Publications by authors named "Kiyoko Oshima"

61 Publications

Liver pathology in pregnancy.

Pathol Int 2021 Nov 24. Epub 2021 Nov 24.

Department of Pathology, Division of Gastrointestinal/Liver Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Liver dysfunction occurs in up to 3% of pregnancies and can be due to pregnancy-associated liver injury, exacerbation of pre-existing liver disease, or co-incident with pregnancy. The most common form of pregnancy-associated liver injury is intrahepatic cholestasis of pregnancy (ICP). This condition is typically benign and self-limited, but is associated with fetal morbidity and mortality with high levels of serum bile acids. Acute fatty liver of pregnancy (AFLP) and the hypertensive disorders of pregnancy (including pre-eclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome) are more commonly associated with maternal and fetal complications and may necessitate expedient delivery. Histologically, ICP shows nonspecific features of cholestasis, while AFLP and the hypertensive disorders have more characteristic histologic findings. While not a true liver disease, hyperemesis gravidarum can cause elevated liver enzymes. Pregnant patients are at increased risk of developing severe hepatitis E and herpesvirus infections, Budd-Chiari syndrome, and gallstones, and they may also experience worsening of known chronic liver disease. Mass lesions in pregnancy including hemangiomas, focal nodular hyperplasia, and hepatocellular adenomas and carcinomas can present unique challenges for diagnosis and management. This review will explore the pathophysiology, presentation, histologic features, and management of these conditions.
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http://dx.doi.org/10.1111/pin.13186DOI Listing
November 2021

Black raspberries attenuate colonic adenoma development in mice: Relationship to hypomethylation of promoters and gene bodies.

Food Front 2020 Sep 9;1(3):234-242. Epub 2020 Sep 9.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Recent studies have suggested that in addition to promoter region, DNA methylation in intragenic and intergenic regions also changes during physiological processes and disease. The current study showed that feeding of black raspberries (BRBs) to mice suppressed colon and intestinal tumors. MBDCap-seq suggested that dietary BRBs hypomethylated promoter, intragenic, and intergenic regions. Annotation of those regions highlighted genes in pathways involved in immune regulation, inflammatory signaling, production of nitric oxide and reactive oxygen species, and progression of colorectal cancer. BRB phytochemicals (e.g., ellagic acid, anthocyanins, oligosaccharides) and their gut bacterial metabolites (e.g., urolithin, protocatechuic acid, short-chain fatty acids) inhibited DNMT1 and DNMT3B activities in a cell-free assay. Our results suggest that BRBs' hypomethylating activities result from the combined effects of multiple BRB phytochemicals and their gut bacterial metabolites. Because similar substances are found in many plant products, our results with BRBs might also apply to commonly consumed fruits and vegetables.
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http://dx.doi.org/10.1002/fft2.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457619PMC
September 2020

Effects of Dietary Interventions on Gut Microbiota in Humans and the Possible Impacts of Foods on Patients' Responses to Cancer Immunotherapy.

eFood 2020 Aug 27;1(4):279-287. Epub 2020 Aug 27.

Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou, China.

The gut microbiota-the community of microorganisms in the gut-has been implicated in many physical and mental disorders in addition to intestinal diseases. Diets are the most studied and promising factors for altering it. Indeed, certain dietary interventions that increase fiber intake rapidly change levels of certain nutrients that can modify the composition of the microbiota, promoting richness and diversity. Recent intriguing evidence from several human clinical trials suggested that the composition and diversity of patients' gut microbiotas at baseline can influence their responses to cancer immunotherapy. If the factors that influence the gut microbiota were fully understood, it is conceivable that manipulating them could boost therapeutic responses in cancer patients. In this review, we investigate the possibility of using fruits, vegetables, or whole grains to enhance response to cancer therapies in humans, as current evidence suggests that these dietary components can manipulate and enhance diversity of the gut microbiota. Accordingly, dietary interventions with locally available fruits, vegetables, and whole grains might be an affordable and safe approach to enhancing the diversity of the gut microbiota before immunotherapy, in turn improving patients' responses to their treatments.
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http://dx.doi.org/10.2991/efood.k.200824.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301224PMC
August 2020

Transplanting fecal material from wild-type mice fed black raspberries alters the immune system of recipient mice.

Food Front 2020 Sep 5;1(3):253-259. Epub 2020 Aug 5.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Wauwatosa, Wisconsin.

