Exp Pathol Research Articles

Retracted] Tetramethylpyrazine inhibits prostate cancer progression by downregulation of forkhead box M1.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell invasion assay data shown in Fig. 3B on p. 839 were strikingly similar to data that had already appeared in another article written by different authors at different research institutes [Mao Y, Zhang L, Yuan L, Yan M and He Y: MiR‑218 suppresses cell progression by targeting APC in cervical cancer. Int J Clin Exp Pathol: 10, 2259‑2269, 2017]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 38: 837‑842, 2017; DOI: 10.3892/or.2017.5768].

Overexpression of ZEB1 and YAP1 is related to poor prognosis in patients with gliomas with different IDH1 status: Int J Clin Exp Pathol. 2023; 16(7): 138-149

Overexpression of ZEB1 and YAP1 is related to poor prognosis in patients with gliomas with different IDH1 status: Int J Clin Exp Pathol. 2023; 16(7): 138-149

Poverty and antibiotic misuse: a complex association

Poverty and antibiotic misuse: a complex association

A dissection … of the Dacron?

A dissection … of the Dacron?

CHRONIC CAVITARY PULMONARY ASPERGILLOSIS IN A PATIENT WITH IDIOPATHIC PULMONARY FIBROSIS

TOPIC: Diffuse Lung Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Chronic cavitary pulmonary aspergillosis (CCPA) is a rare form of aspergillosis involving patients with structural lung diseases. Here we will describe a case of CCPA in a patient with idiopathic pulmonary fibrosis (IPF), which is rarely reported. CASE PRESENTATION: The patient was a 78-year-old male with a medical history significant for IPF diagnosed 13 years prior, on oral pirfenidone and long-term oxygen therapy, who presented to the hospital for worsening shortness of breath, productive cough, and fatigue of two months duration. The patient was initially hospitalized in another facility for the above symptoms where he received two courses of antibiotics without significant improvement. Chest examination showed bilateral fine inspiratory crackles, worse on the right side. The results of routine blood tests were normal. The nasal swab for the respiratory viral panel was negative. Chest X-ray showed fibrotic lung disease with a superimposed alveolar and interstitial process involving the lung bases and right upper lobe. Computed Tomography (CT) scan of the chest was suggestive of a thick-walled cavitary lesion in the right apex measuring 4.8 x 3.3 cm, enlarged mediastinal and right hilar lymph nodes along with other chronic changes. Three sets of sputum acid-fast bacilli (AFB) smears along with serum Quantiferon TB gold plus test were negative. The patient was empirically started on intravenous (IV) ceftriaxone and azithromycin. Later, blood and sputum cultures were reported negative for bacteriological growth. Interestingly, the sputum cultures were positive for Aspergillus species along with positive serum Aspergillus immunoglobulin (Ig)G level. The patient was diagnosed with CCPA based on the serology, culture results, and radiological findings. IV antibiotics were discontinued and the patient was started on oral posaconazole 300 mg daily resulting in clinical improvement. Currently, the patient is on a 6-month posaconazole regimen. DISCUSSION: Pulmonary aspergillosis is a common opportunistic infection that can present as aspergilloma, allergic bronchopulmonary aspergillosis, CCPA, and invasive pulmonary aspergillosis based on lung changes. Mycobacterium infection and obstructive lung diseases are the most frequent underlying pulmonary diseases that are associated with CCPA. However, IPF with CCPA is rare, and its clinical features and radiological findings lack specificity leading to delays in diagnosis and treatment. Once confirmed, the treatment is straightforward with long-term triazole antifungals. CONCLUSIONS: In a patient with IPF, presenting with rapidly progressing radiologic findings suggestive of pulmonary cavitation, CCPA should be considered in the differential diagnosis. REFERENCE #1: Liu C, Yang J, Lu Z. Idiopathic pulmonary fibrosis with chronic necrotizing pulmonary aspergillosis: a case report. Int J Clin Exp Pathol. 2019 Jul 1;12(7):2653-2656. PMID: 31934094; PMCID:PMC6949565 REFERENCE #2: Graham KG, Nasir A. Chronic Cavitary Pulmonary Aspergillosis: A Case Report and Review of the Literature. Am J Case Rep. 2019 Aug 18;20:1220-1224 doi: 10.12659/AJCR.915893. PMID: 31422416; PMCID: PMC6711266. REFERENCE #3: Sehgal IS, Dhooria S, Muthu V, Prasad KT, Agarwal R. An overview of the available treatments for chronic cavitary pulmonary aspergillosis. Expert Rev Respir Med. 2020 Jul;14(7):715-727. doi: 10.1080/17476348.2020.1750956. Epub 2020 Apr 20. PMID: 32249630. DISCLOSURES: No relevant relationships by Rabab Elmezayen, source=Web Response No relevant relationships by Syed yousaf Shah, source=Web Response

