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Complete, closed bacterial genomes from microbiomes using nanopore sequencing. Nature biotechnology Moss, E. L., Maghini, D. G., Bhatt, A. S. 2020
Abstract

Microbial genomes can be assembled from short-read sequencing data, but the assembly contiguity of these metagenome-assembled genomes is constrained by repeat elements. Correct assignment of genomic positions of repeats is crucial for understanding the effect of genome structure on genome function. We applied nanopore sequencing and our workflow, named Lathe, which incorporates long-read assembly and short-read error correction, to assemble closed bacterial genomes from complex microbiomes. We validated our approach with a synthetic mixture of 12 bacterial species. Seven genomes were completely assembled into single contigs and three genomes were assembled into four or fewer contigs. Next, we used our methods to analyze metagenomics data from 13 human stool samples. We assembled 20 circular genomes, including genomes of Prevotella copri and a candidate Cibiobacter sp. Despite the decreased nucleotide accuracy compared with alternative sequencing and assembly approaches, our methods improved assembly contiguity, allowing for investigation of the role of repeat elements in microbial function and adaptation.

View details for DOI 10.1038/s41587-020-0422-6

View details for PubMedID 32042169
Microbes and microbiomes in 2020 and beyond. Nature communications Natarajan, A., Bhatt, A. S. 2020; 11 (1): 4988
View details for DOI 10.1038/s41467-020-18850-6

View details for PubMedID 33020496
MetaRibo-Seq measures translation in microbiomes. Nature communications Fremin, B. J., Sberro, H., Bhatt, A. S. 2020; 11 (1): 3268
Abstract

No method exists to measure large-scale translation of genes in uncultured organisms in microbiomes. To overcome this limitation, we develop MetaRibo-Seq, a method for simultaneous ribosome profiling of tens to hundreds of organisms in microbiome samples. MetaRibo-Seq was benchmarked against gold-standard Ribo-Seq in a mock microbial community and applied to five different human fecal samples. Unlike RNA-Seq, Ribo-Seq signal of a predicted gene suggests it encodes a translated protein. We demonstrate two applications of this technique: First, MetaRibo-Seq identifies small genes, whose identification until now has been challenging. For example, MetaRibo-Seq identifies 2,091 translated, previously unannotated small protein families from five fecal samples, more than doubling the number of small proteins predicted to exist in this niche. Second, the combined application of RNA-Seq and MetaRibo-Seq identifies differences in the translation of transcripts. In summary, MetaRibo-Seq enables comprehensive translational profiling in microbiomes and identifies previously unannotated small proteins.

View details for DOI 10.1038/s41467-020-17081-z

View details for PubMedID 32601270
A Bioinformatic Analysis of Integrative Mobile Genetic Elements Highlights Their Role in Bacterial Adaptation. Cell host & microbe Durrant, M. G., Li, M. M., Siranosian, B. A., Montgomery, S. B., Bhatt, A. S. 2019
Abstract

Mobile genetic elements (MGEs) contribute to bacterial adaptation and evolution; however, high-throughput, unbiased MGE detection remains challenging. We describe MGEfinder, a bioinformatic toolbox that identifies integrative MGEs and their insertion sites by using short-read sequencing data. MGEfinder identifies the genomic site of each MGE insertion and infers the identity of the inserted sequence. We apply MGEfinder to 12,374 sequenced isolates of 9 prevalent bacterial pathogens, includingMycobacterium tuberculosis, Staphylococcus aureus, and Escherichia coli, and identify thousands of MGEs, including candidate insertion sequences, conjugative transposons, and prophage elements. The MGE repertoire and insertion rates vary across species, and integration sites often cluster near genes related to antibiotic resistance, virulence, and pathogenicity. MGE insertions likely contribute to antibiotic resistance in laboratory experiments and clinical isolates. Additionally, we identified thousands of mobility genes, a subset of which have unknown function opening avenues for exploration. Future application of MGEfinder to commensal bacteria will further illuminate bacterial adaptation and evolution.

View details for DOI 10.1016/j.chom.2019.10.022

View details for PubMedID 31862382
Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes. Cell Sberro, H., Fremin, B. J., Zlitni, S., Edfors, F., Greenfield, N., Snyder, M. P., Pavlopoulos, G. A., Kyrpides, N. C., Bhatt, A. S. 2019
Abstract

Small proteins are traditionally overlooked due to computational and experimental difficulties in detecting them. To systematically identify small proteins, we carried out a comparative genomics study on 1,773 human-associated metagenomes from four different body sites. We describe >4,000 conserved protein families, the majority of which are novel; 30% of these protein families are predicted to be secreted or transmembrane. Over 90% of the small protein families have no known domain and almost half are not represented in reference genomes. We identify putative housekeeping, mammalian-specific, defense-related, and protein families that are likely to be horizontally transferred. We provide evidence of transcription and translation for a subset of these families. Our study suggests that small proteins are highly abundant and those of the human microbiome, in particular, may perform diverse functions that have not been previously reported.

View details for DOI 10.1016/j.cell.2019.07.016

View details for PubMedID 31402174
Surveying Gut Microbiome Research in Africans: Toward Improved Diversity and Representation. Trends in microbiology Brewster, R., Tamburini, F. B., Asiimwe, E., Oduaran, O., Hazelhurst, S., Bhatt, A. S. 2019
Abstract

Descriptive and translational investigations into the human gut microbiome (GM) are rapidly expanding; however, studies are largely restricted to industrialized populations in the USA and Europe. Little is known about microbial variability and its implications for health and disease in other parts of the world. Populations in Africa are particularly underrepresented. What limited research has been performed has focused on a few subject domains, including the impact of long-term lifestyle and dietary factors on GM ecology, its maturation during infancy, and the interrelationships between the microbiome, infectious disease, and undernutrition. Recently, international consortia have laid the groundwork for large-scale genomics and microbiome studies on the continent, with a particular interest in the epidemiologic transition to noncommunicable disease. Here, we survey the current landscape of GM scholarship in Africa and propose actionable recommendations to improve research capacity and output.

View details for DOI 10.1016/j.tim.2019.05.006

View details for PubMedID 31178123
Precision identification of diverse bloodstream pathogens in the gut microbiome NATURE MEDICINE Tamburini, F. B., Andermann, T. M., Tkachenko, E., Senchyna, F., Banaei, N., Bhatt, A. S. 2018; 24 (12): 1809-+
View details for DOI 10.1038/s41591-018-0202-8

View details for Web of Science ID 000452392200008
High-quality genome sequences of uncultured microbes by assembly of read clouds NATURE BIOTECHNOLOGY Bishara, A., Moss, E. L., Kolmogorov, M., Parada, A. E., Weng, Z., Sidow, A., Dekas, A. E., Batzoglou, S., Bhatt, A. S. 2018; 36 (11): 1067-+
View details for DOI 10.1038/nbt.4266

View details for Web of Science ID 000450374000020
Digesting New Developments in Biosensors NEW ENGLAND JOURNAL OF MEDICINE Bhatt, A. S. 2018; 379 (7): 686?88
View details for DOI 10.1056/NEJMcibr1806952

View details for Web of Science ID 000441659100015
Gut microbiome profiling of a rural and urban South African cohort reveals biomarkers of a population in lifestyle transition. BMC microbiology Oduaran, O. H., Tamburini, F. B., Sahibdeen, V., Brewster, R., Gomez-Olive, F. X., Kahn, K., Norris, S. A., Tollman, S. M., Twine, R., Wade, A. N., Wagner, R. G., Lombard, Z., Bhatt, A. S., Hazelhurst, S. 2020; 20 (1): 330
Abstract

BACKGROUND: Comparisons of traditional hunter-gatherers and pre-agricultural communities in Africa with urban and suburban Western North American and European cohorts have clearly shown that diet, lifestyle and environment are associated with gut microbiome composition. Yet, little is known about the gut microbiome composition of most communities in the very diverse African continent. South Africa comprises a richly diverse ethnolinguistic population that is experiencing an ongoing epidemiological transition and concurrent spike in the prevalence of obesity, largely attributed to a shift towards more Westernized diets and increasingly inactive lifestyle practices. To characterize the microbiome of African adults living in more mainstream lifestyle settings and investigate associations between the microbiome and obesity, we conducted a pilot study, designed collaboratively with community leaders, in two South African cohorts representative of urban and transitioning rural populations. As the rate of overweight and obesity is particularly high in women, we collected single time-point stool samples from 170 HIV-negative women (51 at Soweto; 119 at Bushbuckridge), performed 16S rRNA gene sequencing on these samples and compared the data to concurrently collected anthropometric data.RESULTS: We found the overall gut microbiome of our cohorts to be reflective of their ongoing epidemiological transition. Specifically, we find that geographical location was more important for sample clustering than lean/obese status and observed a relatively higher abundance of the Melainabacteria, Vampirovibrio, a predatory bacterium, in Bushbuckridge. Also, Prevotella, despite its generally high prevalence in the cohorts, showed an association with obesity. In comparisons with benchmarked datasets representative of non-Western populations, relatively higher abundance values were observed in our dataset for Barnesiella (log2fold change (FC)=4.5), Alistipes (log2FC=3.9), Bacteroides (log2FC=4.2), Parabacteroides (log2FC=3.1) and Treponema (log2FC=1.6), with the exception of Prevotella (log2FC=-4.7).CONCLUSIONS: Altogether, this work identifies putative microbial features associated with host health in a historically understudied community undergoing an epidemiological transition. Furthermore, we note the crucial role of community engagement to the success of a study in an African setting, the importance of more population-specific studies to inform targeted interventions as well as present a basic foundation for future research.