By constantly stimulating intestinal immunity, gut microbes play important regulatory roles, and their possible involvement in human physical and mental disorders beyond intestinal diseases suggests the importance of maintaining homeostasis in the gut microbiota. Both transplantation of fecal microbiota and dietary interventions have been shown to restore microbial homeostasis in recipients. In the current study with wild-type mice, we combined these two approaches to determine if transplanting fecal material from mice fed black raspberries (BRB, 5%) altered recipients' immune system. The donors received a control or 5% BRB diet, and fecal transplantation was performed every other day 15 times into recipients fed control diet. Afterward, we used flow cytometry to analyze populations of CD3 T, CD4 T, CD8 T cells, and NK cells among bone marrow cells, splenocytes, and peripheral blood mononuclear cells (PBMCs) collected from the recipients. We found that BRB-fecal material that contained both fecal microbiota and their metabolites increased NK cell populations among bone marrow cells, splenocytes, and PBMCs, and raised levels of CD8 T cells in splenocytes. Our findings suggest that fecal transplantation can modulate the immune system and might therefore be valuable for managing a range of physical and mental disorders.
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http://dx.doi.org/10.1002/fft2.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301209PMC
September 2020

Drug-induced liver injury from elexacaftor/ivacaftor/tezacaftor.

J Cyst Fibros 2021 Jul 16. Epub 2021 Jul 16.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jcf.2021.07.001DOI Listing
July 2021

Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma.

JCI Insight 2021 06 22;6(12). Epub 2021 Jun 22.

Division of Gastroenterology and Hepatology and.

Hepatocellular carcinoma (HCC) is the sixth most common and the fourth most deadly cancer worldwide. The development cost of new therapeutics is a major limitation in patient outcomes. Importantly, there is a paucity of preclinical HCC models in which to test new small molecules. Herein, we implemented potentially novel patient-derived organoid (PDO) and patient-derived xenografts (PDX) strategies for high-throughput drug screening. Omacetaxine, an FDA-approved drug for chronic myelogenous leukemia (CML), was found to be a top effective small molecule in HCC PDOs. Next, omacetaxine was tested against a larger cohort of 40 human HCC PDOs. Serial dilution experiments demonstrated that omacetaxine is effective at low (nanomolar) concentrations. Mechanistic studies established that omacetaxine inhibits global protein synthesis, with a disproportionate effect on short-half-life proteins. High-throughput expression screening identified molecular targets for omacetaxine, including key oncogenes, such as PLK1. In conclusion, by using an innovative strategy, we report - for the first time to our knowledge - the effectiveness of omacetaxine in HCC. In addition, we elucidate key mechanisms of omacetaxine action. Finally, we provide a proof-of-principle basis for future studies applying drug screening PDOs sequenced with candidate validation in PDX models. Clinical trials could be considered to evaluate omacetaxine in patients with HCC.
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http://dx.doi.org/10.1172/jci.insight.138197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262474PMC
June 2021

A Novel NIPBL-NACC1 Gene Fusion Is Characteristic of the Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma.

Am J Surg Pathol 2021 11;45(11):1550-1560

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.

We report a novel NIPBL-NACC1 gene fusion in a rare primary hepatic neoplasm previously described as the "cholangioblastic variant of intrahepatic cholangiocarcinoma." The 2 index cases were identified within our consultation files as morphologically distinctive primary hepatic neoplasms in a 24-year-old female and a 54-year-old male. The neoplasms each demonstrated varied architecture, including trabecular, organoid, microcystic/follicular, and infiltrative glandular patterns, and biphasic cytology with large, polygonal eosinophilic cells and smaller basophilic cells. The neoplasms had a distinctive immunoprofile characterized by diffuse labeling for inhibin, and patchy labeling for neuroendocrine markers (chromogranin and synaptophysin) and biliary marker cytokeratin 19. RNA sequencing of both cases demonstrated an identical fusion of NIBPL exon 8 to NACC1 exon 2, which was further confirmed by break-apart fluorescence in situ hybridization assay for each gene. Review of a tissue microarray including 123 cases originally diagnosed as well-differentiated neuroendocrine neoplasm at one of our hospitals resulted in identification of a third case with similar morphology and immunophenotype in a 52-year-old male, and break-apart fluorescence in situ hybridization probes confirmed rearrangement of both NIPBL and NACC1. Review of The Cancer Genome Atlas (TCGA) sequencing data and digital images from 36 intrahepatic cholangiocarcinomas (www.cbioportal.org) revealed one additional case with the same gene fusion and the same characteristic solid, trabecular, and follicular/microcystic architectures and biphasic cytology as seen in our genetically confirmed cases. The NIPBL-NACC1 fusion represents the third type of gene fusion identified in intrahepatic cholangiocarcinoma, and correlates with a distinctive morphology described herein.
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http://dx.doi.org/10.1097/PAS.0000000000001729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516671PMC
November 2021

Dysregulated Free Fatty Acid Receptor 2 Exacerbates Colonic Adenoma Formation in Mice: Relation to Metabolism and Gut Microbiota Composition.