An Unusual Cause of Recurrent Subepithelial Mass in the Stomach

Question: A 58-year-old woman presented with a subepithelial tumor, approximately 2 cm in size, incidentally detected in the posterior wall of upper body of the stomach during a screening endoscopy (Figure A). The sample from an endoscopic ultrasound-guided fine-needle biopsy revealed spindle-shaped cells arranged in a fascicular pattern. The spindle cells were immunopositive for c-Kit, cluster of differentiation 34, DOG-1, and smooth muscle actin. The patient was diagnosed with a gastrointestinal stromal tumor (GIST) and underwent laparoscopic wedge resection. The tumor was completely resected with clear margins. The maximal tumor size was 2.3 cm, and the mitotic count was 2 per 50 high-power fields; therefore, it was diagnosed as a GIST with a low risk of malignant potential. Follow-up abdominal computed tomography after 2 years showed a new low-density mass in the previous resection site (Figure B, arrow). Endoscopy showed no definite lesion at the resection site (Figure C), and endoscopic ultrasound revealed a 1.5-cm heterogeneous hypoechoic lesion originating from the muscularis propria (Figure D). Laparoscopic wedge resection was performed again for a definitive diagnosis and treatment. What is your diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Histopathologic examination of the resected specimen revealed sweeping fascicles of bland and uniform spindle cells with collagenous stroma and compressed, thin-walled vessels (Figure E). The spindle cells were immunonegative for c-Kit (Figure F), cluster of differentiation 34 (Figure G), DOG-1 (Figure H), and S-100 protein, and were immunopositive for smooth muscle actin (Figure I), which suggested the exclusion of GIST. Therefore, additional immunohistochemistry was performed for the differential diagnosis. The tumor cells were negative for anaplastic lymphoma kinase but positive for nuclear β-catenin (Figure J). Based on morphologic and immunohistochemical findings, a diagnosis of a desmoid tumor occurring at the previous resection site of the gastric GIST was made. No further treatment was provided because the tumor was completely resected. No signs of recurrence or metastasis were found during 12 months of follow-up. Desmoid tumors are rare mesenchymal tumors occurring in patients with risk factors, such as a previous history of abdominal surgery, familial adenomatous polyposis, or pregnancy, and they can be easily mistaken for GIST because both tumors show similar clinical presentation and morphology.1Murshid A.A. Al-Maghraby H.Q. Subsequent development of desmoid tumor after a resected gastrointestinal stromal tumor.Case Rep Pathol. 2018; 2018: 1082956Google Scholar The desmoid tumor and GIST are both microscopically characterized by spindle-cell proliferation, and the differential diagnosis of these two tumors is performed mainly by immunohistochemistry. Because desmoid tumors usually have activating mutations in β-catenin, abnormal nuclear positivity of β-catenin is seen in most desmoid tumors.2Lu Q. Wang K. Liu D. et al.Stomach desmoid tumor: a case report and review of the literature.Int J Clin Exp Pathol. 2017; 10: 10531-10538Google Scholar Surgical resection with a negative margin is currently the treatment of choice. When local recurrence occurs or complete surgical resection is not feasible, radiotherapy, chemotherapy, and other comprehensive therapies, such as estrogen receptor antagonists and nonsteroidal anti-inflammatory drugs, should be provided.2Lu Q. Wang K. Liu D. et al.Stomach desmoid tumor: a case report and review of the literature.Int J Clin Exp Pathol. 2017; 10: 10531-10538Google Scholar Owing to the rarity of gastric desmoid tumors, information about their prognosis is very limited. According to a review of the literature on gastric desmoid tumors, no recurrence was reported during follow-up assessments,2Lu Q. Wang K. Liu D. et al.Stomach desmoid tumor: a case report and review of the literature.Int J Clin Exp Pathol. 2017; 10: 10531-10538Google Scholar indicating a good prognosis. However, considering the local recurrence rate of 13% for intra-abdominal sporadic desmoid tumors,3Wilkinson M.J. Fitzgerald J.E. Thomas J.M. et al.Surgical resection for nonfamilial adenomatous polyposis-related intraabdominal fibromatosis.Br J Surg. 2012; 99: 706-713Google Scholar regular follow-up is mandatory.