View details for DOI 10.1186/s12866-020-02017-w

View details for PubMedID 33129264
Recommendations from the ASCO Academic Global Oncology Task Force. JCO global oncology Gralow, J. R., Asirwa, F. C., Bhatt, A. S., Bourlon, M. T., Chu, Q., Eniu, A. E., Loehrer, P. J., Lopes, G., Shulman, L. N., Close, J., Von Roenn, J., Tibbits, M., Pyle, D. 2020; 6: 1666?73
Abstract

In recognition of the rising incidence and mortality of cancer in low- and middle-resource settings, as well as the increasingly international profile of its membership, ASCO has prioritized efforts to enhance its engagement at a global level. Among the recommendations included in the 2016 Global Oncology Leadership Task Force report to the ASCO Board of Directors was that ASCO should promote the recognition of global oncology as an academic field. The report suggested that ASCO could serve a role in transitioning global oncology from an informal field of largely voluntary activities to a more formal discipline with strong research and well-defined training components. As a result of this recommendation, in 2017, ASCO formed the Academic Global Oncology Task Force (AGOTF) to guide ASCO's contributions toward formalizing the field of global oncology. The AGOTF was asked to collect and analyze key issues and barriers toward the recognition of global oncology as an academic discipline, with an emphasis on training, research, and career pathways, and produce a set of recommendations for ASCO action. The outcome of the AGOTF was the development of recommendations designed to advance the status of global oncology as an academic discipline.

View details for DOI 10.1200/GO.20.00497

View details for PubMedID 33151772
Glucagon like peptide-2 for Intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans. Blood Norona, J., Apostolova, P., Schmidt, D., Ihlemann, R., Reischmann, N., Taylor, G., Kohler, N., de Heer, J., Heeg, S., Andrieux, G., Siranosian, B. A., Schmitt-Graeff, A., Pfeifer, D., Catalano, A., Frew, I., Proietti, M., Grimbacher, B., Bulashevska, A., Bhatt, A. S., Brummer, T., Clauditz, T. S., Zabelina, T., Kroeger, N., Blazar, B. R., Boerries, M., Ayuk, F., Zeiser, R. 2020
Abstract

Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). While currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PC) and intestinal stem cells (ISC). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone, produced by intestinal L-cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L-cells in intestinal biopsies and high serum levels of GLP-2 were associated with higher incidence of non-relapse mortality in patients undergoing allo-HCT. Our findings indicate that L-cells are a target of GVHD and that GLP-2-based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.

View details for DOI 10.1182/blood.2020005957

View details for PubMedID 32542357
GUT DECONTAMINATION ALTERS THE INTESTINAL MICROBIOTA DURING ALLOGENIC BONE MARROW TRANSPLANT Severyn, C., London, W., Kao, P., Silverstein, S., Li, M., Verrill, K., Ritz, J., Bhatt, A., Whangbo, J. WILEY. 2020: S11?S12
View details for Web of Science ID 000530720700020
Assessing and Addressing the Need for Cancer Patient Education in a Resource-Limited Setting in Haiti. The oncologist Schleimer, L. E., Desameau, P., Damuse, R., Olsen, M., Manzo, V., Cardenas, C., Mehrtash, H., Krakauer, E. L., Masamba, L., Wang, C., Bhatt, A. S., Shulman, L. N., Huang, F. W. 2020
Abstract

PURPOSE: Misinformation and lack of information about cancer and its treatment pose significant challenges to delivering cancer care in resource-limited settings and may undermine patient engagement in care. We aimed to investigate patients' knowledge and attitudes toward cancer and its treatment and to adapt, implement, and evaluate a low-literacy cancer patient education booklet at the Hopital Universitaire de Mirebalais (HUM) in rural Haiti.MATERIALS AND METHODS: A low-literacy cancer patient education booklet was adapted into Haitian Creole in collaboration with clinicians at HUM. Patients were recruited for structured interviews (n =20) and two focus groups (n =13) designed to explore patients' attitudes toward cancer and its treatment and to assess whether the booklet increased patients' knowledge via an investigator-designed knowledge test.RESULTS: Participants reported a subjective lack of knowledge about cancer and its treatments and described views of cancer as deadly or incurable. Patients of varying education levels valued receiving written materials that set expectations about cancer treatment and expressed a desire to share the booklet with caregivers and others in their community. Participants across all levels of education significantly increased their performance on a knowledge test after counseling using the booklet (p < .001).CONCLUSION: We found that an educational booklet about cancer developed in collaboration with local providers was well received by patients with variable literacy levels and improved their knowledge of cancer and its treatment in a resource-limited setting. Such educational materials have the potential to serve as tools to engage patients with cancer and their families in care.IMPLICATIONS FOR PRACTICE: Misinformation and lack of information pose significant challenges to delivering cancer care in resource-limited settings; however, there are often no culturally and literacy appropriate tools available to aid in patient education. This article shows that written educational materials are well received by patients of variable literacy levels and can be effective tools for increasing patients' knowledge of cancer and its treatment in a limited-resource setting. Furthermore, we have made our educational booklet, Cancer and You, freely available online and welcome the opportunity to connect with readers of The Oncologist interested in implementing this educational booklet in clinical care.

View details for DOI 10.1634/theoncologist.2019-0258

View details for PubMedID 32335989
The gastrointestinal microbiota controls cancer cell intrinsic mechanisms to promote the progression of acute lymphoblastic leukemia. Mahauad-Fernandez, W., Zlitni, S., Bhatt, A., Felsher, D. AMER ASSOC CANCER RESEARCH. 2020: 58?59
View details for Web of Science ID 000526057000081
Strain-resolved microbiome sequencing reveals mobile elements that drive bacterial competition on a clinical timescale. Genome medicine Zlitni, S., Bishara, A., Moss, E. L., Tkachenko, E., Kang, J. B., Culver, R. N., Andermann, T. M., Weng, Z., Wood, C., Handy, C., Ji, H. P., Batzoglou, S., Bhatt, A. S. 2020; 12 (1): 50
Abstract

Populations of closely related microbial strains can be simultaneously present in bacterial communities such as the human gut microbiome. We recently developed a de novo genome assembly approach that uses read cloud sequencing to provide more complete microbial genome drafts, enabling precise differentiation and tracking of strain-level dynamics across metagenomic samples. In this case study, we present a proof-of-concept using read cloud sequencing to describe bacterial strain diversity in the gut microbiome of one hematopoietic cell transplantation patient over a 2-month time course and highlight temporal strain variation of gut microbes during therapy. The treatment was accompanied by diet changes and administration of multiple immunosuppressants and antimicrobials.We conducted short-read and read cloud metagenomic sequencing of DNA extracted from four longitudinal stool samples collected during the course of treatment of one hematopoietic cell transplantation (HCT) patient. After applying read cloud metagenomic assembly to discover strain-level sequence variants in these complex microbiome samples, we performed metatranscriptomic analysis to investigate differential expression of antibiotic resistance genes. Finally, we validated predictions from the genomic and metatranscriptomic findings through in vitro antibiotic susceptibility testing and whole genome sequencing of isolates derived from the patient stool samples.During the 56-day longitudinal time course that was studied, the patient's microbiome was profoundly disrupted and eventually dominated by Bacteroides caccae. Comparative analysis of B. caccae genomes obtained using read cloud sequencing together with metagenomic RNA sequencing allowed us to identify differences in substrain populations over time. Based on this, we predicted that particular mobile element integrations likely resulted in increased antibiotic resistance, which we further supported using in vitro antibiotic susceptibility testing.We find read cloud assembly to be useful in identifying key structural genomic strain variants within a metagenomic sample. These strains have fluctuating relative abundance over relatively short time periods in human microbiomes. We also find specific structural genomic variations that are associated with increased antibiotic resistance over the course of clinical treatment.

