Search

Cardiac computed tomography angiogram (cCTA) is often performed in adults with coarctation of the aorta (CoA). As the population ages, assessment of atherosclerotic cardiovascular disease (ASCVD) burden is important. CoA patients ≥16 years of age seen at a referral center with cCTA or chest

A multidisciplinary method combining transcriptional data, specificity profiling, and biological characterization of an enzyme may be used to predict novel substrates. By integrating protease substrate profiling with microarray gene coexpression data from nearly 2,000 human normal and cancerous tissue samples, three fundamental components of a protease-activated signaling pathway were identified. We find that MT-SP1 mediates extracellular signaling by regulating the local activation of the prometastatic growth factor MSP-1. We demonstrate MT-SP1 expression in peritoneal macrophages, and biochemical methods confirm the ability of MT-SP1 to cleave and activate pro-MSP-1 in vitro and in a cellular context. MT-SP1 induced the ability of MSP-1 to inhibit nitric oxide production in bone marrow macrophages. Addition of HAI-1 or an MT-SP1-specific antibody inhibitor blocked the proteolytic activation of MSP-1 at the cell surface of peritoneal macrophages. Taken together, our work indicates that MT-SP1 is sufficient for MSP-1 activation and that MT-SP1, MSP-1, and the previously shown MSP-1 tyrosine kinase receptor RON are required for peritoneal macrophage activation. This work shows that this triad of growth factor, growth factor activator protease, and growth factor receptor is a protease-activated signaling pathway. Individually, MT-SP1 and RON overexpression have been implicated in cancer progression and metastasis. Transcriptional coexpression of these genes suggests that this signaling pathway may be involved in several human cancers.

Objectives: To design, implement and assess a patient and physician centered virtual visit program. Methods: Patients within the Cardiology and Neurology departments were enrolled in a real-time videoconferencing virtual visits program between April 1st 2014 and June 3rd 2015. Surveys were sent to patients who had at least one virtual visit between in the first 8 months to assess response to the use of the system and satisfaction, including the Consumer Assessment of Healthcare Providers and Systems survey (CAHPS). Results: There were 131 virtual visits in Cardiology and 419 visits in Neurology. The great majority of patients (83%) responded that they would definitely recommend a virtual visit to family or friends. Patients found the platform easy to use, with 74% of patients easily installing the product. Despite 42.5% reporting at least one technical problem, the overall patient satisfaction was high based on the CAHPS measures (Figure 1), and more than half of patients said they would even be willing to pay an up to $50 copay if needed for such visits. More than half of patients and providers felt that the quality of the visit was the same as in the office. While 45% of Cardiology patients felt the same during a virtual visit as in the office, 45% felt a stronger connection in person. Most providers felt virtual visits were either more efficient (38.5%) or just as long as office visits (50%), while 90% of patients thoughts their clinicians spent just as much time with them. Only 23.2% of patients overall however felt that a telephone call could definitely have addressed the same issue, emphasizing the value of the video conferencing platform. Conclusion: Virtual visits are well received by patients and providers, and considered by both to be efficient and useful. Implementing a virtual visit program with a design approach to assess and respond promptly to user feedback has encouraged adoption and holds promise for increasing the scale and integration into models of care delivery.

Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is the most prevalent pediatric autoinflammatory syndrome. For unexplained reasons tonsillectomy induces remission. The etiology of PFAPA is unknown; however, mutations of TNF receptor superfamily 1A (TNFRSF1A) and elevated circulating TNF-a have been described in some patients.

Background To date, there have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma. We sought to characterize the DNA copy-number profile in a cohort of metastatic samples and compare them to a cohort of primary urothelial carcinoma samples in order to identify changes that are associated with progression from primary to metastatic disease. Methods Using molecular inversion probe array analysis we compared genome-wide chromosomal copy-number alterations between 30 metastatic and 29 primary UC samples. Whole transcriptome RNA-Seq analysis was also performed in primary and matched metastatic samples which was available for 9 patients. Results Based on a focused analysis of 32 genes in which alterations may be clinically actionable, there were significantly more amplifications/deletions in metastases (8.6% vs 4.5%, p

Background. Five neuroinvasive Bacillus cereus infections (4 fatal) occurred in hospitalized patients with acute myelogenous leukemia (AML) during a 9-month period, prompting an investigation by infection control and public health officials. Methods. Medical records of case-patients were reviewed and a matched case-control study was performed. Infection control practices were observed. Multiple environmental, food, and medication samples common to AML patients were cultured. Multilocus sequence typing was performed for case and environmental B cereus isolates. Results. All 5 case-patients received chemotherapy and had early-onset neutropenic fevers that resolved with empiric antibiotics. Fever recurred at a median of 17 days (range, 9–20) with headaches and abrupt neurological deterioration. Case-patients had B cereus identified in central nervous system (CNS) samples by (1) polymerase chain reaction or culture or (2) bacilli seen on CNS pathology stains with high-grade B cereus bacteremia. Two case-patients also had colonic ulcers with abundant bacilli on autopsy. No infection control breaches were observed. On case-control analysis, bananas were the only significant exposure shared by all 5 case-patients (odds ratio, 9.3; P = .04). Five environmental or food isolates tested positive for B cereus, including a homogenized banana peel isolate and the shelf of a kitchen cart where bananas were stored. Multilocus sequence typing confirmed that all case and environmental strains were genetically distinct. Multilocus sequence typing-based phylogenetic analysis revealed that the organisms clustered in 2 separate clades. Conclusions. The investigation of this neuroinvasive B cereus cluster did not identify a single point source but was suggestive of a possible dietary exposure. Our experience underscores the potential virulence of B cereus in immunocompromised hosts.

