IRTA1 positivity helps identify a MALT-lymphoma-like subset of primary cutaneous marginal zone lymphomas, largely but not exclusively defined by IgM expression.

BACKGROUND: It has been proposed that primary cutaneous marginal zone lymphomas (PCMZLs) include a MALT-lymphoma-like IgM+ subset and a class-switched subset, which is unlike most other MALT lymphomas. Whether expression of the MALT lymphoma-associated biomarkers IRTA1 and MNDA would support this concept and whether they might help explain why some patients have both subtypes is uncertain. METHODS: Twenty-five PCMZLs from 21 patients were stained for IRTA1 by in situ hybridization and for MNDA by immunohistochemistry. In two patients, polymerase chain reaction (PCR)-based B-cell clonality studies were performed on biopsy specimens of metachronous lesions, which expressed different heavy chains. All results were correlated with the histopathologic and clinical findings. RESULTS: Five of six IgM+ PCMZLs were IRTA1+ vs three of 18 evaluable class-switched cases (P = 0.0069). Two of the class-switched IRTA1+ cases were in patients with clonally-related IRTA1+ IgM+ PCMZLs. IRTA1 positivity showed a statistically significant correlation with several MALT-lymphoma-associated histopathologic findings. In contrast, all PCMZL cases showed at least some MNDA expression with no differences between IgM+ and class-switched cases. CONCLUSIONS: IRTA1 identifies MALT-lymphoma-like PCMZLs that are largely but not exclusively IgM+. This supports the concept of two PCMZL subsets but suggests their distinction should not be based solely on their heavy chain expression.

Inter-Institutional Partnerships to Develop Veterinarian-Investigators through the NIH Comparative Biomedical Scientist Training Program Benefit One Health Goals.

Limitations in workforce size and access to resources remain perennial challenges to greater progress in academic veterinary medicine and engagement between human and veterinary medicine (One Health). Ongoing resource constraints occur in part due to limited public understanding of the role veterinarians play in improving human health. One Health interactions, particularly through interdisciplinary collaborations in biomedical research, present constructive opportunities to inform resource policies and advance health care. To this end, inter-institutional partnerships between individual veterinary medical education programs (VMEPs) and several National Institutes of Health (NIH) intramural research programs have created synergies beyond those provided by individual programs. In the NIH Comparative Biomedical Scientist Training Program (CBSTP), interdisciplinary cross-training of veterinarians consisting of specialty veterinary medicine coupled with training in human disease research leading to a PhD, occurs collaboratively on both VMEP and NIH campuses. Pre-doctoral veterinary student research opportunities have also been made available. Through the CBSTP, NIH investigators and national biomedical science policy makers gain access to veterinary perspective and expertise, while veterinarians obtain additional opportunities for NIH-funded research training. CBSTP Fellows serve as de facto ambassadors enhancing visibility for the profession while in residence at NIH, and subsequently through a variety of university, industry, and government research appointments, as graduates. Thus, the CBSTP represents an inter-institutional opportunity that not only addresses critical needs for veterinarian-scientists in the biomedical workforce, but also simultaneously exposes national policy makers to veterinarian-scientists' specialized training, leading to more effective realization of One Health goals to benefit human and animal health.

B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis.