J Cancer Prev 2021 Mar;26(1):32-40

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Free fatty acid receptor 2 () has been reported as a tumor suppressor in colon cancer development. The current study investigated the effects of signaling on energy metabolism and gut microbiota profiling in a colorectal cancer mouse model ( ). deficiency promoted colonic polyp development and enhanced fatty acid oxidation and bile acid metabolism. Gut microbiome sequencing analysis showed distinct clustering among wild-type, , and - mice. The relative abundance of and was significantly increased in the - mice compared to the mice. In addition, knocking-down in the human colon cancer cell lines (SW480 and HT29) resulted in increased expression of several key enzymes in fatty acid oxidation, such as carnitine palmitoyltransferase 2, acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, C-2 to C-3 short chain, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit. Collectively, these results demonstrated that deficiency significantly altered profiles of fatty acid metabolites and gut microbiome, which might promote colorectal cancer development.
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http://dx.doi.org/10.15430/JCP.2021.26.1.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020170PMC
March 2021

Microvillus inclusion disease with novel MYO5B pathogenic variants.

Histopathology 2021 07 14;79(1):119-121. Epub 2021 Apr 14.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1111/his.14348DOI Listing
July 2021

Black Raspberries Suppress Colorectal Cancer by Enhancing Smad4 Expression in Colonic Epithelium and Natural Killer Cells.

Front Immunol 2020 14;11:570683. Epub 2020 Dec 14.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States.

Innate immune cells in the tumor microenvironment have been proposed to control the transition from benign to malignant stages. In many cancers, increased infiltration of natural killer (NK) cells associates with good prognosis. Although the mechanisms that enable NK cells to restrain colorectal cancer (CRC) are unclear, the current study suggests the involvement of Smad4. We found suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Moreover, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated mice and adenocarcinomas in AOM/DSS-treated mice. Other studies have shown that Smad4 loss or weak expression in colonic epithelium associates with poor survival in CRC patients. Therefore, targeting Smad4 in both colonic epithelium and NK cells could provide an excellent opportunity to manage CRC. Toward this end, we showed that dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in patients with FAP or CRC and in the two CRC mouse models. Also, benzoate metabolites of BRBs, such as hippurate, upregulated Smad4 and Gzmb expression that might enhance the cytotoxicity of primary human NK cells. Of note, increased levels of hippurate is a metabolomic marker of a healthy gut microbiota in humans, and hippurate also has antitumor effects. In conclusion, our study suggests a new mechanism for the action of benzoate metabolites derived from plant-based foods. This mechanism could be exploited clinically to upregulate Smad4 in colonic epithelium and NK cells, thereby delaying CRC progression.
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http://dx.doi.org/10.3389/fimmu.2020.570683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793748PMC
May 2021

Anti-colonic Inflammation by Black Raspberries through Regulating Toll-like Receptor-4 Signaling in Interlukin-10 Knockout Mice.

J Cancer Prev 2020 Jun;25(2):119-125

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon, with a steadily rising prevalence in Western and newly industrialized countries. UC patients have a cancer incidence as high as 10% after 20 years of the disease. Although the importance of fruits and vegetables in defense against UC is beginning to be appreciated, the mechanisms remain largely unclear. In the current study, we reported that dietary black raspberries (BRBs) decreased colonic inflammation in the mucosa and submucosa of interleukin (IL)-10 knockout (KO) mice. We then used colon, spleen, and plasma from those mice to investigate whether BRBs exert their anti-inflammatory effects by correcting dysregulated toll-like receptor (TLR)-4 signaling to downregulate prostaglandin E2 (PGE2). Other studies reported that spleen is the reservoir of macrophages and depletion of macrophages in IL-10 KO mice prevents the development of colitis. Our results showed that BRBs decreased the percentages of macrophages in spleens of IL-10 KO mice. Moreover, mechanistically, the BRB diet corrected dysregulated TLR-4 signaling in cells from the colon and spleen, decreased PGE2 and prostaglandin I2, and increased 15-lipoxygenase and its product, 13-S-hydroxyoctadecadienoic acid, in plasma of IL-10 KO mice. Therefore, we have elucidated one of the anti-inflammatory mechanisms of BRBs, and have identified biomarkers that could be indicators of response in UC patients treated with them. Our findings with BRBs could well apply to many other commonly consumed fruits and vegetables.
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http://dx.doi.org/10.15430/JCP.2020.25.2.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337002PMC
June 2020

Increased SPARC expression is associated with neoadjuvant therapy in resectable pancreatic ductal adenocarcinoma.

Pract Lab Med 2020 Aug 29;21:e00171. Epub 2020 May 29.

Medical College of Wisconsin, #University of Alabama at Birmingham, United States.

