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Thrombotic thrombocytopenic purpura may be seen with several autoimmune disorders such as immune thrombocytopenia purpura, immune hemolytic anemia, and systemic lupus erythematosus, but it is rarely associated with Graves’ disease. We report a patient with thrombotic thrombocytopenic purpura associated with Graves’ disease.

Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Revision of the World Health Organization Classification. This indolent entity, which is frequently discovered incidentally, is currently classified under the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), an aggressive lymphoma with poor survival. Several authors have proposed that it be classified separately since, in contrast to DLBCL-CI, transformation to aggressive lymphoma has rarely been reported and this entity has distinct clinical and histological features. We describe a rare case of a 62-year-old male with FA-DLBCL associated with atrial myxoma, which was incidentally discovered. In contrast to typically described immunophenotypic features of this entity, that is, activated B-cell phenotype (ABC) and Epstein-Barr virus (EBV) positivity, our case showed germinal center B-cell (GCB) phenotype and was EBV negative. Clinical staging revealed no evidence of lymphoma elsewhere in the body, and the patient did not receive adjuvant chemotherapy after surgical excision and remains in remission. This case illustrates that occasionally FA-DLBCL can show GCB phenotype, as opposed to the typical ABC phenotype. Moreover, we propose that the definition of the entity be expanded to include EBV-negative cases.

Extramedullary hematopoiesis (EMH) is a well-known phenomenon occurring during fetal development. In the postfetal condition, EMH is commonly associated with hematologic conditions including chronic myeloproliferative or lymphoproliferative disorders, leukemias, and chronic and inherited anemias. We report an unusual location for EMH that masqueraded as a cranial tumor.

Magnetic resonance imaging (MRI) has specific limitations in theater and has unique requirements for its safe use with patients which require additional technician training and strict adherence to MRI-specific safety protocols. Neuroimaging is recommended for the evaluation of service members with clinical red flags new onset or persistent or worsening symptoms, and individuals whose recovery is not progressing as anticipated. This article is a brief discussion of when MRI is appropriate.

Lymphangioleiomyomatosis (LAM) is a rare cystic pulmonary disease that may occur in association with mutations in the tuberous sclerosis genes or arise sporadically. The histologic hallmark of the disease is the "LAM" cell, a spindled to epithelioid smooth muscle-like cell that bears morphologic and immunohistochemical resemblance to the perivascular epithelioid cell tumors (PEComas). The origin of the "LAM" cell is unknown; emerging theories suggest that a member of the PEComa family, the renal angiomyolipoma, may be the primary source and that both LAM and angiomyolipomas are associated with the genetic syndrome tuberous sclerosis. We present a young woman with LAM with an aggressive renal angiomyolipoma confirmed at autopsy.

Background Epithelial‐to‐mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor‐β (TGF‐β), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR‐TKI responsiveness in NSCLC. Methods The protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR‐TKI treatment. The correlation between APE1 expression and progression‐free survival (PFS), overall survival (OS), or response rate were analyzed. The impact of APE1 on the response to EGFR‐TKIs was measured by exogenous manipulation of APE1 in EGFR‐TKI‐sensitive and EGFR‐TKI‐resistant cells. Results We indicate that low expression of APE1 in tumors is associated with a significantly longer PFS (20.8 months vs 8.4 months, P = 0.008) and a preferential OS (39.0 months vs 17.0 months, P = 0.001), with no difference in initial response rate to EGFR‐TKIs. We observed that APE1 protein level was significantly increased in EGFR‐TKI‐resistant cells and was associated with downregulated E‐cadherin and upregulated vimentin. The EMT phenotype, as well as the levels of TGF‐β, was suppressed in APE1 knockdown HCC827/IR and PC‐9/ER cells, while the EMT phenotype was promoted in APE1‐overexpressed HCC827 and PC‐9 cells. Furthermore, a specific APE1 redox inhibitor (ie, E3330) effectively reversed the EMT phenotype and further sensitized the cells to EGFR‐TKIs. Conclusion This study revealed a significant role of APE1 in EGFR‐TKI resistance via novel regulatory effects on the EMT phenotype in NSCLC.

// Shiheng Zhang 1, * , Le He 1, * , Nan Dai 1 , Wei Guan 1 , Jinlu Shan 1 , Xueqin Yang 1 , Zhaoyang Zhong 1 , Yi Qing 1 , Feng Jin 1 , Chuan Chen 1 , Yuxin Yang 1 , Hongyi Wang 4 , Laura Baugh 4 , Gianluca Tell 2 , David M. Wilson III 3 , Mengxia Li 1 , Dong Wang 1 1 Cancer Center of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China 2 Laboratory of Molecular Biology and DNA repair, Department of Medical and Biological Sciences, University of Udine, Udine 33100, Italy 3 Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA 4 Department of Pathology, Baylor University Medical Center, Dallas, TX 75246, USA 5 Tianjin HUABOTE Biotechnological Inc., Tianjin 300350, China * These authors contributed equally to this work Correspondence to: Mengxia Li, email: mengxia.li@outlook.com Dong Wang, email: dongwang64@hotmail.com Keywords: APE1, NSCLC, chemotherapy, biomarker Received: March 17, 2016 Accepted: October 14, 2016 Published: November 02, 2016 ABSTRACT Purpose: To define the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in predicting the prognosis and chemotherapeutic response of non-small cell lung cancer patients receiving platinum-containing chemotherapy. Results: Our investigations found that serum APE1 level was significantly elevated in 229 of 412 NSCLC patients and correlated with its level in tissue ( r 2 = 0.639, p < 0.001). The elevated APE1 level in both tissue and serum of patients prior to chemotherapy was associated with worse progression-free survival (HR: 2.165, p < 0.001, HR: 1.421, p = 0.012), but not with overall survival. After 6 cycles of chemotherapy, a low APE1 serum level was associated with better overall survival (HR: 0.497, p = 0.010). Experimental Design: We measured APE1 protein levels in biopsy tissue from 172 NSCLC patients and sera of 412 NSCLC patients receiving platinum-based chemotherapy by immunohistochemistry and a newly established sensitive and specific enzyme-linked immunosorbent assay, respectively. APE1 levels in sera of 523 healthy donors were also determined as control. Conclusions: Our studies indicate that APE1 is a biomarker for predicting prognosis and therapeutic efficacy in NSCLC. The chemotherapy-naive serum APE1 level, which correlated with its tissue level inversely associated with progression-free survival of platinum-containing doublet chemotherapy, whereas post-treatment serum APE1 level was inversely associated with overall survival.