View details for DOI 10.1186/s13073-020-00747-0

View details for PubMedID 32471482
Acquisition, transmission and strain diversity of human gut-colonizing crAss-like phages. Nature communications Siranosian, B. A., Tamburini, F. B., Sherlock, G., Bhatt, A. S. 2020; 11 (1): 280
Abstract

CrAss-like phages are double-stranded DNA viruses that are prevalent in human gut microbiomes. Here, we analyze gut metagenomic data from mother-infant pairs and patients undergoing fecal microbiota transplantation to evaluate the patterns of acquisition, transmission and strain diversity of crAss-like phages. We find that crAss-like phages are rarely detected at birth but are increasingly prevalent in the infant microbiome after one month of life. We observe nearly identical genomes in 50% of cases where the same crAss-like clade is detected in both the mother and the infant, suggesting vertical transmission. In cases of putative transmission of prototypical crAssphage (p-crAssphage), we find that a subset of strains present in the mother are detected in the infant, and that strain diversity in infants increases with time. Putative tail fiber proteins are enriched for nonsynonymous strain variation compared to other genes, suggesting a potential evolutionary benefit to maintaining strain diversity in specific genes. Finally, we show that p-crAssphage can be acquired through fecal microbiota transplantation.

View details for DOI 10.1038/s41467-019-14103-3

View details for PubMedID 31941900
Automated Prediction and Annotation of Small Open Reading Frames in Microbial Genomes. Cell host & microbe Durrant, M. G., Bhatt, A. S. 2020
Abstract

Small open reading frames (smORFs) and their encoded microproteins play central roles in microbes. However, there is a vast unexplored space of smORFs within human-associated microbes. A recent bioinformatic analysis used evolutionary conservation signals to enhance prediction of small protein families. To facilitate the annotation of specific smORFs, we introduce SmORFinder. This tool combines profile hidden Markov models of each smORF family and deep learning models that better generalize to smORF families not seen in the training set, resulting in predictions enriched for Ribo-seq translation signals. Feature importance analysis reveals that the deep learning models learn to identify Shine-Dalgarno sequences, deprioritize the wobble position in each codon, and group codon synonyms found in the codon table. A core-genome analysis of 26 bacterial species identifies several core smORFs of unknown function. We pre-compute smORF annotations for thousands of RefSeq isolate genomes and Human Microbiome Project metagenomes and provide these data through a public web portal.

View details for DOI 10.1016/j.chom.2020.11.002

View details for PubMedID 33290720
Improved high-molecular-weight DNA extraction, nanopore sequencing and metagenomic assembly from the human gut microbiome. Nature protocols Maghini, D. G., Moss, E. L., Vance, S. E., Bhatt, A. S. 2020
Abstract

Short-read metagenomic sequencing and de novo genome assembly of the human gut microbiome can yield draft bacterial genomes without isolation and culture. However, bacterial genomes assembled from short-read sequencing are often fragmented. Furthermore, these metagenome-assembled genomes often exclude repeated genomic elements, such as mobile genetic elements, compromising our understanding of the contribution of these elements to important bacterial phenotypes. Although long-read sequencing has been applied successfully to the assembly of contiguous bacterial isolate genomes, extraction of DNA of sufficient molecular weight, purity and quantity for metagenomic sequencing from stool samples can be challenging. Here, we present a protocol for the extraction of microgram quantities of high-molecular-weight DNA from human stool samples that are suitable for downstream long-read sequencing applications. We also present Lathe ( www.github.com/bhattlab/lathe ), a computational workflow for long-read basecalling, assembly, consensus refinement with long reads or Illumina short reads and genome circularization. Altogether, this protocol can yield high-quality contiguous or circular bacterial genomes from a complex human gut sample in approximately 10 d, with 2 d of hands-on bench and computational effort.

View details for DOI 10.1038/s41596-020-00424-x

View details for PubMedID 33277629
Structured RNA Contaminants in Bacterial Ribo-Seq. mSphere Fremin, B. J., Bhatt, A. S. 2020; 5 (5)
Abstract

Ribosome profiling (Ribo-Seq) is a powerful method to study translation in bacteria. However, Ribo-Seq signal can be observed across RNAs that one would not expect to be bound by ribosomes. For example, Escherichia coli Ribo-Seq libraries also capture reads from most noncoding RNAs (ncRNAs). While some of these ncRNAs may overlap coding regions, this alone does not explain the majority of observed signal across ncRNAs. These fragments of ncRNAs in Ribo-Seq data pass all size selection steps of the Ribo-Seq protocol and survive hours of micrococcal nuclease (MNase) treatment. In this work, we specifically focus on Ribo-Seq signal across ncRNAs and provide evidence to suggest that RNA structure, as opposed to ribosome binding, protects them from degradation and allows them to persist in the Ribo-Seq sequencing library preparation. By inspecting these "contaminant reads" in bacterial Ribo-Seq, we show that data previously disregarded in bacterial Ribo-Seq experiments may, in fact, be used to gain partial information regarding the in vivo secondary structure of ncRNAs.IMPORTANCE Structured ncRNAs are pivotal mediators of bioregulation in bacteria, and their functions are often reliant on their specific structures. Here, we first inspect Ribo-Seq reads across noncoding regions, identifying contaminant reads in these libraries. We observe that contaminant reads in bacterial Ribo-Seq experiments that are often disregarded, in fact, strongly overlap with structured regions of ncRNAs. We then perform several bioinformatic analyses to determine why these contaminant reads may persist in Ribo-Seq libraries. Finally, we highlight some structured RNA contaminants in Ribo-Seq and support the hypothesis that structures in the RNA protect them from MNase digestion. We conclude that researchers should be cautious when interpreting Ribo-Seq signal as coding without considering signal distribution. These findings also may enable us to partially resolve RNA structures, identify novel structured RNAs, and elucidate RNA structure-function relationships in bacteria at a large scale and in vivo through the reanalysis of existing Ribo-Seq data sets.

View details for DOI 10.1128/mSphere.00855-20

View details for PubMedID 33087519
Intestinal microbiota domination under extreme selective pressures characterized by metagenomic read cloud sequencing and assembly. BMC bioinformatics Kang, J. B., Siranosian, B. A., Moss, E. L., Banaei, N., Andermann, T. M., Bhatt, A. S. 2019; 20 (Suppl 16): 585
Abstract

BACKGROUND: Low diversity of the gut microbiome, often progressing to the point of intestinal domination by a single species, has been linked to poor outcomes in patients undergoing hematopoietic cell transplantation (HCT). Our ability to understand how certain organisms attain intestinal domination over others has been restricted in part by current metagenomic sequencing technologies that are typically unable to reconstruct complete genomes for individual organisms present within a sequenced microbial community. We recently developed a metagenomic read cloud sequencing and assembly approach that generates improved draft genomes for individual organisms compared to conventional short-read sequencing and assembly methods. Herein, we applied metagenomic read cloud sequencing to four stool samples collected longitudinally from an HCT patient preceding treatment and over the course of heavy antibiotic exposure.RESULTS: Characterization of microbiome composition by taxonomic classification of reads reveals that that upon antibiotic exposure, the subject's gut microbiome experienced a marked decrease in diversity and became dominated by Escherichia coli. While diversity is restored at the final time point, this occurs without recovery of the original species and strain-level composition. Draft genomes for individual organisms within each sample were generated using both read cloud and conventional assembly. Read clouds were found to improve the completeness and contiguity of genome assemblies compared to conventional assembly. Moreover, read clouds enabled the placement of antibiotic resistance genes present in multiple copies both within a single draft genome and across multiple organisms. The occurrence of resistance genes associates with the timing of antibiotics administered to the patient, and comparative genomic analysis of the various intestinal E. coli strains across time points as well as the bloodstream isolate showed that the subject's E. coli bloodstream infection likely originated from the intestine. The E. coli genome from the initial pre-transplant stool sample harbors 46 known antimicrobial resistance genes, while all other species from the pre-transplant sample each contain at most 5 genes, consistent with a model of heavy antibiotic exposure resulting in selective outgrowth of the highly antibiotic-resistant E. coli.CONCLUSION: This study demonstrates the application and utility of metagenomic read cloud sequencing and assembly to study the underlying strain-level genomic factors influencing gut microbiome dynamics under extreme selective pressures in the clinical context of HCT.