Secreted Protein Acid and Rich in Cysteine (SPARC) is an extracellular glycoprotein secreted by fibroblasts and osteoblasts in normal tissues. SPARC overexpression occurs in multiple tumors including pancreatic ductal adenocarcinoma (PDAC) and may predict favorable response to nab-paclitaxel. The prognostic significance of SPARC expression in PDAC is unclear - some reports indicate SPARC overexpression associates with poor outcomes and others find no correlation. Considering neoadjuvant therapy enhances the stromal fibrosis of PDAC and taking into account that SPARC is a component of PDAC stromal fibrosis, we hypothesized that SPARC expression would be greater in neoadjuvant-treated versus treatment-naive PDAC. Quantitative immunohistochemistry was used to measure SPARC expression in resected PDAC in 74 cases of neoadjuvant treated PDAC and 95 cases of treatment-naïve PDAC. SPARC expression was increased 54% in neoadjuvant treated PDAC compared to treatment-naïve PDAC. These data indicate that increased SPARC expression correlates with neoadjuvant therapy in PDAC.
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http://dx.doi.org/10.1016/j.plabm.2020.e00171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284134PMC
August 2020

Three-dimensional analysis of extrahepatic cholangiocarcinoma and tumor budding.

J Pathol 2020 08 3;251(4):400-410. Epub 2020 Jul 3.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Advances in tissue clearing and microscopy make it possible to study human diseases in three dimensions (3D). High-grade tumor budding is known to be associated with poor prognosis in various cancers; however, little is known about the 3D architecture of tumor budding. Using tissue clearing, we analyzed the 3D structure of tumor budding and E-cadherin expression in 31 extrahepatic cholangiocarcinomas. A total of 31 thick slabs (up to 5 mm) were harvested from surgically resected tumor tissue, including 27 hilar and 4 distal cholangiocarcinomas. Twenty-eight cases were adenocarcinoma, and three were undifferentiated carcinoma. After clearing, the tissues were immunolabeled with antibodies to cytokeratin 19 and to E-cadherin, and then visualized using light-sheet and confocal laser scanning microscopy. Tumor budding was evaluated in hematoxylin and eosin-stained sections (2D) using standard pathological criteria. Of the 31 cancers, 13 showed low-grade tumor budding and 18 showed high-grade tumor budding. First, 3D analysis revealed that the neoplastic cells in tumor buds of adenocarcinoma were typically not individual islands of cells, but rather tips of attenuated protrusions connected to the main tumor. Second, adenocarcinomas with low-grade tumor budding were composed predominantly of tubules that only focally form cords at the periphery. By contrast, adenocarcinomas with high-grade tumor budding predominantly formed cords in both centers and peripheries of the tumors. Third, adenocarcinoma with low-grade tumor budding was characterized by a few short protrusions with few branches, whereas adenocarcinoma with high-grade tumor budding was characterized by longer protrusions with more branching. Finally, immunolabeling of E-cadherin was stronger in the center of the adenocarcinoma but decreased at the tips of protrusions. E-cadherin loss was more extensive in the protrusions of high-grade tumor budding than in the protrusions of low-grade tumor budding. Our findings suggest that tumor buds as seen in 2D are, in fact, cross-sections of attenuated but contiguous protrusions extending from the main tumor. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5474DOI Listing
August 2020

Black raspberries suppress pancreatic cancer through modulation of NKp46, CD8, and CD11b immune cells.

Food Front 2020 Mar 26;1(1):70-82. Epub 2020 Mar 26.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a low survival rate (9%). Epidemiologic studies show that healthy dietary patterns enriched of fruits and vegetables lower the risk of PDAC. We previously showed that supplementing black raspberries (BRBs) to patients with colorectal cancer increased tumor-infiltrating NK cells and their cytotoxicity. We aimed to determine whether BRBs combat PDAC by modulating cancer immunity. NOD.SCID mice lacking T and B cells were injected with human Panc-1-Luc cells orthotopically, and immunocompetent mice were fed BRBs. Peripheral blood mononuclear cells (PBMCs) from PDAC patients were treated with butyrate, a microbial metabolite of BRBs. The absence of T and B cells did not dampen BRBs' anti-tumor effects in the NOD.SCID mice. In the mice, BRBs significantly prolonged survival (189 days versus 154 days). In both models, BRBs decreased tumor-infiltrating CD11b cells and the expression of IL-1β, sEH, and Ki67. BRBs also increased tumor-infiltrating NKp46 cells and the expression of CD107a, a functional marker of cytolytic NK and CD8 T cells. In mice, tumor infiltration of CD8 T cells was increased by BRBs. Further using the PBMCs from PDAC patients, we show that butyrate decreased the population of myeloid-derived suppressor cells (MDSCs). Butyrate also reversed CD11b cell-mediated suppression on CD8 T cells. Interestingly, there is a negative association between MDSC changes and patients' survival, suggesting that the more decrease in MDSC population induced by butyrate treatment, the longer the patient had survived. Our study suggests the immune-modulating potentials of BRBs in PDAC.
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http://dx.doi.org/10.1002/fft2.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197210PMC
March 2020

Gastrointestinal Malakoplakia: Clinicopathologic Analysis of 26 Cases.

Am J Surg Pathol 2020 09;44(9):1251-1258

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD.