Program/Project Purpose: Increased recognition of the global cancer burden and inequalities in care and outcomes have led to the growing field of global oncology, focused on strengthening health systems to improve cancer prevention and care. Motivated students and trainees are in need of pathways to approach these challenges. In 2012, Harvard Medical students formed Students for Global Oncology (S4GO), an adjunct to the larger inter-professional organization Global Oncology. The group had three aims: 1) connect students with mentors in the field, 2) develop novel approaches in global oncology, and 3) disseminate global oncology knowledge. Structure/Method/Design: S4GO has created content and organized events to increase awareness about the global cancer burden, while promoting trainee opportunities in research and practical hands-on projects. Engagement was enhanced by mentorship from more senior students and faculty, to interface with existing global oncology projects. Outcomes & Evaluation: Since 2012, S4GO has grown from two to 68 students. Currently, new chapters at seven other institutions in the US and Canada are being developed. As of October 2014, S4GO has developed a case-based cancer care delivery curriculum with six case-based seminars, along with numerous blog entries and interviews of leading researchers in the field of global oncology, all available on the S4GO website. Students have completed projects in over nine countries and are actively involved in technological and on-the-ground efforts to develop creative solutions and collaborations aimed at easing the global cancer burden. Held in February 2014, the inaugural student-led global oncology symposium involved 200 individuals from across the world, including leaders in global health, pharmaceutical industry, public policy and cancer care. This symposium has been viewed by hundreds online and has fostered novel collaborations and projects focused on enhancing cancer care delivery. Going Forward: In the coming years, S4GO will continue efforts to build awareness and catalyze creative solutions for cancer care in resource-limited settings. These efforts will increase exposure for novel and successful student efforts as well as intra-institutional and intra-professional activity. (Less)

Hepsin is a membrane-anchored, trypsin-like serine protease with prominent expression in the human liver and tumours of the prostate and ovaries. To better understand the biological functions of hepsin, we identified macromolecular substrates employing a tetrapeptide PS-SCL (positional scanning-synthetic combinatorial library) screen that rapidly determines the P1-P4 substrate specificity. Hepsin exhibited strong preference at the P1 position for arginine over lysine, and favoured threonine, leucine or asparagine at the P2, glutamine or lysine at the P3, and proline or lysine at the P4 position. The relative activity of hepsin toward individual AMC (7-amino-4-methylcoumarin)-tetrapeptides was generally consistent with the overall peptide profiling results derived from the PC-SCL screen. The most active tetrapeptide substrate Ac (acetyl)-KQLR-AMC matched with the activation cleavage site of the hepatocyte growth factor precursor sc-HGF (single-chain HGF), KQLR downward arrowVVNG (where downward arrow denotes the cleavage site), as identified by a database analysis of trypsin-like precursors. X-ray crystallographic studies with KQLR chloromethylketone showed that the KQLR peptide fits well into the substrate-binding cleft of hepsin. This hepsin-processed HGF induced c-Met receptor tyrosine phosphorylation in SKOV-3 ovarian cancer cells, indicating that the hepsin-cleaved HGF is biologically active. Activation cleavage site mutants of sc-HGF with predicted non-preferred sequences, DPGR downward arrowVVNG or KQLQ downward arrowVVNG, were not processed, illustrating that the P4-P1 residues can be important determinants for substrate specificity. In addition to finding macromolecular hepsin substrates, the extracellular inhibitors of the HGF activator, HAI-1 and HAI-2, were potent inhibitors of hepsin activity (IC50 4+/-0.2 nM and 12+/-0.5 nM respectively). Together, our findings suggest that the HGF precursor is a potential in vivo substrate for hepsin in tumours, where hepsin expression is dysregulated and may influence tumorigenesis through inappropriate activation and/or regulation of HGF receptor (c-Met) functions.

Src kinases are activated and relocalize to the cytoplasm during mitosis, but their mitotic function has remained elusive. We describe here a novel mitotic substrate of src kinases. Trask (transmembrane and associated with src kinases) is a 140 kDa type I transmembrane glycoprotein unrelated to currently known protein families. Src kinases phosphorylate Trask in vitro and mediate its mitotic hyperphosphorylation in vivo. Trask associates with both yes and src, is localized to the cell membrane during interphase, and undergoes cytoplasmic relocalization during mitosis. Overexpression of Trask leads to cell rounding and a loss of adhesion phenotype. Consistent with a function in cell adhesion, Trask interacts with a number of adhesion and matrix proteins including cadherins, syndecans, and the membrane-type serine protease 1 (MT-SP1), and is proteolytically cleaved by MT-SP1. Trask is unique among cell adhesion molecules in that it is under cell cycle regulation and thus links src kinases with the mitotic regulation of cell adhesion. This suggests a potential pathway by which hyperactive src kinases in tumors can deregulate adhesion signaling and mediate the metastatic phenotype.