View details for DOI 10.1186/s12859-019-3073-1

View details for PubMedID 31787070
Longitudinal Changes in the Intestinal Microbiome Composition Following Gut Decontamination in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Patients: A Pilot Study Severyn, C., London, W. B., Kao, P., Silverstein, S., Li, M., Kim, S., Verrill, K., Ritz, J., Bhatt, A. S., Whangbo, J. AMER SOC HEMATOLOGY. 2019
View details for DOI 10.1182/blood-2019-122480

View details for Web of Science ID 000577164607054
Making Progress in Graft-Versus-Host Disease Prophylaxis and Microbiome Analysis in the Blood and Marrow Transplant Clinical Trials Network: Progress III (1703)/MI-Immune (1801) Holtan, S., Bhatt, A. S., Fraser, R., Perales, M., Kean, L., Saber, W., Hamadani, M., Logan, B. R., Bolanos-Meade, J. AMER SOC HEMATOLOGY. 2019
View details for DOI 10.1182/blood-2019-122782

View details for Web of Science ID 000577160403278
Microbiome genome structure drives function. Nature microbiology Durrant, M. G., Bhatt, A. S. 2019; 4 (6): 912?13
View details for DOI 10.1038/s41564-019-0473-y

View details for PubMedID 31118502
Making the microbiome personal NATURE MEDICINE Bhatt, A. S. 2019; 25 (5): 708
View details for DOI 10.1038/s41591-019-0445-z

View details for Web of Science ID 000468247800003
Diversity of resistance mechanisms in carbapenem-resistant Enterobacteriaceae at a health care system in Northern California, from 2013 to 2016 DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE Senchyna, F., Gaur, R. L., Sandlund, J., Truong, C., Tremintin, G., Kutz, D., Gomez, C. A., Tamburini, F. B., Andermann, T., Bhatt, A., Tickler, I., Watz, N., Budvytiene, I., Shi, G., Tenover, F. C., Banaei, N. 2019; 93 (3): 250?57
View details for DOI 10.1016/j.diagmicrobio.2018.10.004

View details for Web of Science ID 000460196900013
Distinct Immune Regulatory Potential of Invariant Natural Killer T (iNKT) Cell Subsets: iNKT2 and iNKT17, but Not iNKT1, Protect from Graft-Versus-Host-Disease Simonetta, F., Maas-Bauer, K., Hirai, T., Wenokur, A., Fazal, F. M., Kambham, N., Ribado, J., Mavers, M., Baker, J., Bhatt, A. S., Chang, H. Y., Negrin, R. S. ELSEVIER SCIENCE INC. 2019
View details for Web of Science ID 000540655500003
Whole blood RNA sequencing reveals a unique transcriptomic profile in patients with ARDS following hematopoietic stem cell transplantation RESPIRATORY RESEARCH Englert, J. A., Cho, M. H., Lamb, A. E., Shumyatcher, M., Barragan-Bradford, D., Basil, M. C., Higuera, A., Isabelle, C., Vera, M., Dieffenbach, P. B., Fredenburgh, L. E., Kang, J. B., Bhatt, A. S., Antin, J. H., Ho, V. T., Soiffer, R. J., Howrylak, J. A., Himes, B. E., Baron, R. M. 2019; 20
View details for DOI 10.1186/s12931-019-0981-6

View details for Web of Science ID 000458078000001
Whole blood RNA sequencing reveals a unique transcriptomic profile in patients with ARDS following hematopoietic stem cell transplantation. Respiratory research Englert, J. A., Cho, M. H., Lamb, A. E., Shumyatcher, M., Barragan-Bradford, D., Basil, M. C., Higuera, A., Isabelle, C., Vera, M. P., Dieffenbach, P. B., Fredenburgh, L. E., Kang, J. B., Bhatt, A. S., Antin, J. H., Ho, V. T., Soiffer, R. J., Howrylak, J. A., Himes, B. E., Baron, R. M. 2019; 20 (1): 15
Abstract

BACKGROUND: The acute respiratory distress syndrome (ARDS) is characterized by the acute onset of hypoxemia and bilateral lung infiltrates in response to an inciting event, and is associated with high morbidity and mortality. Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for ARDS. We hypothesized that HSCT patients with ARDS would have a unique transcriptomic profile identifiable in peripheral blood compared to those that did not undergo HSCT.METHODS: We isolated RNA from banked peripheral blood samples from a biorepository of critically ill ICU patients. RNA-Seqwas performed on 11 patients with ARDS (5 that had undergone HSCT and 6 that had not) and 12 patients with sepsis without ARDS (5 that that had undergone HCST and 7 that had not).RESULTS: We identified 687 differentially expressed genes between ARDS and ARDS-HSCT (adjusted p-value <0.01), including IFI44L, OAS3, LY6E, and SPATS2L that had increased expression in ARDS vs. ARDS-HSCT; these genes were not differentially expressed in sepsis vs sepsis-HSCT. Gene ontology enrichment analysis revealed that many differentially expressed genes were related to response to type I interferon.CONCLUSIONS: Our findings reveal significant differences in whole blood transcriptomic profiles of patients with non-HSCT ARDS compared to ARDS-HSCT patients and point toward different immune responses underlying ARDS and ARDS-HSCT that contribute to lung injury.

View details for PubMedID 30665420
Evaluating Barriers and Opportunities in Delivering High-Quality Oncology Care in a Resource-Limited Setting Using a Comprehensive Needs Assessment Tool JOURNAL OF GLOBAL ONCOLOGY Nwachukwu, C. R., Mudasiru, O., Million, L., Sheth, S., Qamoos, H., Onah, J. O., Okemini, A., Rhodes, M., Barry, M., Banjo, A. A., Habeebu, M., Olasinde, T. A., Bhatt, A. S. 2018; 4
View details for DOI 10.1200/JGO.18.00125

View details for Web of Science ID 000462480700001
Evaluating Barriers and Opportunities in Delivering High-Quality Oncology Care in a Resource-Limited Setting Using a Comprehensive Needs Assessment Tool. Journal of global oncology Nwachukwu, C. R., Mudasiru, O., Million, L., Sheth, S., Qamoos, H., Onah, J. O., Okemini, A., Rhodes, M., Barry, M., Banjo, A. A., Habeebu, M., Olasinde, T. A., Bhatt, A. S. 2018: 1?9
Abstract

PURPOSE: Despite recognition of both the growing cancer burden in low- and middle-income countries and the disproportionately high mortality rates in these settings, delivery of high-quality cancer care remains a challenge. The disparities in cancer care outcomes for many geographic regions result from barriers that are likely complex and understudied. This study describes the development and use of a streamlined needs assessment questionnaire (NAQ) to understand the barriers to providing quality cancer care, identifies areas for improvement, and formulates recommendations for implementation.METHODS: Using a comprehensive NAQ, in-depth interviews were conducted with 17 hospital staff involved in cancer care at two teaching hospitals in Nigeria. Data were analyzed using content analysis and organized into a framework with preset codes and emergent codes, where applicable.RESULTS: Data from the interviews were organized into six broad themes: staff, stuff, system, space, lack of palliative care, and provider bias, with key barriers within themes including: financial, infrastructural, lack of awareness, limited human capacity resources, lack of palliative care, and provider perspective on patient-related barriers to cancer care. Specific solutions based on ability to reasonably implement were subcategorized into short-, medium-, and long-term goals.CONCLUSION: This study provides a framework for a streamlined initial needs assessment and a unique discussion on the barriers to high-quality oncology care that are prevalent in resource-constrained settings. We report the feasibility of collecting and organizing data using a streamlined NAQ and provide a thorough and in-depth understanding of the challenges in this setting. Knowledge gained from the assessments will inform steps to improve oncology cancer in these settings.

View details for PubMedID 30532992
Institutionalizing healthcare hackathons to promote diversity in collaboration in medicine. BMC medical education Wang, J. K., Roy, S. K., Barry, M., Chang, R. T., Bhatt, A. S. 2018; 18 (1): 269
Abstract

BACKGROUND: Medical students and healthcare professionals can benefit from exposure to cross-disciplinary teamwork and core concepts of medical innovation. Indeed, to address complex challenges in patient care, diversity in collaboration across medicine, engineering, business, and design is critical. However, a limited number of academic institutions have established cross-disciplinary opportunities for students and young professionals within these domains to work collaboratively towards diverse healthcare needs.METHODS: Drawing upon best practices from computer science and engineering, healthcare hackathons bring together interdisciplinary teams of students and professionals to collaborate, brainstorm, and build solutions to unmet clinical needs. Over the course of six months, a committee of 20 undergraduates, medical students, and physician advisors organized Stanford University's first healthcare hackathon (November 2016). Demographic data from initial applications were supplemented with responses from a post-hackathon survey gauging themes of diversity in collaboration, professional development, interest in medical innovation, and educational value. In designing and evaluating the event, the committee focused on measurable outcomes of diversity across participants (skillset, age, gender, academic degree), ideas (clinical needs), and innovations (projects).RESULTS: Demographic data (n=587 applicants, n=257 participants) reveal participants across diverse academic backgrounds, age groups, and domains of expertise were in attendance. From 50 clinical needs presented representing 19 academic fields, 40 teams ultimately formed and submitted projects spanning web (n=13) and mobile applications (n=13), artificial intelligence-based tools (n=6), and medical devices (n=3), among others. In post-hackathon survey responses (n=111), medical students and healthcare professionals alike noted a positive impact on their ability to work in multidisciplinary teams, learn from individuals of different backgrounds, and address complex healthcare challenges.CONCLUSIONS: Healthcare hackathons can encourage diversity across individuals, ideas, and projects to address clinical challenges. By providing an outline of Stanford's inaugural event, we hope more universities can adopt the healthcare hackathon model to promote diversity in collaboration in medicine.