UNUSUAL PRESENTATION OF DISSEMINATED LEGIONELLA WITH HYPERTRIGLYCERIDEMIA AND MASSIVE RHABDOMYOLYSIS

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Legionella most commonly presents as pneumonia but can involve multiple organ systems. We present a case of a patient with pneumonia, rhabdomyolysis, renal failure, hypertriglyceridemia, pancreatitis, and cutaneous involvement. CASE PRESENTATION: A 41-year-old black male presented with shortness of breath requiring intubation. Pertinent labs showed elevated white blood cell count, creatinine, and CK. Chest radiograph (fig 1) showed right lower lobe airspace opacity. He was started on broad spectrum antibiotics and admitted to the intensive care unit. Despite aggressive IV fluids, his CK level peaked at 780,000. Kidney function continued to decline, ultimately requiring dialysis. Urine legionella antigen was positive otherwise work up negative. Antibiotics were switched to Levaquin. He was noted to have triglyceride level of 1800, with associated lipase elevation and imaging consistent with pancreatitis. This was managed with fluids and insulin infusion but eventually needed plasma exchange. He also had a 1cm superficial ulcer in the left groin (fig 2) and biopsy revealed a dermal microabscess favoring an underlying infectious process (fig 3). After 2 weeks of levaquin, he clinically improved, however required long-term dialysis. DISCUSSION: Legionella infection typically presents as pneumonia. Rarely, it can present as extra-pulmonary disease involving gastrointestinal, neurological, cardiac, renal, and musculoskeletal systems, and skin and soft tissues. A rare triad of pneumonia, rhabdomyolysis and renal failure has been associated with worse and sometimes fatal outcomes [1]. Our patient’s course is unique as he had severe rhabdomyolysis, renal failure, hypertriglyceridemia, pancreatitis, and cutaneous lesion associated with his legionella infection. To our knowledge this is the first case report of hypertriglyceridemia associated with legionella infection in humans. There have been reports of elevated triglyceride levels in guinea-pigs with legionella [2]. It is likely his pancreatitis was from hypertriglyceridemia, however may be from pancreatic injury due to direct cell infection, toxin release, or cytokine induced inflammation. His skin lesion was very similar to the cutaneous manifestations of legionnaire disease reported in the literature [4]. The biopsy results strongly favored an underlying infectious process and no other infection was identified with tissue stains and culture. Few case reports have described rhabdomyolysis in Legionnaires’ disease. The highest reported CK level was 165,600 [2], our patient peaked at 780,000. The mechanism of action is unclear; direct bacterial invasion into the muscle and the release of endotoxin leading to muscle damage have been postulated [3]. CONCLUSIONS: This case highlights the breath of involvement legionella can have, including the new manifestation of hypertriglyceridemia and severe rhabdomyolysis that has never been reported previously. Reference #1: T. Koufakis, I. Gabranis, M. Chatzopoulou, A. Margaritis, M. Tsiakalou. Severe Legionnaires' disease complicated by rhabdomyolysis and clinically resistant to moxifloxacin in a splenectomised patient: too much of a coincidence? Case Rep. Infect. Dis., 2015 (2015), pp. 1-4 Reference #2: Hambleton P, Bailey NE, Fitzgeorge RB, Baskerville A. Clinical chemical responses to experimental airborne legionellosis in the guinea-pig. Br J Exp Pathol. 1985;66(2):173-183. Reference #3: Johnson DA, Etter HS. Legionnaires' disease with rhabdomyolysis and acute reversible myoglobinuric renal failure. South Med J. 1984;77(6):777-779. doi:10.1097/00007611-198406000-00032 DISCLOSURES: No relevant relationships by Hadi Hatoum, source=Web Response No relevant relationships by Hamel Patel, source=Web Response No relevant relationships by Patrisha Shelley, source=Web Response