Abstract 39 Background: In response to the growing burden of cancer, Global Oncology, Inc., and the National Cancer Institute Center for Global Health launched a free, online, interactive map, the Global Cancer Project Map (GCPM) [ http://gcpm.globalonc.org ], to allow policy makers, researchers, and civil society around the world to search this central repository of international cancer control and research projects. The GCPM serves to catalyze collaboration in cancer research and clinical care, as well as inform research and care gaps. Methods: In addition to search options by project attributes, the GCPM provides map overlays of epidemiological measures using IARC’s GLOBOCAN cancer-specific estimates of incidence, prevalence, and mortality, cancer disability--adjusted life years, and UN Human Development Index country values. Currently, the map displays projects with international collaborators collated from the NCI, NCI-Designated Cancer Centers, UICC and ASCO. Results: The GCPM search options offer countless angles of looking at projects worldwide. Of the 1,479 currently-mapped projects, 44.8% have investigators or collaborators in less-developed countries (LDCs) (as defined by the UN). Of the 1218 with a project type classification, 104 relate to capacity building and/or training, with 69 of these projects (66.3%) occurring in LDCs. Utilizing the cancer type search options, the GCPM currently displays 54 cervical cancer projects with LDC collaborators, where the cervical cancer mortality age--standardized risk is more than 2.5 times higher for LDCs than more-developed countries. Conclusions: The GCPM is a real-time needs assessment tool to allow the cancer community to visualize international efforts in cancer control and link need to action. To better address the growing burden of cancer, the partnership is actively seeking collaboration and additional project submissions. Utilized with cancer statistic overlays, the GCPM can help develop regional priorities in cancer research and control. Funding: This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Ali Chisti No relationship to disclose Nour Sharara No relationship to disclose Manaswi Gupta No relationship to disclose Jane Craycroft No relationship to disclose Ilyana Rosenberg Employment: Connance, Inc., Hayes Management Consulting Camille Morgan No relationship to disclose Kalina Duncan No relationship to disclose Rachel Abudu No relationship to disclose Billy Andre No relationship to disclose Shannon Silkenson No relationship to disclose Jennifer Silva No relationship to disclose Ami Bhatt No relationship to disclose Ted Trimble No relationship to disclose Franklin Huang Stock or Other Ownership: GlaxoSmithKline, Abbvie

Abstract 21 Background: New efforts are being made to bring modern cancer medicine to patients in low- resource settings, where limited public awareness of cancer and health literacy pose significant challenges. Partners In Health (PIH) launched its first cancer program in Haiti in collaboration with Dana-Farber Cancer Institute and Brigham and Women's Hospital; however, no patient education materials appropriate for Haiti existed. Global Oncology has developed written educational materials based on cancer patient needs in low-resource settings. Objectives are to: 1) Adapt Global Oncology's patient education materials to be culturally and literacy appropriate for Haiti; 2) Assess the effectiveness of written materials for cancer patient education in a low-resource setting. Methods: Feedback from staff at the PIH-affiliated Hôpital Universitaire de Mirebalais (HUM) was incorporated into the pilot materials. We recruited 33 chemotherapy patients at HUM for interviews (n=20) and two focus groups (n=13). Patients were presented the booklet by the Oncology social worker, and pre- and post-counseling tests were administered. Qualitative data regarding booklet design and content was collected through observation of counseling sessions, interview questions and focus group discussions. Providers were surveyed with a questionnaire and proposed modifications to the booklet were discussed during a provider focus group. Results: Patients across all levels of education significantly increased their knowledge from pre-test (m=49.2%, sd= 19.5%) to post-test (m=87.9% sd = 8.9%; t(19)=10.07, pConclusion: Written patient education materials designed for low-resource settings enhance discussions between patients and providers, and can be a tool for disseminating information beyond the hospital to the family, friends and caregivers of cancer patients. Incorporating patient and provider feedback is essential to ensure written materials are culturally and literacy appropriate for the local patient population. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Lauren E. Schleimer No relationship to disclose Peter-Gens Desameau No relationship to disclose Ruth Damuse No relationship to disclose Maia Olsen No relationship to disclose Veronica Manzo No relationship to disclose Rachael Guay No relationship to disclose Ami S. Bhatt No relationship to disclose Carlos Cardenas No relationship to disclose Franklin W. Huang Stock or Other Ownership: GlaxoSmithKline, Abbvie Lawrence N. Shulman No relationship to disclose