Malakoplakia is an inflammatory process related to defective macrophage response to bacterial infection. To further characterize the clinicopathologic manifestations of gastrointestinal malakoplakia, 26 cases were identified from 6 institutions. Hematoxylin and eosin-stained slides and available stains were reviewed, and pertinent clinicopathologic features analyzed. Sixteen patients were women (62%). Mean patient age was 64 (range: 24 to 83). Sites included the colorectum (n=23), appendix (n=1), and stomach (n=2). Clinical indications for tissue procurement included screening (n=14), tumor resection (n=5), diarrhea (n=1), adenoma surveillance (n=1), ulcerative colitis flare (n=1), abdominal pain (n=1), and appendicitis (1). All cases featured histiocytes with abundant, pale, eosinophilic cytoplasm focally containing Michaelis-Gutmann bodies. The process frequently involved the mucosa (n=19), with architectural distortion in 13 cases. Lymphoid aggregates were present in 18 cases, which were prominent or obscuring in 11 (all colon biopsies) and provoked concern for lymphoma in 2. Associated findings included adenocarcinoma (n=5), adenoma (n=2), gastric hyperplastic polyps (n=1), chemical gastritis (n=1), collagenous colitis (n=1), and active chronic colitis (n=2). In cases with available stains, Michaelis-Gutman bodies were highlighted by Periodic Acid-Schiff with diastase, Von Kossa, and iron stains. Although 2 cases were positive for Tropheryma whipplei antibody, no T. whipplei transcripts were detected on real-time polymerase chain reaction. All patients with available follow-up are alive and well with no additional instances of malakoplakia. Malakoplakia of the gastrointestinal tract is a benign, incidental finding. Although histologic features in the stomach and colon resections are similar to those at other sites, exuberant lymphocytic response in colon biopsies and immunoreactivity with T. whippleii antibody may provoke initial confusion and lead to unnecessary time and resource investment.
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http://dx.doi.org/10.1097/PAS.0000000000001491DOI Listing
September 2020

Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability.

Oncogene 2020 05 14;39(21):4257-4270. Epub 2020 Apr 14.

Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.

The mitochondrial HSP70 chaperone mortalin (HSPA9/GRP75) is often upregulated and mislocalized in MEK/ERK-deregulated tumors. Here, we show that mortalin depletion can selectively induce death of immortalized normal fibroblasts IMR90E1A when combined with K-Ras expression, but not with wild-type K-Ras expression, and that K-Ras-driven MEK/ERK activity is necessary for this lethality. This cell death was attenuated by knockdown or inhibition of adenine nucleotide translocase (ANT), cyclophilin D (CypD), or mitochondrial Ca uniporter (MCU), which implicates a mitochondria-originated death mechanism. Indeed, mortalin depletion increased mitochondrial membrane permeability and induced cell death in KRAS-mutated human pancreatic ductal adenocarcinoma (PDAC) and colon cancer lines, which were attenuated by knockdown or inhibition of ANT, CypD, or MCU, and occurred independently of TP53 and p21. Intriguingly, JG-98, an advanced MKT-077 derivative, phenocopied the lethal effects of mortalin depletion in K-Ras-expressing IMR90E1A and KRAS-mutated tumor cell lines in vitro. Moreover, JG-231, a JG-98 analog with improved microsomal stability effectively suppressed the xenograft of MIA PaCa-2, a K-Ras-expressing human PDAC line, in athymic nude mice. These data demonstrate that oncogenic KRAS activity sensitizes cells to the effects of mortalin depletion, suggesting that mortalin has potential as a selective therapeutic target for KRAS-mutated tumors.
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http://dx.doi.org/10.1038/s41388-020-1285-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244387PMC
May 2020

Three-dimensional visualization of cleared human pancreas cancer reveals that sustained epithelial-to-mesenchymal transition is not required for venous invasion.

Mod Pathol 2020 04 7;33(4):639-647. Epub 2019 Nov 7.

Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Venous invasion is three times more common in pancreatic cancer than it is in other major cancers of the gastrointestinal tract, and venous invasion may explain why pancreatic cancer is so deadly. To characterize the patterns of venous invasion in pancreatic cancer, 52 thick slabs (up to 5 mm) of tissue were harvested from 52 surgically resected human ductal adenocarcinomas, cleared with a modified iDISCO method, and labeled with fluorescent-conjugated antibodies to cytokeratin 19, desmin, CD31, p53 and/or e-cadherin. Labeled three-dimensional (3D) pancreas cancer tissues were visualized with confocal laser scanning or light sheet microscopy. Multiple foci of venous and even arterial invasion were visualized. Venous invasion was detected more often in 3D (88%, 30/34 cases) than in conventional 2D slide evaluation (75%, 25/34 cases, P < 0.001). 3D visualization revealed pancreatic cancer cells crossing the walls of veins at multiple points, often at points where preexisting capillary structures bridge the blood vessels. The neoplastic cells often retained a ductal morphology (cohesive cells forming tubes) as they progressed from a stromal to intravenous location. Although immunolabeling with antibodies to e-cadherin revealed focal loss of expression at the leading edges of the cancers, the neoplastic cells within veins expressed e-cadherin and formed well-oriented glands. We conclude that venous invasion is almost universal in pancreatic cancer, suggesting that even surgically resectable PDAC has access to the venous spaces and thus the ability to disseminate widely. Furthermore, we observe that sustained epithelial-mesenchymal transition is not required for venous invasion in pancreatic cancer.
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http://dx.doi.org/10.1038/s41379-019-0409-3DOI Listing
April 2020

Impact of a preoperative low-calorie diet on liver histology in patients with fatty liver disease undergoing bariatric surgery.