The clinical efficacy of B cell targeting therapies highlights the pathogenic potential of B cells in inflammatory diseases. Expression of Fc Receptor like 4 (FcRL4) identifies a memory B cell subset, which is enriched in the joints of patients with rheumatoid arthritis (RA) and in mucosa-associated lymphoid tissue. The high level of RANKL production by this B cell subset indicates a unique pathogenic role. In addition, recent work has identified a role for FcRL4 as an IgA receptor, suggesting a potential function in mucosal immunity. Here, the contribution of FcRL4+ B cells to the specific autoimmune response in the joints of patients with RA was investigated. Single FcRL4+ and FcRL4- B cells were sorted from synovial fluid and tissue from RA patients and their immunoglobulin genes characterized. Levels of hypermutation in the variable regions in both populations were largely consistent with memory B cells selected by an antigen- and T cell-dependent process. Recombinant antibodies were generated based on the IgH and IgL variable region sequences and investigated for antigen specificity. A significantly larger proportion of the recombinant antibodies generated from individual synovial FcRL4+ B cells showed reactivity towards citrullinated autoantigens. Furthermore, both in analyses based on heavy chain sequences and flow cytometric detection, FcRL4+ B cells have significantly increased usage of the IgA isotype. Their low level of expression of immunoglobulin and plasma cell differentiation genes does not suggest current antibody secretion. We conclude that these activated B cells are a component of the local autoimmune response, and through their RANKL expression, can contribute to joint destruction. Furthermore, their expression of FcRL4 and their enrichment in the IgA isotype points towards a potential role for these cells in the link between mucosal and joint inflammation.

Increased rates of intermittent rhythmic delta and theta activity in the electroencephalographies of adult patients with attention-deficit hyperactivity disorder.

INTRODUCTION: Adult attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. In subgroups of patients with a (para)epileptic pathomechanism, this might be due to intermittent rhythmic delta or theta activity (IRDA/IRTA). PARTICIPANTS AND METHODS: Using a fully data-driven analysis, we compared the IRDA/IRTA rates in the resting electroencephalography (EEG) results of 97 adult patients with ADHD and 30 control subjects. The IRDA/IRTA rates before hyperventilation (HV) and for HV difference (difference between IRDA/IRTA rate after and before HV) were compared between groups using a linear model. RESULTS: We detected significantly increased rates of IRDA/IRTA before HV (F=4.209, p=0.042) in patients with ADHD but no significant difference between the groups for HV-difference (F=2.46, p=0.119). DISCUSSION: The increased IRDA/IRTA rates before HV in the group with ADHD might lead to (para)epileptic short-term effects (e.g., impulsivity) via local area network inhibition, and to long-term effects (e.g., cognitive deficits) via connectivistic brain restructuring.

Electroencephalographic findings in schizophreniform and affective disorders.

OBJECTIVE: Pathological findings in electroencephalography (EEG) are discussed as a possible marker of organic mental disorders and a therapeutic response to anticonvulsive medication under these conditions. METHODS: We compared the prevalence of EEG abnormalities in 100 patients with schizophrenia, 100 patients with schizoaffective disorder, 51 patients with acute polymorphic psychotic disorder, 100 patients with bipolar disorder, 100 patients with unipolar major depression and 76 healthy control subjects with the findings of a previous study using well-diagnosed, large control samples (13,658 pilots and aircrew personnel). RESULTS: We detected an increased number of pathological EEG findings with intermittent rhythmic delta or theta activity in 7% of patients with schizophrenia, 7% of patients with schizoaffective disorder, 5.9% of patients with acute polymorphic psychosis, 6% of patients with bipolar disorder, 4% of unipolar depressed patients and 3.9% of the own control group, compared to 1% of strictly controlled healthy subjects. One-sided logistic regression revealed an association between pathological EEGs and the diagnosis of schizophrenia (Wald W = 3.466, p = 0.0315), schizoaffective disorder (W = 3.466, p = 0.0315) and bipolar disorder (W = 2.862, p = 0.0455). CONCLUSIONS: We suggest that the previously developed local area network inhibition model for a potential paraepileptic pathomechanism can explain the relevance of such findings in different psychiatric disorders.

A case of pulmonary primary MALT lymphoma with distinctive bronchoscopic findings.