View details for PubMedID 30458759
Institutionalizing healthcare hackathons to promote diversity in collaboration in medicine BMC MEDICAL EDUCATION Wang, J. K., Roy, S. K., Barry, M., Chang, R. T., Bhatt, A. S. 2018; 18
View details for DOI 10.1186/s12909-018-1385-x

View details for Web of Science ID 000450779900001
Persistence of endothelial thrombomodulin in a patient with infectious purpura fulminans treated with protein C concentrate. Blood advances Bendapudi, P. K., Robbins, A., LeBoeuf, N., Pozdnyakova, O., Bhatt, A., Duke, F., Sells, R., McQuiston, J., Humrighouse, B., Rouaisnel, B., Colling, M., Stephenson, K. E., Saavedra, A., Losman, J. 2018; 2 (21): 2917?21
View details for PubMedID 30396911
Persistence of endothelial thrombomodulin in a patient with infectious purpura fulminans treated with protein C concentrate BLOOD ADVANCES Bendapudi, P. K., Robbins, A., LeBoeuf, N., Pozdnyakova, O., Bhatt, A., Duke, F., Sells, R., McQuiston, J., Humrighouse, B., Rouaisnel, B., Colling, M., Stephenson, K. E., Saavedra, A., Losman, J. 2018; 2 (21): 2917?21
View details for DOI 10.1182/bloodadvances.2018024430

View details for Web of Science ID 000450684800011
Antibiotic practice patterns in hematopoietic cell transplantation: A survey of blood and marrow transplant clinical trials network centers AMERICAN JOURNAL OF HEMATOLOGY Rashidi, A., Wangjam, T., Bhatt, A. S., Weisdorf, D. J., Holtan, S. G., BMT CTN Investigators 2018; 93 (11): E348?E350
View details for PubMedID 30058189

View details for PubMedCentralID PMC6196101
Diversity of resistance mechanisms in carbapenem-resistant Enterobacteriaceae at a health care system in Northern California, from 2013 to 2016. Diagnostic microbiology and infectious disease Senchyna, F., Gaur, R. L., Sandlund, J., Truong, C., Tremintin, G., Kultz, D., Gomez, C. A., Tamburini, F. B., Andermann, T., Bhatt, A., Tickler, I., Watz, N., Budvytiene, I., Shi, G., Tenover, F. C., Banaei, N. 2018
Abstract

The mechanism of resistance in carbapenem-resistant Enterobacteriaceae (CRE) has therapeutic implications. We comprehensively characterized emerging mechanisms of resistance in CRE between 2013 and 2016 at a health system in Northern California. A total of 38.7% (24/62) of CRE isolates were carbapenemase gene-positive, comprising 25.0% (6/24) blaOXA-48 like, 20.8% (5/24) blaKPC, 20.8% (5/24) blaNDM, 20.8% (5/24) blaSME, 8.3% (2/24) blaIMP, and 4.2% (1/24) blaVIM. Between carbapenemases and porin loss, the resistance mechanism was identified in 95.2% (59/62) of CRE isolates. Isolates expressing blaKPC were 100% susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam; blaOXA-48 like-positive isolates were 100% susceptible to ceftazidime-avibactam; and metallo beta-lactamase-positive isolates were nearly all nonsusceptible to above antibiotics. Carbapenemase gene-negative CRE were 100% (38/38), 92.1% (35/38), 89.5% (34/38), and 31.6% (12/38) susceptible to ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and ceftolozane-tazobactam, respectively. None of the CRE strains were identical by whole genome sequencing. At this health system, CRE were mediated by diverse mechanisms with predictable susceptibility to newer beta-lactamase inhibitors.

View details for PubMedID 30482638
Data mining of digitized health records in a resource-constrained setting reveals that timely immunophenotyping is associated with improved breast cancer outcomes BMC CANCER Lopez-Pineda, A., Rodriguez-Moran, M. F., Alvarez-Aguilar, C., Fuentes Valle, S. M., Acosta-Rosales, R., Bhatt, A. S., Sheth, S. N., Bustamante, C. D. 2018; 18
View details for DOI 10.1186/s12885-018-4833-4

View details for Web of Science ID 000445959100003
Data mining of digitized health records in a resource-constrained setting reveals that timely immunophenotyping is associated with improved breast cancer outcomes. BMC cancer Lopez-Pineda, A., Rodriguez-Moran, M. F., Alvarez-Aguilar, C., Fuentes Valle, S. M., Acosta-Rosales, R., Bhatt, A. S., Sheth, S. N., Bustamante, C. D. 2018; 18 (1): 933
Abstract

BACKGROUND: Organizations that issue guidance on breast cancer recommend the use of immunohistochemistry (IHC) for providing appropriate and precise care. However, little focus has been directed to the identification of maximum allowable turnaround times for IHC, which is necessary given the diversity of hospital settings in the world. Much less effort has been committed to the development of digital tools that allow hospital administrators to monitor service utilization histories of their patients.METHODS: In this retrospective cohort study, we reviewed electronic and paper medical records of all suspected breast cancer patients treated at one secondary-care hospital of the Mexican Institute of Social Security (IMSS), located in western Mexico. We then followed three years of medical history of those patients with IHC testing.RESULTS: In 2014, there were 402 breast cancer patients, of which 30 (7.4% of total) were tested for some IHC biomarker (ER, PR, HER2). The subtyping allowed doctors to adjust (56.7%) or confirm (43.3%) the initial therapeutic regimen. The average turnaround time was 56days. Opportune IHC testing was found to be beneficial when it was available before or during the first rounds of chemotherapy.CONCLUSIONS: The use of data mining tools applied to health record data revealed that there is an association between timely immunohistochemistry and improved outcomes in breast cancer patients. Based on this finding, inclusion of turnaround time in clinical guidelines is recommended. As much of the health data in the country becomes digitized, our visualization tools allow a digital dashboard of the hospital service utilization histories.

View details for PubMedID 30261931
A Gut Commensal-Produced Metabolite Mediates Colonization Resistance to Salmonella Infection CELL HOST & MICROBE Jacobson, A., Lam, L., Rajendram, M., Tamburini, F., Honeycutt, J., Trung Pham, Van Treuren, W., Pruss, K., Stabler, S., Lugo, K., Bouley, D. M., Vilches-Moure, J. G., Smith, M., Sonnenburg, J. L., Bhatt, A. S., Huang, K., Monack, D. 2018; 24 (2): 296-+
View details for DOI 10.1016/j.chom.2018.07.002

View details for Web of Science ID 000441083900016
A Gut Commensal-Produced Metabolite Mediates Colonization Resistance to Salmonella Infection. Cell host & microbe Jacobson, A., Lam, L., Rajendram, M., Tamburini, F., Honeycutt, J., Pham, T., Van Treuren, W., Pruss, K., Stabler, S. R., Lugo, K., Bouley, D. M., Vilches-Moure, J. G., Smith, M., Sonnenburg, J. L., Bhatt, A. S., Huang, K. C., Monack, D. 2018
Abstract

The intestinal microbiota provides colonization resistance against pathogens, limiting pathogen expansion and transmission. These microbiota-mediated mechanisms were previously identified by observing loss of colonization resistance after antibiotic treatment or dietary changes, which severely disrupt microbiota communities. We identify a microbiota-mediated mechanism of colonization resistance against Salmonella enterica serovar Typhimurium (S. Typhimurium) by comparing high-complexity commensal communities with different levels of colonization resistance. Using inbred mouse strains with different infection dynamics and S. Typhimurium intestinal burdens, we demonstrate that Bacteroides species mediate colonization resistance against S. Typhimurium by producing the short-chain fatty acid propionate. Propionate directly inhibits pathogen growth invitro by disrupting intracellular pH homeostasis, and chemically increasing intestinal propionate levels protects mice from S.Typhimurium. In addition, administering susceptible mice Bacteroides, but not a propionate-production mutant, confers resistance to S. Typhimurium. This work provides mechanistic understanding into the role of individualized microbial communities in host-to-host variability of pathogen transmission.