Surg Obes Relat Dis 2019 Oct 22;15(10):1766-1772. Epub 2019 Aug 22.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Health, Behavior and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: A low-calorie diet (LCD) before bariatric surgery has been shown to reduce liver volume and facilitate ease of operation. It is estimated that 75%-100% of individuals undergoing bariatric surgery have nonalcoholic fatty liver disease (NAFLD).

Objectives: We aimed to investigate how an LCD affects liver histology in the setting of NAFLD.

Setting: University Hospital, United States.

Methods: Forty intraoperative liver specimens were analyzed histologically as follows: 20 with and 20 without a preoperative 2-week, 1200 kcal/d LCD. Weight was measured prediet, at surgery, and 6 months after surgery. NAFLD activity score was used to grade liver histology at surgery. The NAFLD activity score scores steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis.

Results: The non-LCD group (n = 20) had mean weight at surgery of 136.1 ± 24.1 kg. The LCD group (n = 20) had initial mean weight of 128.6 ± 25.4 kg, with presurgical weight loss of 3.43 kg (range, 0-9.3 kg), mean change in body mass index 1.24 kg/m (2.66% total weight loss) on an LCD. The LCD group had significantly less steatosis (P = .02), fewer foci of lobular inflammation (P = .01), and less hepatocellular ballooning (P = .04) compared with the non-LCD group; with no difference in degree of fibrosis. Fewer patients in the LCD group had nonalcoholic steatohepatitis with ballooning (P = .04). Weight loss on an LCD before bariatric surgery was predictive of weight loss 6 months after surgery (P = .026).

Conclusions: A 2-week LCD before bariatric surgery is associated with significant improvement in steatosis, inflammation, and hepatocellular ballooning in NAFLD. Among LCD patients, preoperative weight loss was associated with improved 6-month weight loss and liver function.
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http://dx.doi.org/10.1016/j.soard.2019.08.013DOI Listing
October 2019

Reply.

Hepatology 2019 06;69(6):2718-2719

Department of Medicine, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.

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http://dx.doi.org/10.1002/hep.30595DOI Listing
June 2019

The immunomodulatory potential of natural compounds in tumor-bearing mice and humans.

Crit Rev Food Sci Nutr 2019 22;59(6):992-1007. Epub 2019 Feb 22.

a Division of Hematology and Oncology, Department of Medicine , Medical College of Wisconsin , Milwaukee , Wisconsin , USA.

Cancer is considered a fetal disease caused by uncontrolled proliferation and progression of abnormal cells. The most efficient cancer therapies suppress tumor growth, prevent progression and metastasis, and are minimally toxic to normal cells. Natural compounds have shown a variety of chemo-protective effects alone or in combination with standard cancer therapies. Along with better understanding of the dynamic interactions between our immune system and cancer development, nutritional immunology-the use of natural compounds as immunomodulators in cancer patients-has begun to emerge. Cancer cells evolve strategies that target many aspects of the immune system to escape or even edit immune surveillance. Therefore, the immunesuppressive tumor microenvironment is a major obstacle in the development of cancer therapies. Because interaction between the tumor microenvironment and the immune system is a complex topic, this review focuses mainly on human clinical trials and animal studies, and it highlights specific immune cells and their cytokines that have been modulated by natural compounds, including carotenoids, curcumin, resveratrol, EGCG, and β-glucans. These natural compounds have shown promising immune-modulating effects, such as inhibiting myeloid-derived suppressor cells and enhancing natural killer and cytolytic T cells, in tumor-bearing animal models, but their efficacy in cancer patients remains to be determined.
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http://dx.doi.org/10.1080/10408398.2018.1537237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508979PMC
October 2019

An Inhibitor of Arginine-Glycine-Aspartate-Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis.

Hepatol Commun 2019 Feb 27;3(2):246-261. Epub 2018 Dec 27.

Division of Gastroenterology and Hepatology Saint Louis University St. Louis MO.