MON-LB129 A Pilot Genome Wide Association Study (GWAS) on Primary Aldosteronism Patients in a Multi-Ethnic Malaysian Cohort

Studies on excised aldosterone-producing lesions have found somatic mutations in five genes (KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1) commonly causes the excess aldosterone production. Interestingly, Oriental cohorts had the highest frequency of KCNJ5 mutations whereas CACNA1D mutations were most common in Black African Caribbean patients, suggesting that genetic background affects the prevalence and distribution of aldosterone-driving somatic mutation. We therefore aimed to identify the common germline variants that associates with excess aldosterone production through performing a pilot genome wide association study (GWAS) on primary aldosteronism (PA) patients. GWAS was performed using the Human Infinium OmniExpressExome-8 v1.4 BeadChip containing 960,919 markers to compare gDNA of 154 PA patients with 78 healthy controls. Samples were checked for sex discordance, heterozygosity rate, missing rate and the degree of recent shared ancestry for each pair of individuals using the PLINK program and Genome Studio (Illumina). In total, 150 patients and 75 controls (112 males and 113 females) were included in the downstream analysis. 630,749 markers that passed quality control steps (missing call rate <95% and minor allele frequency in controls >1%) were used to perform association analysis using the Chi-square Test which was then subjected to multiple testing corrections (Bonferroni correction). As expected with a pilot sample size, no variants passed the suggestive significant threshold of Bonferroni corrected P-value < 5 x 10-6 (-log10 P = 5.3). However, 27 SNPs had the uncorrected P-value<0.0002, odds ratio >2, and differences of frequencies in cases compared to control >0.1 or <-0.2, of which 3 genes (SRGAP3, AUTS2, and RORA) associated with these SNPs were also highlighted in the UK Biobank database of 72 patients with primary aldosteronism (https://biobankengine.stanford. edu/coding/HC189). Of these, RORA has recently been found to be down-regulated in adrenals from PA patients and spontaneously hypertensive rat adrenals compared to control adrenalsa,b. RORA encodes for the protein retinoic acid receptor (RAR)-related orphan receptor alpha, a member of the NR1 subfamily of nuclear hormone receptors (NR1F1). Interestingly, adrenal is the second organ to skin with the highest expression of RORA and treatment of angiotensin II in the adrenocortical cell line H295R increases RORA expressionc,d. Taken together, this pilot GWAS highlights RORA as a potential nuclear hormone receptor that regulates aldosterone production.References aChu et al., Int J Clin Exp Pathol 2017;10(9):10009-10018. bTanaka et al., Hypertens Res 2019;42(2):165-173. cNogueira et al., Mol Cell Endocrinol 2009; 302(2): 230–236. dGTEx Analysis Release V7 (dbGaP Accession phs000424.v7.p2)AcknowledgementsThis research was supported by the Malaysian Ministry of Higher Education Grant (FRGS/1/2015/SKK08/UKM/02/3), The National University of Malaysia (UKM) University Grant (GUP-2016-083), and The UKM Medical Center Fundamental Grant (FF-2016-302).

Lancefield Whole Blood Killing Assay to Evaluate Vaccine Efficacy.

While the Lancefield whole blood killing assay is named after the renowned streptococcal researcher Rebecca Lancefield, the protocol was first described by Todd in 1927 (Br J Exp Pathol 8:1-5, 1927). Initially, the assay was used to identify novel Group A Streptococcal (GAS) serotypes through the supplementation of non-immune human blood (often from infants) with type-specific antisera prepared in rabbits (Lancefield, J Exp Med 106:525-544, 1957; Maxted, Br J Exp Pathol 37:415-422, 1956) and to demonstrate the impressive longevity of type-specific immunity in patients following invasive GAS infection (Lancefield, J Exp Med 110:271-292, 1959). The modern assay is routinely used to screen defined GAS mutants (Wessels, Bronze, Proc Natl Acad Sci U S A 91:12238-12242, 1994; Zinkernagel et al., Cell Host Microbe 4:170-178, 2008) or transposon libraries (Le Breton et al., Infect Immun 81:862-875, 2013) for enhanced susceptibility to opsonophagocytic killing or to screen vaccine antisera (Salehi et al., mSphere 3:e00617-e00618, 2018) or other serological preparations (Reglinski et al., Sci Rep 5:15825, 2015) for anti-streptococcal activity.