Background Infection is a major preventable cause of transplant-related morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HCT). Bacteremia is the most common infectious complication in HCT, often occurring during periods of mucositis when the risk for microbial translocation from the intestine is increased. Prior research in HCT patients using 16S rRNA sequencing demonstrated that gut microbiota dominance by either Enterococcus spp. or Proteobacteria was associated with the development of bacteremia with Enterococcus spp. and Gram-negative organisms, respectively. No studies to date, however, have compared bacteremia isolates and gut microbiota samples at a strain-specific level using next-generation shotgun metagenomic sequencing (NGS). Methods In order to assess the degree of genetic similarity between bacteremia isolates and the gut microbiota, we identified patients who had undergone HCT at Stanford and developed a bacteremia between October 2015 and September 2016 for whom we had both saved blood culture isolates and stool samples within 30 days preceding bacteremia. We identified 15 patients from whom we had 17 bacteremia isolates, and performed NGS (Illumina HiSeq 4000) on stool and isolate DNA. We generated draft assemblies of isolate genomes using the SPAdes assembler, and aligned stool metagenomic reads to the draft isolate genomes using Bowtie2, filtering reads for perfect end-to-end alignment. Results Enteric gram-negative bacteremia isolates were identical to those in the gut microbiota, as has been demonstrated in prior studies using older strain-typing Methods. Surprisingly, we also identified gram-positive organisms that were identical in both the blood and stool prior to bacteremia, which challenges existing dogma regarding sources of gram-positive bacteremia-causing organisms. Conclusion Using a highly sensitive and accurate NGS-based strain typing method, we provide evidence of translocation of organisms from the gut microbiota and subsequent bacteremia. The gut was confirmed as a source for both classic enteric gram-negative and classically non-enteric Gram-positive bacteremia in HCT patients. These findings may have implications for the origins of bacteremia in HCT patients previously classified as CLABSIs. Disclosures A. Bhatt, Janssen Human Microbiome Institute / Johnson and Johnson: Consultant, Consulting fee

Abstract 31 Background: Diagnostic resources are often limited in low- and middle-income countries (LMICs). Transportability of diagnostic specimens facilitates outreach services, potentially giving LMICs access to state-of-the-art services, which results in more precise therapies. The aim of this work was to evaluate the clinical impact of our ongoing international outreach consult service and to identify specific challenges that LMICs face, with the ultimate goal of guiding focused interventions to address needs in LMICs. Methods: Cases received were catalogued, noting demographics, anatomic site, and initial and final diagnoses. Differences between initial and final diagnoses were categorized as minor or major discrepancies with or without clinical impact affecting management and prognosis. A fifth reclassification category was created for cases in which only a broad diagnosis was initially achieved, and for which more definitive classification was subsequently provided. Results: Five hundred forty-five cases were identified. Initial histopathologic diagnoses were available for 318. Of these, 196 (62%) had discrepant definitive diagnoses, including 165 (52%) with clinical impact. Of those with clinical impact, 95 (58%) were reclassifications, 55 (33%) were major discrepancies, and 15 (9%) were minor differences. Of discrepancies with clinical impact, hematopathology cases were most frequent (40; 24%), then neuropathology (28; 17%), soft tissue (27; 16%), bone (18; 11%), and developmental tumors (18; 11%). Conclusion: Global outreach pathology consult services to LMICs have significant clinical and social impact, which is reflected by one half of the cases reviewed resulting in major change or reclassification in diagnoses that significantly impacted clinical management. Although distribution of discrepant diagnoses in this series may reflect a pediatric referral bias, they also provide insight into particular challenges that are faced by pathologists and clinicians from LMICs as a result of limited access to ancillary techniques, such as immunohistochemistry or molecular diagnostics. In addition, many cases were un- or misdiagnosed because of lack of expertise in certain areas. These trends suggest that, other than direct consultative diagnostic support, concerted efforts to improve laboratory infrastructure, resources, and training in LMICs would be efficacious in the long run. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST No COIs from the authors.

To the Editor: We report a case of a combined immunodeficiency syndrome, thymic hyperplasia, and impaired lymphatic system function that strongly resembled the phenotype of the Ikaros-null knockout mouse. The patient was well until her early teenage years when she had bacteremia of unknown cause. At menarche, lymphedema developed in her legs. At 16 years of age, she had disseminated varicella–zoster infection, which culminated in a splenectomy for possible splenic rupture. In her 20s and 30s, she had frequent sinopulmonary infections, and severe IgA deficiency and a profound deficiency of natural killer (NK) and B cells were eventually diagnosed. She . . .

Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile., National Cancer Institute (U.S.), National Human Genome Research Institute (U.S.)

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

Background & Aims: Microbial dysbiosis and aberrant hostâmicrobe interactions in the gut are believed to contribute to the development and progression of Crohnâs disease (CD). Microbiome studies in CD typically have focused on microbiota in feces or superficial mucosal layers of the colon because accessing DNA from deeper layers of the bowel is challenging. In this study, we analyzed the deep tissue microbiome in patients who underwent surgical resection of the small intestine. Methods: Paraffin blocks were obtained from 12 CD patients undergoing ileocecal resection, and healthy ileum samples (inflammatory bowel diseaseâfree controls) were obtained from 12 patients undergoing surgery for right-sided colon cancer. Diseased and healthy-appearing ileum was identified using microscopy, and paraffin blocks were macrodissected using a core needle to specifically isolate DNA. Illumina Whole Genome Sequencing was used for microbial sequence identification and subsequent taxonomic classification using the PathSeq tool. Results: We observed significant differences between the microbiome of CD samples vs inflammatory bowel diseaseâfree controls, including depletion of Bacteroidetes and Clostridia. Notably, microbial composition at the phyla level did not differ markedly between healthy and diseased areas of CD patients. However, we observed enrichment of potentially pathogenic organisms at the species level. Conclusions: Our study showed dysbiosis within deeper layers of the ileum of CD patients, specifically enrichment of enterotoxigenic Staphylococcus aureus and an environmental Mycobacterium species not described previously. Future studies with larger cohort sizes are warranted to confirm these findings. Studies would benefit from effective microbial DNA extraction methods from paraffin sections and host nucleic acid depletion approaches to increase microbial read coverage. Keywords: Crohn's Disease, Deeper Mucosal Layers, Microbial Dysbiosis