The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine-glycine-aspartic acid tripeptide (RGD)-binding, integrin antagonist (3S)-3-(3-bromo-5-(tert-butyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]-12). We hypothesized that RGD-binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM-12 in a choline deficient, amino-acid defined, high-fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM-12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM-12. Fibrosis measured by analysis of liver collagen was reduced by CWHM-12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM-12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. : RGD-binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.
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http://dx.doi.org/10.1002/hep4.1298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357833PMC
February 2019

Effects of Hepatic Ischemia-Reperfusion Injuries and NRF2 on Transcriptional Activities of Bile Transporters in Rats.

J Surg Res 2019 03 24;235:73-82. Epub 2018 Oct 24.

Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

Background: The effect of hepatic ischemia-reperfusion injury (IRI) on bile transporter (BT) gene expression is unknown. We hypothesized that abnormal expression of BTs during hepatic IRI is dependent on nuclear factor erythroid 2-related factor 2 (NRF2), which contributes to the cholestasis after reperfusion.

Methods: Sham surgery and short (60 min) or long (90 min) periods of warm ischemia time (WIT) with or without reperfusion for 24 h were applied to wild-type Sprague-Dawley rats and Nrf2 knockout rats (n = 5 per group). At each stage of IRI, the serum levels of aminotransferase, total bilirubin, and bile acids were measured. In addition, hepatic tissue was sampled to determine the histologic score of IRI (Suzuki score), measure adenosine triphosphate (ATP), and identify the quantitative real-time polymerase chain reactions of BTs (Oatp1, Ntcp, Mrp2, Bsep, and Mrp3).

Results: In short periods of WIT, BT expression increased during the ischemia stage and returned to the baseline after reperfusion. However, in long periods of WIT, BT expression did not increase after ischemia and decreased further after reperfusion. Short WIT did not increase BT expression in Nrf2 knockout animals. The level of BT expression was correlated with the Suzuki score, the serum levels of aminotransferase, bilirubin, and bile acids, and tissue ATP level. Stepwise multiple regression analysis derived equations to predict the Suzuki score (R = 76.8, P < 0.001), serum total bilirubin (R = 61.2, P < 0.001), and tissue ATP (R = 61.1, P < 0.001).

Conclusions: Short WIT induces the transcriptional activities of BT, whereas long WIT depresses them, and the effect was blunted by Nrf2 knockout status. BT expression can be considered a surrogate marker for hepatic IRI.
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http://dx.doi.org/10.1016/j.jss.2018.09.057DOI Listing
March 2019

Gut bacteria are required for the benefits of black raspberries in mice.

J Berry Res 2018 20;8(4):239-249. Epub 2018 Dec 20.

Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

Background: The gut microbiota plays a pivotal role in the development of inflammatory bowel disease and colorectal cancer.

Objective: To determine whether the gut microbiota is required for the chemoprotective effects of black raspberries (BRBs) in mice.

Methods: mice were given (a) a control diet for 8 weeks, or (b) the control diet for 4 weeks and then a 5% BRB diet for additional 4 weeks, or (c) the control diet and antibiotics for 4 weeks followed by the 5% BRB diet and antibiotics for the next 4 weeks. At the end of the study, all the mice were euthanized, and colonic and intestinal polyps were counted. mRNA expression levels of and were determined in colon and small intestine of these mice by quantitative real-time PCR.

Results: 5% BRBs significantly suppressed intestinal and colonic polyp development in the mice, whereas antibiotics significantly abolished BRBs' chemoprotective effects. BRBs decreased mRNA levels of and in colon, whereas significantly enhanced mRNA levels of and were observed in small intestine of BRB-treated mice fed antibiotics.

Conclusions: The gut microbiota is required for BRBs' chemoprotection against polyp development in mice.
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http://dx.doi.org/10.3233/JBR-180337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326590PMC
December 2018

Measured residual tumor cellularity correlates with survival in neoadjuvant treated pancreatic ductal adenocarcinomas.

Ann Diagn Pathol 2019 Feb 5;38:93-98. Epub 2018 Nov 5.

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.anndiagpath.2018.10.013DOI Listing
February 2019

An immunological perspective for preventing cancer with berries.

J Berry Res 2018 3;8(3):163-175. Epub 2018 Aug 3.

Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

Berries and their phytochemicals have well documented chemopreventive roles, but understanding their ability to regulate cancer immunology is only beginning to be explored. The literature, including human studies, suggests that berry components can modulate our immune system to delay cancer development. Moreover, their wide spectrum of phytochemicals suggests that they might influence the functions of multiple immune cells and different aspects of cancer immunity. Cancer immune-therapies are showing promise for some types of cancer because they boost T cells' ability to recognize tumor cells - an essential prelude to destruction. Recognition occurs after dendritic cells present antigen, such as tumor antigen, to T cells, generating an adaptive response. Therefore, the potential of berries to aid cancer immune-therapies by, for example, regulating dendritic cells, warrants further investigation in animal and human studies. More information is also needed about berries' effects on the entire spectrum of immunity so that a comprehensive view can inform efforts to use berries to enhance immune responses during cancer prevention and treatment. This review summarizes the effects of berries as anti-tumor agents from the immunological perspective in tumor-bearing animals and humans.
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http://dx.doi.org/10.3233/JBR-180305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110394PMC
August 2018

PET-based Treatment Response Assessment for Neoadjuvant Chemoradiation in Pancreatic Adenocarcinoma: An Exploratory Study.