In this single-center, double-blind, randomized, sham-controlled, prospective trial at the U.S. Air Force School of Aerospace Medicine, the effects of 2.4 atmospheres absolute (ATA) hyperbaric oxygen (HBO₂) on post-concussion symptoms in 50 military service members with at least one combat-related, mild traumatic brain injury were examined. Each subject received 30 sessions of either a sham compression (room air at 1.3 ATA) or HBO₂ treatments at 2.4 ATA over an 8-week period. Individual and total symptoms scores on Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT®) and composite scores on Post-traumatic Disorder Check List-Military Version (PCL-M) were measured just prior to intervention and 6 weeks after completion of intervention. Difference testing of post-intervention means between the sham-control and HBO₂ group revealed no significant differences on the PCL-M composite score (t=-0.205, p=0.84) or on the ImPACT total score (t=-0.943, p=0.35), demonstrating no significant effect for HBO₂ at 2.4 ATA. PCL-M composite scores and ImPACT total scores for sham-control and HBO(2) groups revealed significant improvement over the course of the study for both the sham-control group (t=3.76, p=0.001) and the HBO₂ group (t=3.90, p=0.001), demonstrating no significant HBO₂ effect. Paired t-test results revealed 10 ImPACT scale scores in the sham-control group improved from pre- to post-testing, whereas two scale scores significantly improved in the HBO₂ group. One PCL-M measure improved from pre- to post-testing in both groups. This study showed that HBO₂ at 2.4 ATA pressure had no effect on post-concussive symptoms after mild TBI.

Traumatic brain injury (TBI) has been not only a major focus of concern during the recent conflicts in Afghanistan and Iraq, but also among our garrison service members. The prevalence of these injuries has compelled the nation and Congress to invest in the development of policies and programs that support evidence-based care for the full continuum of TBI, from mild (otherwise known as concussion) to severe and penetrating brain injuries. Although, the Department of Defense has made great strides in the areas of TBI clinical care, education, and research, there remains a great need to leverage scientific, policy, and clinical advancement to maximize care of the service member. The purpose of this article is to outline the 7 major areas of work currently being undertaken to help advance the field of TBI. The 7 areas include: (1) eliminating undetected mild traumatic brain injury through prompt early diagnosis, (2) ensuring force readiness and addressing cultural barriers, (3) improving collaborations with the Department of Veterans Affairs, other federal agencies, and academic and civilian organizations, (4) improving deployment-related assessments, (5) deploying effective treatments, (6) conducting military-relevant and targeted research, and (7) enhancing information technology systems.

A 56-year-old Texas rancher with a prior diagnosis of acquired erythropoietic protoporphyria secondary to an underlying myelodysplastic disorder developed an uncommon tumor, blastic plasmacytoid dendritic cell neoplasm (BPDCN). During his initial disease, analysis revealed a TET2 mutation, which is the most common mutation associated with BPDCN. This article discusses this unusual hematopoietic neoplasm, the possible evolution from erythropoietic protoporphyria, and the underlying myelodysplastic process.

Dually targeted mitochondrial proteins usually possess an unconventional mitochondrial targeting sequence (MTS), which makes them difficult to predict by current bioinformatics approaches. Human apurinic/apyrimidinic endonuclease (APE1) plays a central role in the cellular response to oxidative stress. It is a dually targeted protein preferentially residing in the nucleus with conditional distribution in the mitochondria. However, the mitochondrial translocation mechanism of APE1 is not well characterized because it harbors an unconventional MTS that is difficult to predict by bioinformatics analysis. Two experimental approaches were combined in this study to identify the MTS of APE1. First, the interactions between the peptides from APE1 and the three purified translocase receptors of the outer mitochondrial membrane (Tom) were evaluated using a peptide array screen. Consequently, the intracellular distribution of green fluorescent protein-tagged, truncated, or mutated APE1 proteins was traced by tag detection. The results demonstrated that the only MTS of APE1 is harbored within residues 289–318 in the C terminus, which is normally masked by the intact N-terminal structure. As a dually targeted mitochondrial protein, APE1 possesses a special distribution pattern of different subcellular targeting signals, the identification of which sheds light on future prediction of MTSs.

Neurocardiogenic syncope is not an uncommon occurrence in the general population and affects people across a wide range of age groups. Several sub-specialties are involved in the management of this phenomenon and quite often a multidisciplinary approach is needed for arriving at the final diagnosis and deciding on the optimal treatment for this condition. Often, a thorough history and physical examination will aid in narrowing the differential of syncope and, in the right setting, both passive and provocative testing can be complementary. Neurocardiogenic syncope with a malignant course is a serious entity and usually needs prompt identification of its underlying etiology. It has been generally attributed to a severe cardioinhibitory or vasodepressor mechanism and most cases required tailored therapy. We describe a case which has many of the elements described above - a multidisciplinary approach, malignant neurocardiogenic syncope with profound asystole from a cardioinhibitory response, simplistic bed-side provocative testing, and tailored therapy.