View details for PubMedID 30057174
The Microbiome and Hematopoietic Cell Transplantation: Past, Present, and Future BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Andermann, T. M., Peled, J. U., Ho, C., Reddy, P., Riches, M., Storb, R., Teshima, T., van den Brink, M. M., Alousi, A., Balderman, S., Chiusolo, P., Clark, W. B., Holler, E., Howard, A., Kean, L. S., Koh, A. Y., McCarthy, P. L., McCarty, J. M., Mohty, M., Nakamura, R., Rezvani, K., Segal, B. H., Shaw, B. E., Shpall, E. J., Sung, A. D., Weber, D., Whangbo, J., Wingard, J. R., Wood, W. A., Perales, M., Jenq, R. R., Bhatt, A. S., Blood Marrow Transplant Clinical 2018; 24 (7): 1322?40
View details for DOI 10.1016/j.bbmt.2018.02.009

View details for Web of Science ID 000440879800004
Transient Osmotic Perturbation Causes Long-Term Alteration to the Gut Microbiota. Cell Tropini, C., Moss, E. L., Merrill, B. D., Ng, K. M., Higginbottom, S. K., Casavant, E. P., Gonzalez, C. G., Fremin, B., Bouley, D. M., Elias, J. E., Bhatt, A. S., Huang, K. C., Sonnenburg, J. L. 2018; 173 (7): 1742
Abstract

Osmotic diarrhea is a prevalent condition in humans caused by food intolerance, malabsorption, and widespread laxative use. Here, we assess the resilience of the gut ecosystem to osmotic perturbation at multiple length and timescales using mice as model hosts. Osmotic stress caused reproducible extinction of highly abundant taxa and expansion of less prevalent members in human and mouse microbiotas. Quantitative imaging revealed decimation of the mucus barrier during osmotic perturbation, followed by recovery. The immune system exhibited temporary changes in cytokine levels and a lasting IgG response against commensal bacteria. Increased osmolality prevented growth of commensal strains invitro, revealing one mechanism contributing to extinction. Environmental availability of microbiota members mitigated extinction events, demonstrating how species reintroduction can affect community resilience. Our findings (1) demonstrate that even mild osmotic diarrhea can cause lasting changes to the microbiota and host and (2) lay the foundation for interventions that increase system-wide resilience.

View details for PubMedID 29906449
Transient Osmotic Perturbation Causes Long-Term Alteration to the Gut Microbiota CELL Tropini, C., Moss, E., Merrill, B., Ng, K., Higginbottom, S., Casavant, E., Gonzalez, C., Fremin, B., Bouley, D., Elias, J., Bhatt, A., Huang, K., Sonnenburg, J. 2018; 173 (7): 1742-+
View details for DOI 10.1016/j.cell.2018.05.008

View details for Web of Science ID 000437004000021
AGBT meeting report GENOME BIOLOGY Bhatt, A. S., Curtis, C. 2018; 19: 60
Abstract

The Annual Advances in Genome Biology and Technology (AGBT) General Meeting was held in Orlando, Florida, USA, on the 12-15 February 2018. Professors Ami S. Bhatt and Christina Curtis from Stanford University, USA, report advances and applications in the field that were discussed at the meeting.

View details for PubMedID 29784033
The Microbiome and Hematopoietic Cell Transplantation: Past, Present, and Future. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Andermann, T. M., Peled, J. U., Ho, C., Reddy, P., Riches, M., Storb, R., Teshima, T., van den Brink, M. R., Alousi, A., Balderman, S., Chiusolo, P., Clark, W. B., Holler, E., Howard, A., Kean, L. S., Koh, A. Y., McCarthy, P. L., McCarty, J. M., Mohty, M., Nakamura, R., Rezvani, K., Segal, B. H., Shaw, B. E., Shpall, E. J., Sung, A. D., Weber, D., Whangbo, J., Wingard, J. R., Wood, W. A., Perales, M., Jenq, R. R., Bhatt, A. S., Blood and Marrow Transplant Clinical Trials Network 2018
View details for PubMedID 29471034
Read cloud sequencing elucidates microbiome dynamics in a hematopoietic cell transplant patient Kang, J., Siranosian, B., Moss, E., Andermann, T., Bhatt, A., Zheng, H., Callejas, Z., Griol, D., Wang, H., Hu, Schmidt, H., Baumbach, J., Dickerson, J., Zhang, L. IEEE. 2018: 234?41
View details for Web of Science ID 000458654000043
With Probiotics, Resistance Is Not Always Futile. Cell host & microbe Severyn, C. J., Bhatt, A. S. 2018; 24 (3): 334?36
Abstract

Probiotics and other bacteriotherapies are actively being explored and applied as symptom- and disease-modifying agents. In a recent issue of Cell, two papers contribute to our understanding of how live bacterial therapies variably affect individuals and the short- and longer-term impact of these therapies on colonization and host response.

View details for PubMedID 30212646
In Translation: With probiotics, resistance is not always futile Cell Host & Microbe Severyn, C. J., Bhatt, A. S. 2018; 24: 334-336
View details for DOI 10.1016/j.chom.2018.08.014
Household triclosan and triclocarban effects on the infant and maternal microbiome EMBO MOLECULAR MEDICINE Ribado, J. V., Ley, C., Haggerty, T. D., Tkachenko, E., Bhatt, A. S., Parsonnet, J. 2017; 9 (12): 1732?41
View details for DOI 10.15252/emmm.201707882

View details for Web of Science ID 000416867700009
Allied Commensal Forces against Vancomycin-Resistant Enterococci CELL HOST & MICROBE Fremin, B. J., Bhatt, A. S. 2017; 21 (5): 559?60
Abstract

In this issue of Cell Host & Microbe, Caballero et�al. (2017) define a precise, limited consortium of commensal bacteria that restores resistance to colonization by clinically vexing vancomycin-resistant Enterococcus species.

View details for PubMedID 28494236

View details for PubMedCentralID PMC5603308
Quantitative Computed Tomography Assessment of Bronchiolitis Obliterans Syndrome after Lung Transplantation. Clinical transplantation Gazourian, L., Ash, S., Meserve, E. E., Diaz, A., Estepar, R. S., El-Chemaly, S. Y., Rosas, I. O., Divo, M., Fuhlbrigge, A. L., Camp, P. C., Ho, V. T., Bhatt, A. S., Goldberg, H. J., Sholl, L. M., Washko, G. R. 2017
Abstract

Bronchiolitis obliterans syndrome (BOS) is a clinical manifestation of chronic allograft rejection following lung transplantation. We examined the quantitative measurements of the proximal airway and vessels and pathologic correlations in subjects with BOS.Patients who received a lung transplant at the Brigham and Women's Hospital between December 1, 2002 and December 31, 2010 were included in this study. We characterized the quantitative CT measures of proximal airways and vessels and pathological changes.Ninety-four (46.1%) of the 204 subjects were included in the study. There was a significant increase in the airway vessel ratio in subjects who developed progressive BOS compared to controls and non-progressors. There was a significant increase in airway lumen area and decrease in vessel cross-sectional area in patients with BOS compared to controls. Patients with BOS had a significant increase in proximal airway fibrosis compared to controls.BOS is characterized by central airway dilation and vascular remodeling, the degree of which is correlated to decrements in lung function. Our data suggest that progressive BOS is a pathologic process that affects both the central and distal airways.

View details for DOI 10.1111/ctr.12943

View details for PubMedID 28244139
Technological solutions for global hematology and oncology BLOOD ADVANCES Bhatt, A. S. 2017; 1 (6): 396
View details for PubMedID 29296953
Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation BONE MARROW TRANSPLANTATION Whangbo, J., Ritz, J., Bhatt, A. 2017; 52 (2): 183-190
Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with severe benign and malignant hematologic disorders. The success of allogeneic HSCT is limited by the development of transplant-related complications such as acute graft-versus-host disease (GvHD). Early pre-clinical studies suggested that intestinal microflora contribute to the pathogenesis of acute GvHD, and that growth suppression or eradication of intestinal bacteria prevented the development of acute GvHD even in MHC-mismatched transplants. These observations led to the practice of gut decontamination (GD) with oral non-absorbable antibiotics in patients undergoing allogeneic HSCT as a method of acute GvHD prophylaxis. Microbiome studies in the modern sequencing era are beginning to challenge the benefit of this practice. In this review, we provide a historical perspective on the practice of GD and highlight findings from the limited number of clinical trials evaluating the use of GD for acute GvHD prevention in allogeneic HSCT patients. In addition, we examine the role of the gut microbiota in allogeneic HSCT in the context of recent studies linking the microflora to regulation of intestinal immune homeostasis. We discuss the implications of these findings for future strategies to reduce acute GvHD risk by selective manipulation of the microbiota.Bone Marrow Transplantation advance online publication, 15 August 2016; doi:10.1038/bmt.2016.206.

