Ileocaecal TB with multiple hepatic granuloma mimicking malignancy with metastasis to liver

Introduction: Abdominal tuberculosis is a rare manifestation of  tuberculosis1. It can involve any part of the gastrointestinal tract but the most likely sites of infection are the peritoneum and the ileo-caecal region. We present unusual a case of Ileocaecal TB with multiple hepatic  granuloma mimicking malignancy with metastasis to liver.Case presentation: A 38 years old male, Sudanese, had two months history of painful tender mass in the right iliac fossa that was associated with low grade fever, constipation and loss of appetite. He had no symptoms or signs related to other systems and he denied any contact with chronic cough patient. ESR 100mm/hr, normal CXR, ultrasound revealed multiple hypoechoic liver focal lesions, multiple para-aortic Lymph node and a thick wall terminal ilium. CT abdomen showed bowel segment with wall thickening and irregular lumen in the right iliac fossa, enlarge para-aortic lymph nodes and multiple hepatic focal lesions which gave the impression of caecal carcinoma with liver metastasis. OGD was reported as normal. Colonoscopy revealed an abnormal mucosa at the caecum, suspicious of carcinoma caecum. Multiple biopsies were taken.  Histopathology revealed epithelioid granulomas with Langhans giant cells as well as areas of mild cryptitis, could be either tuberculosis or Crohns disease, Ultrasound guided liver biopsy from the focal lesions revealedepithelioid cells and poorly formed granulomas with areas of caseation and fibrosis suggestive of tuberculosis. PCR for aspirate from liver focal lesion biopsy was positive for tuberculosis. The patient was treated with  antituberculous chemotherapy. Complete cure was obtained during followup.Keywords: Abdominal tuberculosis, Ileocaecal tuberculosis hepatic granuloma

Targeted Oral Delivery of Paclitaxel Using Colostrum-Derived Exosomes

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, including lung. While efficacious, PAC generally is not well tolerated and its limitations include low aqueous solubility, and significant toxicity. To overcome the dose-related toxicity of solvent-based PAC, we utilized bovine colostrum-derived exosomes as a delivery vehicle for PAC for the treatment of lung cancer. Colostrum provided higher yield of exosomes and could be loaded with higher amount of PAC compared to mature milk. Exosomal formulation of PAC (ExoPAC) showed higher antiproliferative activity and inhibition of colony formation against A549 cells compared with PAC alone, and also showed antiproliferative activity against a drug-resistant variant of A549. To further enhance its efficacy, exosomes were attached with a tumor-targeting ligand, folic acid (FA). FA-ExoPAC given orally showed significant inhibition (\u3e50%) of subcutaneous tumor xenograft while similar doses of PAC showed insignificant inhibition. In the orthotopic lung cancer model, oral dosing of FA-ExoPAC achieved greater efficacy (55% growth inhibition) than traditional i.v. PAC (24–32% growth inhibition) and similar efficacy as i.v. Abraxane (59% growth inhibition). The FA-ExoPAC given i.v. exceeded the therapeutic efficacy of Abraxane (76% growth inhibition). Finally, wild-type animals treated with p.o. ExoPAC did not show gross, systemic or immunotoxicity. Solvent-based PAC caused immunotoxicity which was either reduced or completely mitigated by its exosomal formulations. These studies show that a tumor-targeted oral formulation of PAC (FA-ExoPAC) significantly improved the overall efficacy and safety profile while providing a user-friendly, cost-effective alternative to bolus i.v. PAC and i.v. Abraxane

Extracellular Vesicle-Mediated Macrophage Activation: An Insight Into the Mechanism of Thioredoxin-Mediated Immune Activation

Extracellular vesicles (EVs) generated from redox active anticancer drugs are released into the extracellular environment. These EVs contain oxidized molecules and trigger inflammatory responses by macrophages. Using a mouse model of doxorubicin (DOX)-induced tissue injury, we previously found that the major sources of circulating EVs are from heart and liver, organs that are differentially affected by DOX. Here, we investigated the effects of EVs from cardiomyocytes and those from hepatocytes on macrophage activation. EVs from H9c2 rat cardiomyocytes (H9c2 EVs) and EVs from FL83b mouse hepatocytes (FL83 b EVs) have different levels of protein-bound 4-hydroxynonenal and thus different immunostimulatory effects on mouse RAW264.7 macrophages. H9c2 EVs but not FL83 b EVs induced both pro-inflammatory and anti-inflammatory macrophage activation, mediated by NFκB and Nrf-2 pathways, respectively. DOX enhanced the effects of H9c2 EVs but not FL83 b EVs. While EVs from DOX-treated H9c2 cells (H9c2 DOXEVs) suppressed mitochondrial respiration and increased glycolysis of macrophages, EVs from DOX-treated FL83b cells (FL83b DOXEVs) enhanced mitochondrial reserve capacity. Mechanistically, the different immunostimulatory functions of H9c2 EVs and FL83 b EVs are regulated, in part, by the redox status of the cytoplasmic thioredoxin 1 (Trx1) of macrophages. H9c2 DOXEVs lowered the level of reduced Trx1 in cytoplasm while FL83b DOXEVs did the opposite. Trx1 overexpression alleviated the effect of H9c2 DOXEVs on NFκB and Nrf-2 activation and prevented the upregulation of their target genes. Our findings identify EVs as a novel Trx1-mediated redox mediator of immune response, which greatly enhances our understanding of innate immune responses during cancer therapy

Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-Cell Chronic Lymphocytic Leukemia

Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors

Oxidative Stress-Induced JNK/AP-1 Signaling is a Major Pathway Involved in Selective Apoptosis of Myelodysplastic Syndrome Cells by Withaferin-A

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS

Radiation Induced Apoptosis of Murine Bone Marrow Cells is Independent of Early Growth Response 1 (EGR1)

An understanding of how each individual 5q chromosome critical deleted region (CDR) gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs). Early Growth Response 1 (EGR1) is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell) quiescence as well as the master regulator of apoptosis—p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise. We evaluated radiation induced apoptosis of Egr1+/+ and Egr1-/- bone marrow cells in vitro and in vivo. EGR1 is not required for radiation induced apoptosis of murine bone marrow cells. Neither p53 mRNA (messenger RNA) nor protein expression is regulated by EGR1 in these cells. Radiation induced apoptosis of bone marrow cells by double strand DNA breaks induced p53 activation. These results suggest EGR1 dependent signaling mechanisms do not contribute to aberrant apoptosis of malignant cells in myeloid malignancies

Experimental and Monte Carlo verification of Acuros XB calculations near low and high density heterogeneities

The purpose of this study was to examine the accuracy of AcurosXB and AAA algorithms near low and high density heterogeneities of different densities using EBT2 film, MOSFET detector “MOSkin” and Monte Carlo calculations using BEAMnrc/DOSXYZnrc. Three different interfaces were used that included a solid water phantom with 2x2x30cm3 rectangular air gap, rectangular steel insert, and a slab of water embedded between two slabs of lung material. 6MV photon beam with field size of 10x10cm2 was used for the first two geometries and a 3x3cm2-field was used for the third. Percentage Depth Doses were measured and calculated at the beam central axis. Calculation voxel of 0.1x0.1x0.1cm3 was used by all three algorithms. For all configurations, AcurosXB and AAA agreed to within ±1.3% with MC before the inhomogeneity. The PDD measurements using MOSkin and EBT2 in water, apart from 0.2cm layer near heterogeneity, agreed with the MC within ±2.2%. Within 0.1cm before the water-air interface AcurosXB and AAA overestimated the dose by 4.7% and 1.6%, respectively. Whereas, in the 0.1cm beyond the air-water interface, AcurosXB and AAA overestimated the dose by 2.4% and 16.2% respectively. In the 0.1cm before the water-steel interface, AcurosXB overestimated the dose by 4.7% and AAA underestimated the dose by 9.5%; beyond the steel-water interface AcurosXB and AAA overestimated the dose by 3.6% and 7.7% respectively. For the lung phantom configuration, AcurosXB and AAA were in agreement with MC within 2% throughout the phantom. These results demonstrate improved performance of AcurosXB as compared to AAA in considered conditions

Validation of Poststack Seismic Inversion using Rock Physics Analysis and 3D Seismic and Well Correlation

Inversion of poststack seismic data is validated with rock physics analysis from the well data. The acoustic impedance is computed throughout the well-seismic-tie and synthetic seismogram generation. Seismic attributes, including velocities and results of inversion, are generated to study the potential prospect in the Maui Field, Taranaki Basin, New Zealand. Seismic interpretation generated structure and amplitude horizon slices as well as the recursive algorithmic attribute are applied to invert the seismic traces to provide quantitative predictions on the reservoir properties. Stratigraphic evaluation is obtained from the interpretation. After evaluating the petrophysical parameters from well logs, the poststack inversion of the seismic data is validated. The results are reliable for future use in an artificial neural network

Characteristics of influenza patients and risk factors for death: retrospective analysis of sentinel surveillance data, Saudi Arabia, 2017

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