Mucosa-associated lymphoid tissue (MALT) is a low-grade lymphoma, but cases in which it has transformed into a high-grade lymphoma have been reported, necessitating an accurate diagnosis. The patient was a 79-year-old nonsmoking Japanese female with history of ocular sarcoidosis. A computed tomography scan of her chest revealed a 35-mm nodule in the left S1 + 2, contiguous with the lymph nodes. Additional nodules were observed around the left B5 and B10a. Bronchoscopy revealed stenosis caused by a white, glossy, elevated lesion with angiogenesis at the orifice of the left upper lobe bronchus. The biopsy specimen demonstrated the dominance of lymphoid cells and tested positive for CD20, CD79a, Bcl-2, and IRTA-1, which is consistent with the findings in MALT lymphoma. Therefore, in the presence of multiple infiltrative shadows along the bronchi with glossy elevated lesions without necrosis on bronchoscopy, it is important to consider MALT lymphoma as a differential diagnosis.

Nodal reactive and neoplastic proliferation of monocytoid and marginal zone B cells: an immunoarchitectural and molecular study highlighting the relevance of IRTA1 and T-bet as positive markers.

AIMS: Marginal zone B cells (MZCs) and monocytoid B cells (MBCs) appear to be related lymphoid cells that take part in reactive and neoplastic marginal zone proliferations. These lesions are not yet well characterized, and the aim of this study was to find better diagnostic criteria for them. METHODS AND RESULTS: We analysed 60 nodal lesions with MBC and/or MZC proliferation for their morphological, immunophenotypic, molecular genetic and IG gene rearrangement features. On the basis of the results of the rearrangement assay and immunoglobulin light chain restriction, the lesions were divided into reactive and neoplastic groups. Among the neoplastic lesions, polymorphic and monomorphic subgroups emerged. All reactive lesions had morphological features of the polymorphic subgroup. By immunohistochemistry, IRTA1 and/or T-bet expression was found in all reactive lesions and in 90% of neoplastic lesions. CONCLUSIONS: IRTA1 and T-bet are positive markers for the identification of MZC/MBC proliferations, and thus for the diagnosis of nodal marginal zone lymphoma (NMZL). Polymorphic and monomorphic subgroups of NMZL could be distinguished. Most morphological and immunophenotypic patterns in reactive and neoplastic nodal expansions of MZCs and MBCs overlapped. Therefore, PCR clonality assay of the immunoglobulin heavy and light chain gene loci is the most reliable method for their differentiation.

Immunohistochemistry for IRTA1 and MNDA helps differentiate gastric MALT lymphoma from chronic gastritis/reactive lymphocyte hyperplasia.

It is difficult to histologically differentiate extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) from chronic gastritis (CG)/ reactive lymphoid hyperplasia (RLH). To determine whether immunohistochemistry for IRTA1 and MNDA can differentiate gastric MALT lymphoma from CG/RLH, we investigated 81 stomach biopsy specimens [Wotherspoon grade (WG) 1, 11 cases; WG 2, 9 cases; WG 3, 20 cases; WG 4, 31 cases; and WG 5, 10 cases]. According to a previously reported algorithm involving PCR for immunoglobulin heavy (IgH) chain locus rearrangement, all 81 cases were divided into three groups: CG/RLH (55 cases), MALT lymphoma (19 cases) groups, and IgH undetectable group (7 cases). We analyzed the CG/RLH and MALT lymphoma groups. The median percentage of IRTA1-positive cells was 0% (range 0%-90.6%) in the CG/RLH group and 43.5% (range 0%-97.6%) in the MALT lymphoma group (p < 0.0001). The median percentage of MNDA-positive cells was 32.4% (range 0%-97.6%) in the CG/RLH group and 55.1% (range 0%-97.6%) in the MALT lymphoma group (p = 0.0044). These results indicate that immunohistochemistry for IRTA1 and MNDA can help differentiate gastric MALT lymphoma from CG/RLH.