Clinical Challenge and Call for Research on Keloid Disorder: Meeting Report from The 3rd International Keloid Research Foundation Symposium, Beijing 2019

Clinical Challenge and Call for Research on Keloid Disorder: Meeting Report from The 3rd International Keloid Research Foundation Symposium, Beijing 2019

Retracted: Clinical Importance of Somatostatin Receptor 2 (SSTR2) and Somatostatin Receptor 5 (SSTR5) Expression in Thyrotropin-Producing Pituitary Adenoma (TSHoma).

In the article entitled, "Clinical Importance of Somatostatin Receptor 2 (SSTR2) and Somatostatin Receptor 5 (SSTR5) Expression in Thyrotropin-Producing Pituitary Adenoma (TSHoma)", which was published in Medical Science Monitor 2017-04-23, Med Sci Monit 2017; 23: 1947-1955, the text has been directly copied from a previously published article entitled, "Immunohistochemical expression of somatostatin receptor subtypes 2 and 5 in thyrotropin-secreting pituitary adenomas: a consecutive case series of pituitary adenomas" by Hong-Juan Fang, Yang-Fang Li, Yu Fu, Li-Yong Zhong, and Ya-Zhuo Zhan in Int J Clin Exp Pathol 2017;10(1): 479-488 (www.ijcep.com /ISSN: 1936-2625/IJCEP0042895). Thus, owing to the duplicity of text, the article is being retracted.

Abstract B01: Histone acetyltransferase 1 contributes to colon cancer initiating cell chemoresistance through DNA damage repair pathways

Abstract Despite advances in treatment, Colorectal cancer (CRC) remains a leading cause of cancer related deaths in North America. Most CRCs contain a subset of self-renewing colon cancer-initiating cells (CC-ICs) responsible for tumor initiation and maintenance. CC-ICs are relatively chemoresistant as compared to the bulk tumor cells, however the mechanisms of this chemoresistance are poorly understood. An increasing amount of evidence suggests that epigenetic regulators may be playing a central role in driving CC-IC chemoresistance; one such example being histone acetyltransferase (HAT1), which plays an important role in cancer cell proliferation and response to DNA damage (Xue et al, Int J Clin Exp Pathol, 2014). The cytoplasmic HAT1/HAT2 complex acetylates histone H4 on lysine residues 5 and/or 12. Acetylated histone H4 is then bound to histone H3 and the complex is transported to the nucleus where the HAT1/HAT2 complex aids in depositing H3/H4 onto DNA (Parthum, Oncogene, 2007). In normal colon, HAT1 is predominantly localized to the nucleus in cells at the crypt base, whereas in primary and metastatic colorectal tumors, HAT1 expression is upregulated, mostly cytoplasmic, and diffuse throughout the tissue (Seiden-Long et al, Oncogene, 2006). To investigate HAT1 localization in our primary derived CC-IC enriched cell lines we used protein fractionation and western blot analysis. In our samples, we consistently see elevated cytoplasmic HAT1 expression compared to nuclear extracts. To determine the effect of the loss of HAT1 on CC-IC viability we infected our CC-IC enriched cell lines with lentiviral shRNA to knockdown HAT1. We observed no changes in growth or cell viability at baseline between the HAT1 knockdown cells and controls, however, previous studies have shown that HAT1 knockdown increases cancer cell sensitivity to DNA damaging agents such as camptothecin (CPT) or methyl methane sulfonate (MMS) by controlling Rad52 degradation, accumulating replication block double stranded breaks and prolonging G2 arrest, indicating that it is important for DNA repair processing (Barman et al, BBRC, 2006). To determine whether HAT1 contributes to CC-IC chemoresistance we treated our HAT1 knockdown cells with standard of care (SOC) chemotherapy (oxaliplatin). Viability assays showed that after 10 days of treatment there is a 40% decrease in cell viability compared to controls. To investigate whether the decrease in cell viability seen in HAT1 knockdown cells is due to an increase in DNA damage we stained cells for DNA damage marker γH2AX. Immunofluorescence analysis revealed a higher level of γH2AX staining in HAT1 knockdown cells treated with SOC chemotherapy. To examine the effects of HAT1 knockdown on CC-IC function when combined with SOC chemotherapy, we preformed a limiting dilution assay. Untreated CC-IC enriched HAT1 knockdown cells had no significant difference in CC-IC frequency, however, treating these cells with SOC chemotherapy resulted in a decrease in CC-IC frequency in vitro (212.2 vs 52.8). Our current research suggests that HAT1 plays an important role in CC-IC function, chemoresistance and response to DNA damage. We are further investigating HAT1 as a potential therapeutic target in order to improve outcomes for CRC patients. Citation Format: Lauren Agro, Cherry Leung, Yadong Wang, Evelyne Lima-Fernandes, Catherine O'Brien. Histone acetyltransferase 1 contributes to colon cancer initiating cell chemoresistance through DNA damage repair pathways [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B01.

