell lymphoma (PMLBCL) and classic Hodgkin lymphoma (CHL) represent two major types of mature B-cell lymphomas of the mediastinum. Although PMLBCL and mediastinal CHL share many clinicopathologic characteristics, their treatment strategies and responses are remarkably different. We therefore aimed to find distinctive histologic or protein markers to better differentiate these two lesions. METHODS: Search for primary mediastinal B-cell lymphomas found 52 consecutive cases from 3 university hospitals of Korea during 2005 to 2012. Among them, 32 cases that were available for additional immunohistochemistry (IHC) assessment were enrolled in this study. These cases consisted of the following: CHL (N = 13), PMLBCL (N = 16), and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL (gray zone lymphoma, N = 3). Along with the clinicopathologic findings, the expression of p63, GATA3 and cyclin E was investigated by IHC in the three categorized lesions mentioned above. RESULTS: Most clinical features overlapped between PMLBCL and CHL except for the increased disease progression and mortality found in PMLBCL. In the pathologic review, the presence of epithelioid granuloma favored a diagnosis of CHL, whereas reticulated or alveolar patterns of fibrosis were characteristic of PMLBCL. For protein markers, p63 was predominantly positive in PMLBCL (15/16) compared with CHL (2/13), which indicates that p63 is a marker of the highest diagnostic accuracy when calculated by the area under the ROC curve. GATA3 was expressed in the majority of CHL cases (10/13) compared with PMLBCL (0/16), while the expression of cyclin E was only rarely present in a minor population of PMLBCL. CONCLUSIONS: P63 expression in tumor cells, even focal expression, and no GATA3 is the most helpful feature in distinguishing PMLBCL from mediastinal CHL.