Relevance of Additional Immunohistochemical Markers in the Differential Diagnosis of Small B-Cell Lymphomas: A Case-Control Study

Objective: Clinical and pathological differential diagnosis of small B-cell lymphomas (SBCLs) is still controversial and may be difficult due to their overlapping morphology, phenotype, and differentiation to plasma cells. We aimed to examine the expression of the immune receptor translocation-associated protein 1 (IRTA1), myeloid cell nuclear differentiation antigen (MNDA), lymphoid enhancer-binding factor-1 (LEF1), and stathmin 1 (STMN1) markers in SBCL cases involving different sites that may have plasma cell differentiation. Materials and Methods: We studied 154 tissue samples with lymphoma involvement from 116 patients and evaluated the staining distribution of the markers. Expressions were evaluated in 21 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 7 follicular lymphoma (FL), 14 nodal marginal zone lymphoma, 17 extranodal marginal zone lymphoma, 55 splenic marginal zone lymphoma, 22 marginal zone lymphoma-not otherwise specified, and 18 lymphoplasmacytic lymphoma/Waldenström macroglobulinemia cases by immunohistochemistry. Results: The results confirmed that LEF1 was the most sensitive and specific marker for CLL/SLL and STMN1 was the most sensitive and specific marker for FL (p<0.001). MNDA and IRTA1 were useful markers to distinguish marginal zone lymphomas. Conclusion: Our results suggest that LEF1 for CLL/SLL and STMN1 for FL are reliable markers. LEF1, MNDA, STMN1, and IRTA1 are helpful with other routinely used immunohistochemical markers in a diagnostic algorithm considering their limitations.

Dissecting druggability of ABC transporter proteins in Mycobacterium species through network modeling.

Mycobacterium tuberculosis (Mtb) is an infectious disease that affects nearly 9.6 million people every year. Metals are important determinants of growth and pathogenicity of mycobacterium. In the present study, we have analyzed protein-protein interaction networks belonging to the iron, sulfur and molybdenum metabolism of Mycobacterium. Our analysis has identified some of the important target proteins one among them being irtA. Iron taken up by siderophores from the host is transported to irtA through which iron enters Mycobacterium. Thus, irtA plays a major role as an iron transporter in Mycobacterium. As irtA protein structure was not solved experimentally, we have predicted 3D structure of irtA. After successful model evaluation, we have identified thiosemicarbazones as possible drug candidates for irtA. Henceforth, we have designed five analogues of thiosemicarbazones and tested in silico for their efficacy against irtA using molecular docking, among them analogue 1 showed a very good efficacy.Communicated by Ramaswamy H. Sarma.

Immunoglobulin characteristics and RNAseq data of FcRL4+ B cells sorted from synovial fluid and tissue of patients with rheumatoid arthritis.

This manuscript is a companion paper to Amara et al. [1]. Data shown here include detailed clinical characteristics from anonymized patients, the Ig subclass data generated from B cells sorted from four individual patients, tables detailing variable gene region sequences from sorted cells linked to the patient information and the sequence yields from individual patients. Furthermore a URL link to the RNAseq datasets submitted to GEO is included.

Immunohistochemical analysis of the novel marginal zone B-cell marker IRTA1 in malignant lymphoma.

Marginal zone lymphoma (MZL) is a low-grade B-cell lymphoma derived from marginal zone B cells. Because of a lack of specific immunohistochemical markers, MZL is mainly diagnosed based on the cytological appearance and growth pattern of the tumor. Marginal zone B cells were recently shown to selectively express immunoglobulin superfamily receptor translocation-associated 1 (IRTA1), but the antibody used in that study is not commercially available. We therefore investigated the IRTA1 expression in nonneoplastic lymphoid tissues and 261 malignant lymphomas, examining the ability of a commercially available antibody to accurately diagnose MZL. Among 37 MZLs, 23 of 25 extranodal MZLs of mucosa-associated lymphoid tissue (MALT lymphomas), 3 of 6 splenic MZLs and 3 of 6 nodal MZLs were positive for IRTA1. Among the 98 diffuse large B-cell lymphomas, 33 were positive for IRTA1, including 1 of 38 follicular lymphomas, and all precursor B-lymphoblastic (2/2) and T-lymphoblastic (7/7) leukemia/lymphomas. Other mature B-cell and T-cell lymphomas, and Hodgkin lymphoma were negative for IRTA1. In MALT lymphoma, positive cells were detected mainly in intraepithelial and subepithelial marginal zone B cells. In 1 case of grade 3 follicular lymphoma, IRTA1 was also expressed in the area of large cell transformation. When tumors were classified as germinal center B cell-like (GCB) or non-GCB using the algorithm of Hans, positive expression of IRTA1 was correlated significantly with non-GCB diffuse large B-cell lymphomas (P < .05). These results demonstrated the ability of the commercially available IRTA1 antibody to distinguish MALT lymphoma from other low-grade B-cell lymphomas.