Tumorsuppressive MicroRNA-188-5p Reveals Novel Oncogenes for Hepatocellular Carcinoma

Background & Aims: MicroRNAs are known to be dysregulated in Hepatocellular Carcinoma (HCC) and to play crucial roles in tumor development and progression. In a preliminary study, our group found that miR-188-5p is downregulated in activated synovial fibroblasts in rheumatoid arthritis (RASF). RASF reveal tumor-like features such as enhanced migration and proliferation. Re-Expression of miR-188-5p strongly inhibited migration in RASF (Int J Clin Exp Pathol, 2015). Chloride voltage-gated channel 5 (CLCN5), which is the host gene for miR-188-5p, was shown to be induced by Hepatocyte nuclear factor (HNF) 1 (Am J Physiol Renal Physiol., 2010). Interestingly, our group demonstrated in a previous study that HNF-1 is a lost tumorsuppressor in HCC (Gut, 2008). Therefore, in this project, our aim was to explore a possible role of miR-188-5p in cancer development and progression with a focus on HCC.

Axl Receptor Axis: A New Therapeutic Target in Lung Cancer

Abstract The Axl receptor tyrosine kinase belongs to the TAM (Tyro3, Axl, Mer) family of proteins and is upregulated in multiple types of cancers, including non-small cell lung cancer. In normal tissues, TAM receptor tyrosine kinases contribute to immune regulation. In cancer, Axl expression is associated with poor outcomes and is controlled through various transcriptional and epigenetic mechanisms. Preclinical studies have shown that Axl is involved in cancer cell migration, growth, survival and resistance to chemotherapy through activation of multiple downstream signaling pathways, such as Ras/MAPK, PI3K and Rac1. Axl is also expressed on endothelial cells and plays a role in angiogenesis. In preclinical models, Axl inhibition decreases cancer growth and impedes lung cancer metastases. Small molecule Axl inhibitors have been developed and are currently being used as monotherapy or in combination with cytotoxic chemotherapy or anti-EGFR therapy in early clinical trials. Here, we review Axl structure, functions, regulation, and preclinical and clinical studies in lung cancer.

Expression and Function of Histone Deacetylase 10 (HDAC10) in B Cell Malignancies.

Histone deacetylase 10 (HDAC10) belongs to the class IIb HDAC family and its biological role remains mostly unidentified. A decreased HDAC10 expression has been reported in patients with aggressive solid tumors (Osada et al. Int J Cancer 112: 26-32, 2004; Jin et al. Int J Clin Exp Pathol 7: 5872-5879, 2014), suggesting that loss of HDAC10 expression might confer a survival advantage to malignant cells. Consequently, results from our lab suggests that overexpression of HDAC10 in aggressive mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) Z138c and MEC1 cells, respectively, resulted in a rapid induction of cell death in vitro with only 5 % of cells being alive at 48 h, cell cycle arrest, and up-regulation of co-stimulatory molecules. Here we present several standard methods to study the function of HDAC10 in B cell malignancies.