Transl Oncol 2018 Oct 17;11(5):1104-1109. Epub 2018 Jul 17.

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address:

Purpose: Performance of anatomical metrics of Response Evaluation Criteria in Solid Tumors (RECIST1.1) versus Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST1.0) for neoadjuvant chemoradiation (nCR) of pancreatic adenocarcinoma was evaluated based on the pathological treatment response (PTR) data.

Methods And Materials: The pre- and post-nCR CT and PET data for 14 patients with resectable or borderline resectable pancreatic head adenocarcinoma treated with nCR followed by surgery were retrospectively analyzed. These data were compared with the PTR which were graded according to tumor cell destruction (cellularity), with Grade 0, 1, 2 or 3 (G0, G1, G2 or G3) for complete, moderate, minimal and poor responses, respectively. Maximum standardized uptake value (SUVmax) was defined using body-weight (SUVbw). PERCIST1.0 was defined using lean-body mass normalized SUV (SUVlb or SUL). RECIST1.1 was defined by contouring the whole pancreas head on the CT image. Pre- and post-SUL-peak and SUVmax, RECIST1.1 and PETRECIST1.0 were correlated with PTR using Pearson's correlation coefficient test.

Results: The average mean and SD in SUL-peak for all patients analyzed were lower in post-nCR (3.63±1.06) compared to those at pre-nCR (4.29±0.89). Using PERCIST1.0, 62% of patients showed stable metabolic disease (SMD), 23% partial metabolic response (PMR), and 15% progressive metabolic disease (PMD). Using RECIST1.1, 85% of patients showed stable disease (SD), 8% partial response (PR), and 7% progressive diseases (PD). A poor insignificant correlation was established between PRT and PERECIST1.0 (r=0.121), whereas no correlation was seen with RECIST1.1.

Conclusions: PERCIST1.0 appears to increase the chance of detecting patients with progressive disease compared to the conventional anatomical-based assessment of RECIST1.1. The integration of these additional radiographic metrics in assessing treatment response to nCR for pancreatic adenocarcinoma may provide a promising strategy to better select patients that are most suitable for therapeutic intensification.
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http://dx.doi.org/10.1016/j.tranon.2018.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070701PMC
October 2018

Nodular Regenerative Hyperplasia Associated With Immune Checkpoint Blockade.

Hepatology 2018 12 5;68(6):2431-2433. Epub 2018 Nov 5.

Departments of Medicine, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.

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http://dx.doi.org/10.1002/hep.30157DOI Listing
December 2018

Inhibition of the development of N-nitrosomethylbenzylamine-induced esophageal tumors in rats by strawberries and aspirin, alone and in combination.

J Berry Res 2018 17;8(2):137-146. Epub 2018 May 17.

Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

Background: Esophageal squamous cell carcinoma (ESCC) is one of two subtypes of esophageal cancer, with high incidence and mortality rates in developing countries.

Objective: The current study investigated the potential chemoprotective effects of strawberries and aspirin against the development of rat esophageal papillomas, the precursors to ESCC.

Methods: Using a prevention model, we administered study diets to rats before, during, and after -nitrosomethylbenzylamine (NMBA) treatment. The effects of the four diets were evaluated: the control diet, 5% strawberry powder in the control diet, 0.01% aspirin in the drinking water, and the combination of strawberries and aspirin. At week 25, we euthanized all the rats and collected their esophagi to quantify tumor incidence, multiplicity, and burden, as well as for molecular analysis.

Results: Both strawberries and aspirin significantly decreased esophageal tumor multiplicity, with the combination causing the most robust suppression. Aspirin alone and the combination decreased the total tumor burden in the esophagus. None of the diets had a significant effect on tumor incidence or the expression of COX-1 and COX-2. Strawberries and aspirin, alone and in combination, significantly suppressed squamous epithelial cell proliferation (PCNA).

Conclusions: Strawberries, aspirin, and their combination exhibit chemoprotective effects against NMBA-induced esophageal tumors in rats.
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http://dx.doi.org/10.3233/JBR-170291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029707PMC
May 2018

Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors.

Int J Cancer 2018 08 30;143(4):886-896. Epub 2018 Mar 30.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, RM C4930, 8701 Watertown Plank Rd, Milwaukee, WI, 53226.

Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the Apc and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the Apc /DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP-PKA-CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2-deficient mice. ChIP-qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors (e.g., sfrp1, dkk3, socs1), resulting in decreased expression of these genes in the FFAR2-deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2-deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis.
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http://dx.doi.org/10.1002/ijc.31366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041131PMC
August 2018
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