Abstract 8 Background: Schistosoma haematobium has an extensive history in Egypt, with certain regions of the country reporting infection rates as high as 70%. This parasite has also been linked to bladder cancer since the beginning of the 20th century. However, little was done to elucidate a causal linkage between schistosomiasis and bladder cancer prior to the 1940s. This paper examines the reasons for this lack of attention, and the conditions that eventually stimulated research in Egypt on the connection between the two diseases. Methods: Through a review of secondary sources, interpretation of primary sources, and archival research at the Rockefeller Foundation, I have been able to trace and analyze the relationship between schistosomiasis and bladder cancer in Egypt. Results: Much of the research spearheaded by imperial powers during the colonial era focused on maintaining the short-term health of agricultural workers crucial to the colonial economy. As a long-term sequelae of infection, bladder cancer did not immediately impede the efficiency of this labor force. Thus, while research into schistosomiasis infection boomed throughout the colonial period, inquiry into its relationship to bladder cancer was stifled until power transitioned to Egyptians themselves and reforms took hold that brought Egyptian scientists to the forefront. Conclusion: Renewed interest in the link between schistosomiasis and bladder cancers from the 1940s followed an important shift in the political structures that governed scientific research in Egypt and led to the ascendancy of Egyptian scientists and physicians. This shift changed research agendas. As public health and medical practitioners work globally to advance health systems, lessons learned from Egypt's early experiences in schistosomiasis control and bladder cancer intervention are a reminder of the importance of including local scientific communities and internal organizations in the process of producing medical knowledge and public health infrastructures. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Afkera Daniel No relationship to disclose Ami Bhatt Patents, Royalties, Other Intellectual Property: I have a patent pending focused on therapeutic, diagnostic and interventional approaches to targeting of Bradyrhizobium enterica, a novel bacterium I and colleagues discovered that appears to be associated with a complication of stem cell transplantation.

e18048Background: In response to the growing global burden of cancer, Global Oncology, Inc., and NCI’s Center for Global Health propose a call to action to populate work in low- and middle-income a...

Hematologic problems are common and often clinically significant in patients with systemic lupus erythematosus (SLE). The purpose of this chapter is to provide an overview of potential hematologic complications of SLE, with a focus on the prognostic significance, pathophysiology, workup, and treatment options for lupus-associated anemia, thrombocytopenia, immunological defects, and coagulopathies.

MT-SP1 is a type II transmembrane serine protease implicated in a range of human cancers including those of the breast, cervix, ovaries, prostate, colon and gastrointestinal tract. Mouse models have shown it to be critical for proper epidermal development and postnatal survival. However, the role of this enzyme in normal and malignant biology has not yet been fully elucidated. Several groups have identified putative substrates of MT-SP1 in an effort to understand the possible biological processes in which this protease may be involved. Methods for substrate identification include comparing known protein cleavage sequences with MT-SP1 specificity data, in vitro cleavage assays, examining genetic microarrays for enzyme/substrate coexpression, immunohistochemistry for colocalization, and a variety of phenotypic observations using cell culture and mouse models. Given the inherent limitations of each individual method, substrate plausibility is best substantiated using a combination of experimental approaches. Here we review MT-SP1 substrates identified to date and the possible physiological implications of substrate cleavage in cell-microenvironment interactions. This data indicates that MT-SP1 is capable of playing roles in growth factor activation, receptor activation and inactivation, protease activation, and ectodomain shedding. We also present for the first time vascular endothelial growth factor receptor 2 (VEGFR-2) as a putative substrate for MT-SP1.

Notch pathway antagonists such as γ-secretase inhibitors (GSIs) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole-exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A. The three gain-of-function mutations were absent from remission marrow cells, but the DNMT3A mutation persisted in heterozygous form in remission marrow, consistent with an origin for the patient's ETP-ALL from clonal hematopoiesis. Ex vivo culture of ETP-ALL blasts confirmed high levels of activated NOTCH1 that were repressed by GSI treatment, and RNA-seq documented that GSIs downregulated multiple known Notch target genes. Surprisingly, one potential target gene that was unaffected by GSIs was MYC, a key Notch target in GSI-sensitive T-ALL of cortical T-cell type. H3K27ac super-enhancer landscapes near MYC showed a pattern previously reported in acute myeloid leukemia (AML) that is sensitive to BRD4 inhibitors, and in line with this ETP-ALL blasts downregulated MYC in response to the BRD4 inhibitor JQ1. To our knowledge, this is the first example of complete response of a Notch-mutated ETP-ALL to a Notch antagonist and is also the first description of chromatin landscapes associated with ETP-ALL. Our experience suggests that additional attempts to target Notch in Notch-mutated ETP-ALL are merited.