Abstract 3884: Genome-wide analysis of somatic mutations shared by co-occurring ovarian high-grade serous carcinomas and serous tubal intraepithelial carcinomas

Abstract INTRODUCTION Serous tubal intra-epithelial carcinoma (STIC) in the fallopian tube has been proposed as a putative precursor of ovarian high-grade serous carcinoma (HGSC)[1,2]. Association of STIC and HGSCs is seen in ∼50% of cases, and in ∼15% of women undergoing prophylactic removal of fallopian tubes. Clonal STIC-HGSC relationship is suggested by shared TP53 mutations and overexpression[3]. To further investigate the relationship, we applied genome-wide sequencing of same-patient STIC, HGSC and normal tube DNAs isolated from FFPE tumor specimens of 4 ovarian cancer patients. Here we report extended patterns of somatic alterations shared between STIC and HGSC and identify the affected homeostatic pathways. METHODS We established the STIC-HGSC co-occurrence by pathological evaluation and immunohistochemistry for TP53 and MKI67 positivity. Overlapping TP53 mutations were determined by Sanger sequencing. DNA was isolated from STIC, HGSC and normal tissue areas of paraffin sections, with laser-capture microdissection and whole-genome DNA amplification employed for STICs due to the small cellular content. 250 ng of DNA was converted to sequencing libraries (Kapa Biosystems kit) and exome enrichment done by SeqCap EZ System, Nimblegen, Roche. Exomes were sequenced on Illumina HiSeq2500 at ∼100x coverage in 100-bp paired-end run. Somatic mutations were analyzed by MuTect and FreeBayes callers to determine unique as well as overlapping STIC and HGSC alterations. RESULTS Deep sequencing expanded the number of shared STIC-HGSC mutations to 20-55 per patient. ETV5, LPAR4, MTOR, and PAK3 genes harbored recurrent mutations in HGSCs, and the shared STIC-HGSC mutations involved genes acting in the pathways of response to stress, regulation of apoptosis, autophagy, RAS and small GTPase-mediated signaling, and actin cytoskeleton organization (e.g. MTOR, NF1, BECN1, ARHGEF18, RASA1, PREX2, TTN). Our findings were corroborated for 80 STIC-HGSC-shared gene mutants by the cBioportal/The Cancer Genome Atlas data on ovarian serous carcinoma. CONCLUSIONS The broad patterns of somatic alterations shared by STIC and HGSC document a clonal relationship of these neoplastic lesions and possible origins of ovarian carcinomas in the tubal epithelium. We propose that our genome-wide strategy, once reproduced in a higher patient number, may facilitate future development of approaches to HGSC screening, treatment and prevention. ACKNOWLEDGMENTS IARC Regular Budget; IARC Postdoctoral Fellowship Program (supported by the European Commission FP7 Marie Curie Actions COFUND). NYU Genome Technology Center (supported in part by NIH/NCI P30CA016087). We thank Dr E. Kuhn for assistance with pathology evaluations. REFERENCES 1. Li HX, et al. Int J Clin Exp Pathol. 2014 Feb 15;7(3):848-57. 2. Kurman RJ. Ann Oncol. 2013 Dec;24 Suppl 10:x16-21. 3. Kuhn E, et al. J Pathol. 2012 Feb;226(3):421-6. Citation Format: Yan Song, Maude Ardin, Vincent Cahais, Christine Carreira, Reetta Holmila, Stephanie Villar, Xavier Castells, Maxime Vallee, Adriana Heguy, Pierre-Paul Bringuier, Qin Guo, Xun Zhang, Jiri Zavadil. Genome-wide analysis of somatic mutations shared by co-occurring ovarian high-grade serous carcinomas and serous tubal intraepithelial carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3884. doi:10.1158/1538-7445.AM2015-3884

Mimicry of sugar tumor and minute pulmonary meningothelial-like nodule to metastatic lung deposits in a patient with rectal adenocarcinoma

Several reports have described different lung lesions mimicking primary or metastatic neoplasms. In this paper, we describe the different features of two uncommon and benign lung lesions mimicking metastasis from a primary large bowel adenocarcinoma. Our patient is a 75-year old female with a history of invasive rectal adenocarcinoma. One month after her surgery, she started complaining of coughing and shortness of breath. Clear cell sugar tumor and minute meningothelial-like nodules had been found incidentally and simultaneously during her chest x-ray. The diagnosis had been made based on morphology and was supported by a positive staining to a panel of immunohistochemical stains including CD34, vimentin, HMB45, melan A and S100. An ultra-structural examination was also performed and confirmed the presence of melanosomes in sugar tumor. The coexistence of lung sugar tumor and minute pulmonary meningothelial-like nodules has never been reported in the literature and an awareness of these lesions is essential to correctly diagnose and stage patients.