Increased Prevalence of Intermittent Rhythmic Delta or Theta Activity (IRDA/IRTA) in the Electroencephalograms (EEGs) of Patients with Borderline Personality Disorder.

INTRODUCTION: An increased prevalence of pathological electroencephalography (EEG) signals has been reported in patients with borderline personality disorder (BPD). In an elaborative case description of such a patient with intermittent rhythmic delta and theta activity (IRDA/IRTA), the BPD symptoms where linked to the frequency of the IRDAs/IRTAs and vanished with the IRDAs/IRTAs following anticonvulsive therapy. This observation raised a question regarding the prevalence of such EEG abnormalities in BPD patients. The aim of this retrospective study was to identify the frequency of EEG abnormalities in a carefully analyzed psychiatric collective. Following earlier reports, we hypothesized an increased prevalence of EEG abnormalities in BPD patients. PARTICIPANTS AND METHODS: We recruited 96 consecutive patients with BPD from the archive of a university clinic for psychiatry and psychotherapy, and compared the prevalence of EEG abnormalities to those of 76 healthy controls subjects. The EEGs were rated by three different blinded clinicians, including a consultant specializing in epilepsy from the local epilepsy center. RESULTS: We found a significant increase in the prevalence of IRDAs and IRTAs in BPD patients (14.6%) compared to the control subjects (3.9%; p = 0.020). DISCUSSION: In this blinded retrospective case-control study, we were able to confirm an increased prevalence of pathological EEG findings (IRDAs/IRTAs only) in BPD patients. The major limitation of this study is that the control group was not matched on age and gender. Therefore, the results should be regarded as preliminary findings of an open uncontrolled, retrospective study. Future research performing prospective, controlled studies is needed to verify our findings and answer the question of whether such EEG findings might predict a positive response to anticonvulsive pharmacological treatment.

Research jobs for recent college graduates: A comparison between traditional lab technician positions and NIH's postbaccalaureate IRTA fellowship.

The features that distinguish the Postbaccalaureate IRTA experience from a normal lab tech job are the enhanced educational opportunities, greater independence, more organized social outlets and networking opportunities, life in the DC Metro area, and the NIH itself. Also, research experience looks great on a CV when applying for research jobs or graduate schools, and the NIH name and Postbaccalaureate IRTA fellowship are impressive to potential employers and admissions committees. On the other hand, lab tech jobs often require fewer commitments outside of a normal 9-to-5 work day and usually have better pay and benefits than the Postbaccalaureate IRTA fellowship. In addition, working at a specific university often carries the benefit of being closer to one's family, friends, and/or significant others. Someone who does not like cities can choose to work at a university that has ready access to the beach, mountains, or regions of the country that are more personally appealing than the Washington, DC, area. Lab tech jobs also usually require at least a two year commitment, whereas the Postbac IRTA fellowship is generally a one year commitment (possibly two). Regardless of which option you choose, you should be active in searching for a job that lets you fulfill the goals you set for yourself in the years between graduating and starting graduate or medical school. Whether those goals are to publish, get experience, save money, or just enjoy yourself, with careful questioning and circumspection, you should be able to maximize the possibility that you will meet your goals.