BACKGROUND. Prostase/KLK4isamemberofthehumankallikrein(KLK)genefamilythat is expressed in prostate epithelial cells under the regulation of androgenic hormones. In this study, we sought to characterize the substrate specificity of KLK4 in order to gain insight into potential physiological roles of the enzyme. METHODS. A chimeric form of KLK4 was constructed in which the pro-region of KLK4 was replaced with the signal and propeptide sequence of trypsinogen (proT-KLK4) to create an activation site susceptible to enterokinase cleavage. proT-KLK4 was expressed in Drosophila S2 cells, purified, and activated with enterokinase to generate mature KLK4. The extended substrate specificity of KLK4 was defined by screening tetrapeptide positional scanning synthetic combinatorial libraries (PS-SCL). RESULTS. The preferred P1-P4 positions as determined by PS-SCL were: P1-Arg; P2-Gln/ Leu/Val; P3-Gln/Ser/Val; P4-Ile/Val. The trypsin-like specificity of KLK4 was further confirmed using synthetic chromogenic peptides. Based upon the optimal cleavage site residues, a database search for potential KLK4 substrates identified several proteins with potential roles mediating normal prostate physiology or neoplastic growth including KLK3/ PSA, parathyroid hormone-related peptide (PTHrP), and members of the bone morphogenetic protein (BMP) family. Recombinant KLK4 was able to activate pro-PSA/KLK3 and degrade members of the insulin-like growth factor (IGF) binding protein (IGFBP) family. CONCLUSIONS. TheseresultsidentifypotentialKLK4substratesthatmayservetodefinethe role of this protease in normal prostate physiology, and facilitate studies of the consequences of KLK4 expression in pathological conditions. Prostate 62: 1–13, 2005. # 2004 Wiley-Liss, Inc.

Membrane type serine protease 1 (MT-SP1) is a representative member of a large family of related enzymes known as type II transmembrane serine proteases or membrane type serine proteases. MT-SP1 has been implicated in the selective proteolysis of key extracellular substrates but its physiological role is still not fully understood. MT-SP1 expression at the protein and RNA level has been previously examined by non-quantitative methods such as in situ hybridization, Northern blotting and immunohistochemistry. To establish an introductory understanding of the quantitative mRNA expression of MT-SP1 and to correlate these levels with urokinase-type plasminogen activator receptor (uPAR), a key component of extracellular proteolysis, quantitative RT-PCR was carried out. RNA expression was analyzed in 34 human cancer cell lines, 26 human tissues and 18 primary human breast cancer tissue samples. MT-SP1 mRNA is highly expressed in many breast, ovarian, prostate and colon cancer cell lines and normal human tissues of endodermal origin. At the transcript level, MT-SP1 shows a highly statistically significant correlation (Pearson's product moment correlation r = 0.784, p < 0.001) with uPAR in human breast cancer tissue. The exact role of MT-SP1 in concert with proteins such as uPAR and other members of the plasminogen activator cascade has yet to be ascertained. However, the significant correlation between MT-SP1 and uPAR transcript levels in this initial study suggests further work to establish the role of MT-SP1 as a possible prognostic, diagnostic or therapeutic target for breast cancer.