View details for DOI 10.1038/bmt.2016.206

View details for Web of Science ID 000394134300003
Microbes prevent HSPCs from "NOD"-ing off. Blood Bhatt, A. S. 2017; 129 (2): 139-140
View details for DOI 10.1182/blood-2016-11-750562

View details for PubMedID 28082290
Household triclosan and triclocarban effects on the infant and maternal microbiome. EMBO molecular medicine Ribado, J. V., Ley, C., Haggerty, T. D., Tkachenko, E., Bhatt, A. S., Parsonnet, J. 2017; 9 (12): 1732?41
Abstract

In 2016, the US Food and Drug Administration banned the use of specific microbicides in some household and personal wash products due to concerns that these chemicals might induce antibiotic resistance or disrupt human microbial communities. Triclosan and triclocarban (referred to as TCs) are the most common antimicrobials in household and personal care products, but the extent to which TC exposure perturbs microbial communities in humans, particularly during infant development, was unknown. We conducted a randomized intervention of TC-containing household and personal care products during the first year following birth to characterize whether TC exposure from wash products perturbs microbial communities in mothers and their infants. Longitudinal survey of the gut microbiota using 16S ribosomal RNA amplicon sequencing showed that TC exposure from wash products did not induce global reconstruction or loss of microbial diversity of either infant or maternal gut microbiotas. Broadly antibiotic-resistant species from the phylum Proteobacteria, however, were enriched in stool samples from mothers in TC households after the introduction of triclosan-containing toothpaste. When compared by urinary triclosan level, agnostic to treatment arm, infants with higher triclosan levels also showed an enrichment of Proteobacteria species. Despite the minimal effects of TC exposure from wash products on the gut microbial community of infants and adults, detected taxonomic differences highlight the need for consumer safety testing of antimicrobial self-care products on the human microbiome and on antibiotic resistance.

View details for PubMedID 29030459
Long-term taxonomic and functional divergence from donor bacterial strains following fecal microbiota transplantation in immunocompromised patients. PloS one Moss, E. L., Falconer, S. B., Tkachenko, E., Wang, M., Systrom, H., Mahabamunuge, J., Relman, D. A., Hohmann, E. L., Bhatt, A. S. 2017; 12 (8): e0182585
Abstract

Immunocompromised individuals are at high risk of developing Clostridium difficile-associated disease (CDAD). Fecal microbiota transplantation (FMT) is a highly effective therapy for refractory or recurrent CDAD and, despite safety concerns, has recently been offered to immunocompromised patients. We investigated the genomics of bacterial composition following FMT in immunocompromised patients over a 1-year period. Metagenomic, strain and gene-level bacterial dynamics were characterized in two CDAD-affected hematopoietic stem cell (HCT) recipients following FMT. We found alterations in gene content, including loss of virulence and antibiotic resistance genes. These alterations were accompanied by long-term bacterial divergence at the species and strain levels. Our findings suggest limited durability of the specific bacterial consortium introduced with FMT and indicate that alterations of the functional potential of the microbiome are more complex than can be inferred by taxonomic information alone. Our observation that FMT alone cannot induce long-term donor-like alterations of the microbiota of HCT recipients suggests that FMT cannot indefinitely supersede environmental and/or host factors in shaping bacterial composition.

View details for PubMedID 28827811
The Burden of Cancer in Asian Americans: A Report of National Mortality Trends by Asian Ethnicity CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Thompson, C. A., Gomez, S. L., Hastings, K. G., Kapphahn, K., Yu, P., Shariff-Marco, S., Bhatt, A. S., Wakelee, H. A., Patel, M. I., Cullen, M. R., Palaniappan, L. P. 2016; 25 (10): 1371-1382
Abstract

Asian Americans (AA) are the fastest growing U.S. population, and when properly distinguished by their ethnic origins, exhibit substantial heterogeneity in socioeconomic status, health behaviors, and health outcomes. Cancer is the second leading cause of death in the United States, yet trends and current patterns in the mortality burden of cancer among AA ethnic groups have not been documented.We report age-adjusted rates, standardized mortality ratios, and modeled trends in cancer-related mortality in the following AA ethnicities: Asian Indians, Chinese, Filipinos, Japanese, Koreans, and Vietnamese, from 2003 to 2011, with non-Hispanic whites (NHW) as the reference population.For most cancer sites, AAs had lower cancer mortality than NHWs; however, mortality patterns were heterogeneous across AA ethnicities. Stomach and liver cancer mortality was very high, particularly among Chinese, Koreans, and Vietnamese, for whom these two cancer types combined accounted for 15% to 25% of cancer deaths, but less than 5% of cancer deaths in NHWs. In AA women, lung cancer was a leading cause of death, but (unlike males and NHW females) rates did not decline over the study period.Ethnicity-specific analyses are critical to understanding the national burden of cancer among the heterogeneous AA population.Our findings highlight the need for disaggregated reporting of cancer statistics in AAs and warrant consideration of tailored screening programs for liver and gastric cancers. Cancer Epidemiol Biomarkers Prev; 25(10); 1371-82. �2016 AACR.

View details for DOI 10.1158/1055-9965.EPI-16-0167

View details for PubMedID 27694108
Infection Rates among Acute Leukemia Patients Receiving Alternative Donor Hematopoietic Cell Transplantation. Biology of blood and marrow transplantation Ballen, K., Woo Ahn, K., Chen, M., Abdel-Azim, H., Ahmed, I., Aljurf, M., Antin, J., Bhatt, A. S., Boeckh, M., Chen, G., Dandoy, C., George, B., Laughlin, M. J., Lazarus, H. M., MacMillan, M. L., Margolis, D. A., Marks, D. I., Norkin, M., Rosenthal, J., Saad, A., Savani, B., Schouten, H. C., Storek, J., Szabolcs, P., Ustun, C., Verneris, M. R., Waller, E. K., Weisdorf, D. J., Williams, K. M., Wingard, J. R., Wirk, B., Wolfs, T., Young, J. H., Auletta, J., Komanduri, K. V., Lindemans, C., Riches, M. L. 2016; 22 (9): 1636-1645
Abstract

Alternative graft sources (umbilical cord blood [UCB], matched unrelated donors [MUD], or mismatched unrelated donors [MMUD]) enable patients without a matched sibling donor to receive potentially curative hematopoietic cell transplantation (HCT). Retrospective studies demonstrate comparable outcomes among different graft sources. However, the risk and types of infections have not been compared among graft sources. Such information may influence the choice of a particular graft source. We compared the incidence of bacterial, viral, and fungal infections in 1781 adults with acute leukemia who received alternative donor HCT (UCB, n=?568; MUD, n?=?930; MMUD, n?=?283) between 2008 and 2011. The incidences of bacterial infection at 1 year were 72%, 59%, and 65% (P?
View details for DOI 10.1016/j.bbmt.2016.06.012

View details for PubMedID 27343716
Antibiotics in Hematopoietic Cell Transplantation: Adversaries or Allies? BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Andermann, T. M., Bhatt, A. S. 2016; 22 (6): 972-974
View details for DOI 10.1016/j.bbmt.2016.04.002

View details for PubMedID 27095689
Mapping global cancer research and control in areas of low and middle income: The need for shared data on a single, interactive platform Chisti, A., Sharara, N., Gupta, M., Rosenberg, I., Abudu, R., Morgan, C., Duncan, K., Silkensen, S., Craycroft, J., Silva, J., Andre, B., Trimble, E., Bhatt, A., Huang, F. W. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e18048

View details for Web of Science ID 000404711503193
Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice SCIENCE TRANSLATIONAL MEDICINE Shono, Y., Docampo, M. D., Peled, J. U., Perobelli, S. M., Velardi, E., Tsai, J. J., Slingerland, A. E., Smith, O. M., Young, L. F., Gupta, J., Lieberman, S. R., Jay, H. V., Ahr, K. F., Rodriguez, K. A., Xu, K., Calarfiore, M., Poeck, H., Caballero, S., Devlin, S. M., Rapaport, F., Dudakov, J. A., Hanash, A. M., Gyurkocza, B., Murphy, G. F., Gomes, C., Liu, C., Moss, E. L., Falconer, S. B., Bhatt, A. S., Taur, Y., Pamer, E. G., van den Brink, M. R., Jenq, R. R. 2016; 8 (339)
Abstract

Intestinal bacteria may modulate the risk of infection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients often develop neutropenic fever, which is treated with antibiotics that may target anaerobic bacteria in the gut. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam antibiotics was associated with increased GVHD-related mortality at 5 years (21.5% for imipenem-cilastatin-treated patients versus 13.1% for untreated patients, P = 0.025; 19.8% for piperacillin-tazobactam-treated patients versus 11.9% for untreated patients, P = 0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (P = 0.78 and P = 0.98, respectively). Analysis of stool specimens from allo-HSCT recipients showed that piperacillin-tazobactam administration was associated with perturbation of gut microbial composition. Studies in mice demonstrated aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P < 0.01 and P < 0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (P < 0.05), but no difference in the concentration of short-chain fatty acids or numbers of regulatory T cells. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective mucus lining of the colon (P < 0.01) and the compromising of intestinal barrier function (P < 0.05). Sequencing of mouse stool specimens showed an increase in Akkermansia muciniphila (P < 0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation may contribute to murine GVHD. We demonstrate an underappreciated risk for the treatment of allo-HSCT recipients with antibiotics that may exacerbate GVHD in the colon.