Type VIII Collagen Mediates Vessel Wall Remodeling after Arterial Injury and Fibrous Cap Formation in Atherosclerosis

Collagens in the atherosclerotic plaque signal regulation of cell behavior and provide tensile strength to the fibrous cap. Type VIII collagen, a short-chain collagen, is up-regulated in atherosclerosis; however, little is known about its functions invivo. We studied the response to arterial injury and the development of atherosclerosis in type VIII collagen knockout mice (Col8(-/-) mice). After wire injury of the femoral artery, Col8(-/-) mice had decreased vessel wall thickening and outward remodeling when compared with Col8(+/+) mice. We discovered that apolipoprotein E (ApoE) is an endogenous repressor of the Col8a1 chain, and, therefore, in ApoE knockout mice, type VIII collagen was up-regulated. Deficiency of type VIII collagen in ApoE(-/-) mice (Col8(-/-);ApoE(-/-)) resulted in development of plaques with thin fibrous caps because of decreased smooth muscle cell migration and proliferation and reduced accumulation of fibrillar type I collagen. In contrast, macrophage accumulation was not affected, and the plaques had large lipid-rich necrotic cores. We conclude that in atherosclerosis, type VIII collagen is up-regulated in the absence of ApoE and functions to increase smooth muscle cell proliferation and migration. This is an important mechanism for formation of a thick fibrous cap to protect the atherosclerotic plaque from rupture.

R132C IDH1 Mutations Are Found in Spindle Cell Hemangiomas and Not in Other Vascular Tumors or Malformations

Spindle cell hemangioma (SCH) is a rare, benign vascular tumor of the dermis and subcutis. The lesions can be multifocal and are overrepresented in Maffucci syndrome, in which patients also have multiple enchondromas. Somatic mosaic R132C IDH1 hotspot mutations were recently identified in Maffucci syndrome. We evaluated the presence of mutations in solitary and multiple SCHs in patients without multiple enchondromas and tested a range of other vascular lesions that enter into the differential diagnosis. The R132C IDH1 mutation was identified by hydrolysis probes assay and confirmed by Sanger sequencing in 18 of 28 (64%) SCHs; of the 10 negative cases, 2 harbored a mutation in IDH2 (R172T and R172M) by Sanger sequencing. None of 154 other vascular malformations and tumors harbored an IDH1 R132C mutation, and R132H IDH1 mutations were absent in all 182 cases. All 16 SCHs examined by immunohistochemistry were negative for expression of HIF-1α. In conclusion, 20 of 28 (71%) SCHs harbored mutations in exon 4 of IDH1 or IDH2. Given that mutations were absent in 154 other vascular lesions, the mutation seems to be highly specific for SCH. The mutation does not induce expression of HIF-1α in SCH, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established.

Tubular cell dedifferentiation and peritubular inflammation are coupled by the transcription regulator Id1 in renal fibrogenesis

During renal fibrogenesis, tubular epithelial-mesenchymal transition is closely associated with peritubular inflammation; however, it is not clear whether these two processes are connected. We previously identified the inhibitor of differentiation-1 (Id1), a dominant negative antagonist of basic helix-loop-helix transcription factors, as a major trigger of tubular cell dedifferentiation after injury. Id1 was induced selectively in degenerated proximal tubule and collecting duct epithelia after injury and was present in both the cytoplasm and nucleus, suggesting shuttling between these two compartments. Interestingly, the upregulation of Id1 was associated with peritubular inflammation in mouse and human nephropathies. In vitro, Id1 potentiated NF-κB signaling and augmented RANTES expression in kidney epithelial cells, which led to an enhanced recruitment of inflammatory cells. Id1 also induced Snail1 expression and triggered tubular epithelial dedifferentiation. In vivo, genetic ablation of Id1 in mice reduced peritubular inflammation and decreased tubular expression of RANTES following ureteral obstruction. Mice lacking Id1 were also protected against myofibroblast activation and matrix expression, leading to a reduced total collagen deposition in obstructive nephropathy. Thus, these results indicate that Id1 shuttles between nucleus and cytoplasm and promotes peritubular inflammation and tubular epithelial dedifferentiation, suggesting that these two events are intrinsically coupled during renal fibrogenesis.