Background Bacillus cereus has been associated with central nervous system (CNS) infections in immunocompromised patients.1 We report 5 cases of neuroinvasive B.cereus infections (4 fatal) in patients with acute myelogenous leukemia (AML) at Brigham and Women’s Hospital (BWH) in Boston from May 2013 to February 2014. Methods Clinical Investigation: Cases were defined as patients with positive blood or CNS cultures for B.cereus and/or positive PCR tests from CNS specimens and radiological evidence of acute CNS disease >48 hours after admission. Infection control practices were observed. A case-control analysis of medications and exposures was conducted; odds ratios and p-values were calculated via Fisher’s exact test. Genomic Analysis: Genomic DNA was extracted from patient-derived and environmental B. cereus isolates. Sequencing libraries were prepared and paired-end whole genome sequencing (WGS) was performed. Sequencing reads were computationally assembled using several existing tools (SPAdes, AllPaths-LG, VELVET, and Newbler). Draft genome annotation was performed using RAST and Prodigal. All single copy core genes were aligned using MUSCLE and a phylogenetic tree was generated using FastTree and RAxML. Results Clinical Investigation: All 5 cases were AML patients who received chemotherapy. All had neutropenic fevers early in their course that resolved with empiric antibiotics. Fever recurred > 1 week into hospitalization (median onset 17 days, range 9-20) with headaches, neurological changes, and abnormal CNS imaging. Three had documented B. cereus bacteremia with bacilli identified on CNS pathological stains; two had positive CNS cultures. Four patients expired. Autopsies were notable for intestinal ulcers with Gram-positive bacilli in 2 patients. No infection control breaches were observed. Of 43 environmental samples, 4 tested positive for B.cereus, including a kitchen cart where bananas were stored, the shelf of a blanket warmer, and an air sample near a construction site. On case-control analysis, no medications were associated with cases. The only significant food exposures were bananas (OR 9.3, p=0.04) and cranberry juice (OR 9.6, p=0.04). Genomic Analysis: WGS data was obtained for all B. cereus isolates from BWH (n=4) and swabs of environmental screening efforts from BWH (n=4). Two patient isolates (7299 and 6254) were taken forward for pilot analysis. A comparison of various computational assembly tools demonstrated that the SPAdes assembler exhibited superior performance. SPAdes was thus used for draft genome assembly for the remaining isolates. Phylogenetic analysis of isolates 7299 and 6254 revealed that the organisms were genetically distinct from one another (Fig. 1). Genomic analysis and multilocus sequence typing (performed by WGS and independently by PCR amplification/Sanger sequencing) confirmed that all strains were genetically distinct from one another, and suggested that the environmental strains were relatively divergent from the pathogenic strains studied. Conclusions Neuroinvasive B.cereus infection should be suspected in febrile AML patients with acute neurological symptoms, even those with negative blood cultures. The clinical investigation suggests the outbreak may have been attributable to gastrointestinal inoculation, possibly secondary to bananas. Of note, the B. cereus strain cultured from the suspected banana source was not identical to the pathogenic strains. Multiple changes in practice were instituted as a consequence of this outbreak including enhanced environmental cleanings, temporary modification of empiric antibiotic recommendations for recurrent neutropenic fever (vancomycin, cefepime, and ciprofloxacin) and the placement of all AML patients on diets that excluded fresh fruits, vegetables, and rice. Six months have elapsed since the last case. WGS demonstrated that the case series was not the result of a single, hyper-virulent B. cereus organism. Rather, the infections appear to have been attributable to distinct B. cereus strains that fall into two distinct genotypic clusters. Ongoing comparative microbial genomic and biological efforts are underway and have identified candidate bacterial and host factors that may induce heightened virulence in this patient population. 1. Inoue et al. Leukemia & lymphoma. 2010;51(5):860-9. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Pulmonary complications are a significant cause of morbidity and mortality following Hematopoietic Stem Cell Transplantation (HSCT). It is estimated that they occur in 40-60% of patients, causing 10-40% of transplant-related deaths and resulting in diminished quality of life in those who survive. The wide spectrum of pulmonary complications is believed to be multifactorial, including pretransplant chemoradiation, infection, and graft-versus-host disease (GVHD). The histological spectrum of pulmonary GVHD features interstitial injury, airway injury (including bronchiolitis obliterans), and vascular disease (including veno-occlusive disease). The objective of this study was to compare ante mortem clinical suspicion of pulmonary complications and postmortem findings in a modern HSCT cohort. Methods All patients who underwent allogeneic HSCT at our institution (n=1854) between January 1, 2000 and June 30th 2010 were reviewed. To date we have completed the review of all autopsies (38) in patients who died of any cause greater than one year following HSCT. Presence of pulmonary GVHD was assessed by a pathologist blinded to the autopsy report, according to the categories of injury previously described by Yousem (1995). Lymphocytic infiltration and structural remodeling was scored separately for the airways, vasculature, and interstitium. Cases with extensive lung involvement by infection, malignancy, or other defined process (i.e. aspiration injury) were excluded from analysis. We evaluated the following clinical predictors for an association with development of airway disease and pulmonary vascular disease: patient gender, male patient with female donor, baseline FEV1%, peripheral blood stem cell source, myeloablative conditioning regimen, busulfan based conditioning regimen, patient CMV status, donor CMV status, related donor, matched donor, presence of acute GVHD, presence of chronic GVHD, and donor age. Each predictor was evaluated for significance between cases and controls. Two-sided Fisher’s exact test was used to compare categorical variables between groups, and a 2-sided Wilcoxon Rank-Sum test was used to compare continuous variables. All statistical analyses were performed using SAS9.3. Results A total of 35 (92%) patients had evaluable pathology and were reviewed. Pulmonary complications were felt to contribute to death in 17 (49%) cases, and 28 (80%) of the patients had a diagnosis of chronic GVHD prior to death. Airway disease, interstitial disease, and vascular disease were all clinically under recognized compared to the number of cases detected on autopsy (table 1). Varying degrees of pathological changes were detected (table 2); including 10 (28.6%) patients having bronchiolitis obliterans (BO) and 12 (34.3%) patients having pulmonary veno-oclussive disease (PVOD). Of the patients with PVOD, 12 (86%) also had airway disease (p=0.07). In a univariate analysis, a positive cytomegalovirus (CMV) serology status in the patient was associated with the presence of airway disease (p= Conclusions Pulmonary manifestations of chronic GVHD, particularly BO, were clinically under recognized in our allogeneic HSCT population. Our results also suggest that pulmonary VOD, which has traditionally been considered a rare complication, may be clinically and histologically under recognized. A positive CMV serology status in patients was associated with the occurrence of airway disease. Ablative conditioning and the presence of acute GVHD was associated with the occurrence of vascular disease. Disclosures: No relevant conflicts of interest to declare.

An estimated 15-20% of all human malignancies is caused by infectious agents, such as human papillomavirus (HPV), Epstein-Barr virus (EBV) or Helicobacter pylori (H. pylori). The recent development of massively parallel next generation sequencing technology led to the discovery of Merkel cell polyomavirus, and more recently a significant enrichment of Fusobacterium nucleatum (F. nucleatum) and related Fusobacterium species in colorectal carcinomas compared to non-neoplastic colon tissue from the same patients. However, these studies involved relatively small number of samples and there are likely many additional cancer-associated microbes that are yet to be discovered. TCGA sequencing data from over 20 human cancer types provide an unprecedented opportunity for cancer-associated pathogen discovery. Using PathSeq, software for pathogen discovery by computational subtraction, we have begun analyzing TCGA sequencing data for the presence of viral, fungal or bacterial sequences. We will present our preliminary data from the analysis of mRNA-seq data including evidence for (1) a greater role of viral integration into tumor suppressor gene loci in HPV-driven tumors and (2) complex interplay between viruses, bacteria and host cancer cells in various cancer types. We will also discuss our discovery efforts for previously unannotated pathogens in the TCGA dataset. Citation Format: Joonil Jung, Chandra Sekhar Pedamallu, Aleksander D. Kostic, Samuel Freeman, Akinyemi I. Ojesina, Alice Berger, Ami Bhatt, Fujiko Duke, Gad Getz, Matthew Meyerson. Pan-cancer PathSeq analysis on TCGA data for pathogen discovery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1501. doi:10.1158/1538-7445.AM2013-1501

Urothelial carcinoma (also called transitional cell carcinoma, most commonly of the bladder) is the fourth leading cause of new cancers in men in the United States, and accounts for 13,000 deaths per year. Five-year survival for patients with muscle invasive disease is below 50%. Both genetic mutations and epigenetic events are important in urothelial cancer pathogenesis and prognosis, and environmental triggers such as Schistosoma infection and tobacco have been identified. In this study we have undertaken a transcriptomic analysis of fourteen paired primary tumors and distant metastases in order to identify mutations and potential pathogenic viruses that may play a role in the pathogenesis of urothelial cancer. The contribution of infections to urothelial cancer pathogenesis remains a hotly contested issue with data both supporting and refuting the role of polyomaviruses in the disease. Recently, our colleagues at the Broad Institute discovered a striking similarity in DNA mutation pattern between cervical cancer, which is virally driven, and bladder cancer. Based on this finding, we hypothesize that a subset of urothelial cancers are triggered by a microbial pathogen that can be detected using nucleic acid sequencing methods. The majority of clinical translational studies to date have investigated patient urine samples. While these studies have been unsuccessful in identifying a strong candidate microbial trigger of urothelial cancer, direct analysis of tumor tissue for pathogen discovery has not been rigorously pursued. In order to investigate a potential microbial cause of urothelial cancer, we propose undertaking a “deep sequencing” approach where all RNA will be sequenced, followed by taxonomic classification of microbial sequences. In addition to the microbial characterization of these samples, the transcriptomic data will be analyzed to identify disease-associated mutations, fusions and splicing variants of significance in primary and matched metastasis pairs. This study represents an analysis of the largest matched primary tumor-distant metastasis cohort to our knowledge, to date. We anticipate that discovery of a novel pathogen or significant transcriptomic changes that trigger urothelial cancer could dramatically alter clinical management by enabling development of screening methods and protocols, targeted therapies and vaccines. Citation Format: Ami S. Bhatt, Chandra Sekhar Pedamallu, Fujiko Duke, Joonil Jung, Samuel S. Freeman, Andrew Cherniak, Rachel Park, Jaegil Kim, David Kwiatkowski, Jonathan Rosenberg, Matthew Meyerson. Transcriptomic and pathogen analysis in bladder cancer primary tumor and metastasis pairs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4149. doi:10.1158/1538-7445.AM2013-4149

Objective Adult hospitals are a common location of adult congenital heart disease (ACHD) admissions, including cardiac surgical admissions. Understanding the patterns and predictors of resource use could aid these institutions by identifying and targeting potentially modifiable determinants of high resource use (HRU). Our objectives were to examine resource use during adult congenital heart surgical admissions in adult hospitals, determine the association of HRU with mortality, and identify risk factors for HRU. Design Population-based retrospective study We obtained data from the Nationwide Inpatient Sample 2005–2009 and examined ACHD surgical admissions ages 18–49 years (n = 16 231). Outcome Measures We defined HRU as admissions with >90th percentile for total hospital charges. Results Despite representing 10% of admissions, HRU admissions accounted for 32% of total charges. HRU admissions had a higher mortality rate (9.7% vs. 1.8%, P < .001). Multivariable analysis demonstrated that HRU is associated with government insurance adjusted odds ratio (AOR) 2.0 (95% confidence interval [CI] 1.6,2.4), emergency admissions AOR 3.9 (95% CI 3.1,4.8), complications AOR 4.2 (95% CI 3.3,5.2), renal failure AOR 1.8 (95% CI 1.4,2.2), congestive heart failure AOR 1.2 (95% CI 1,1.4), surgical complexity risk category-2 AOR 2.0 (95% CI 1.0,3.6), and category-3+ AOR 2.3 (95% CI 1.4,3.8). Conclusions HRU admissions for adult congenital heart surgery consumed a disproportionate amount of resources and were associated with higher mortality. HRU risk factors included nonelective admissions, government insurance, heart failure, surgical complexity, renal failure, and complications. Complications, if preventable, may be a target for improvement strategies to decrease resource use. Other risk factors may require a broader patient care approach.