View details for DOI 10.1126/scitranslmed.aaf2311

View details for PubMedID 27194729
Fecal Microbiota Transplant Is a Potentially Safe and Effective Treatment for Clostridium Difficile Infection in Hematopoietic Stem Cell Recipients Falconer, S., Moss, E., Andermann, T., Systrom, H., Mahabamunuge, J., Hohmann, E., Bhatt, A. S. ELSEVIER SCIENCE INC. 2016: S53?S54
View details for DOI 10.1016/j.bbmt.2015.11.340

View details for Web of Science ID 000370910300050
Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation CURRENT HEMATOLOGIC MALIGNANCY REPORTS Andermann, T. M., Rezvani, A., Bhatt, A. S. 2016; 11 (1): 19-28
Abstract

Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota's contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

View details for DOI 10.1007/s11899-016-0302-9

View details for Web of Science ID 000372595100004
Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation. Current hematologic malignancy reports Andermann, T. M., Rezvani, A., Bhatt, A. S. 2016
Abstract

Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota's contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

View details for PubMedID 26780719
Launching an Interactive Cancer Projects Map: A Collaborative Approach to Global Cancer Research and Program Development. Journal of global oncology Trimble, E. L., Chisti, A. A., Craycroft, J. A., Duncan, K., Gupta, M., Gutierrez, D., Rosenberg, I., Sharara, N., Sivaram, S., Topazian, H. M., Wang, J. J., Williams, M. J., Huang, F. W., Bhatt, A. S. 2015; 1 (1): 7?10
View details for PubMedID 28804766
Complete hematologic response of early T-cell progenitor acute lymphoblastic leukemia to the ?-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case. Cold Spring Harbor molecular case studies Knoechel, B., Bhatt, A., Pan, L., Pedamallu, C. S., Severson, E., Gutierrez, A., Dorfman, D. M., Kuo, F. C., Kluk, M., Kung, A. L., Zweidler-McKay, P., Meyerson, M., Blacklow, S. C., DeAngelo, D. J., Aster, J. C. 2015; 1 (1)
Abstract

Notch pathway antagonists such as ?-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.

View details for DOI 10.1101/mcs.a000539

View details for PubMedID 27148573
Epidemiologic Investigation of a Cluster of Neuroinvasive Bacillus cereus Infections in 5 Patients With Acute Myelogenous Leukemia. Open forum infectious diseases Rhee, C., Klompas, M., Tamburini, F. B., Fremin, B. J., Chea, N., Epstein, L., Halpin, A. L., Guh, A., Gallen, R., Coulliette, A., Gee, J., Hsieh, C., Desjardins, C. A., Pedamullu, C. S., DeAngelo, D. J., Manzo, V. E., Folkerth, R. D., Milner, D. A., Pecora, N., Osborne, M., Chalifoux-Judge, D., Bhatt, A. S., Yokoe, D. S. 2015; 2 (3): ofv096-?
Abstract

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.

View details for DOI 10.1093/ofid/ofv096

View details for PubMedID 26269794
The human microbiome in hematopoiesis and hematologic disorders. Blood Manzo, V. E., Bhatt, A. S. 2015; 126 (3): 311-318
Abstract

Humans are now understood to be in complex symbiosis with a diverse ecosystem of microbial organisms, including bacteria, viruses, and fungi. Efforts to characterize the role of these microorganisms, commonly referred as the microbiota, in human health have sought to answer the fundamental questions of what organisms are present, how are they functioning to interact with human cells, and by what mechanism are these interactions occurring. In this review, we describe recent efforts to describe the microbiota in healthy and diseased individuals, summarize the role of various molecular technologies (ranging from 16S ribosomal RNA to shotgun metagenomic sequencing) in enumerating the community structure of the microbiota, and explore known interactions between the microbiota and humans, with a focus on the microbiota's role in hematopoiesis and hematologic diseases.

View details for DOI 10.1182/blood-2015-04-574392

View details for PubMedID 26012569
DNA copy number analysis of metastatic urothelial carcinoma with comparison to primary tumors BMC CANCER Bambury, R. M., Bhatt, A. S., Riester, M., Pedamallu, C. S., Duke, F., Bellmunt, J., Stack, E. C., Werner, L., Park, R., Iyer, G., Loda, M., Kantoff, P. W., Michor, F., Meyerson, M., Rosenberg, J. E. 2015; 15
Abstract

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.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.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?
View details for DOI 10.1186/s12885-015-1192-2

View details for Web of Science ID 000352603600001

View details for PubMedID 25886454
Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Perry, J. A., Kiezun, A., Tonzi, P., Van Allen, E. M., Carter, S. L., Baca, S. C., Cowley, G. S., Bhatt, A. S., Rheinbay, E., Pedamallu, C. S., Helman, E., Taylor-Weiner, A., McKenna, A., DeLuca, D. S., Lawrence, M. S., Ambrogio, L., Sougnez, C., Sivachenko, A., Walensky, L. D., Wagle, N., Mora, J., de Torres, C., Lavarino, C., Aguiar, S. d., Yunes, J. A., Brandalise, S. R., Mercado-Celis, G. E., Melendez-Zajgla, J., Cardenas-Cardos, R., Velasco-Hidalgo, L., Roberts, C. W., Garraway, L. A., Rodriguez-Galindo, C., Gabriel, S. B., Lander, E. S., Golub, T. R., Orkin, S. H., Getz, G., Janeway, K. A. 2014; 111 (51): E5564-E5573
Abstract

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.

View details for DOI 10.1073/pnas.1419260111

View details for Web of Science ID 000346767200013

View details for PubMedID 25512523
Bacillus Cereus: A Leukemia-Specific, Neuroinvasive Pathogen? Rhee, C., Manzo, V., Shea, T., Desjardins, C., van der Auwera, G., Young, S., Riley, A., DeAngelo, D. J., Baden, L. R., Gee, J., Meyerson, M., Klompas, M., Yokoe, D., Weiser, L., Pedamallu, C., Bhatt, A. S. AMER SOC HEMATOLOGY. 2014
View details for Web of Science ID 000349242707200
In Search of a Candidate Pathogen for Giant Cell Arteritis: Sequencing-Based Characterization of the Giant Cell Arteritis Microbiome ARTHRITIS & RHEUMATOLOGY Bhatt, A. S., Manzo, V. E., Pedamallu, C. S., Duke, F., Cai, D., Bienfang, D. C., Padera, R. F., Meyerson, M., Docken, W. P. 2014; 66 (7): 1939-1944
Abstract

To characterize the microbiome of the temporal artery in patients with giant cell arteritis (GCA), and to apply an unbiased and comprehensive shotgun sequencing-based approach to determine whether there is an enrichment of candidate pathogens in the affected tissue.Temporal artery biopsy specimens were collected from patients at a single institution over a period of 4 years, and unbiased DNA sequencing was performed on 17 formalin-fixed, paraffin-embedded specimens. Twelve of the 17 patients fulfilled the clinical and histopathologic criteria for GCA, and the other 5 patients served as controls. Using PathSeq software, human DNA sequences were computationally subtracted, and the remaining non-human DNA sequences were taxonomically classified using a comprehensive microbial sequence database. The relative abundance of microbes was inferred based on read counts assigned to each organism. Comparison of the microbial diversity between GCA cases and controls was carried out using hierarchical clustering and linear discriminant analysis of effect size.Propionibacterium acnes and Escherichia coli were the most abundant microorganisms in 16 of the 17 samples, and Moraxella catarrhalis was the most abundant organism in 1 control sample. Pathogens previously described to be correlated with GCA were not differentially abundant in cases compared to controls. There was not a significant burden of likely pathogenic viruses.DNA sequencing of temporal artery biopsy specimens from GCA cases, in comparison with non-GCA controls, showed no evidence of previously identified candidate GCA pathogens. A single pathogen was not clearly and consistently associated with GCA in this case series.

View details for DOI 10.1002/art.38631

View details for Web of Science ID 000339092800029

View details for PubMedID 24644069

View details for PubMedCentralID PMC4113339
Comprehensive molecular characterization of urothelial bladder carcinoma NATURE Weinstein, J. N., Akbani, R., Broom, B. M., Wang, W., Verhaak, R. G., McConkey, D., Lerner, S., Morgan, M., Creighton, C. J., Smith, C., Kwiatkowski, D. J., Cherniack, A. D., Kim, J., Pedamallu, C. S., Noble, M. S., Al-Ahmadie, H. A., Reuter, V. E., Rosenberg, J. E., Bajorin, D. F., Bochner, B. H., Solit, D. B., Koppie, T., Robinson, B., Gordenin, D. A., Fargo, D., Klimczak, L. J., Roberts, S. A., Au, J., Laird, P. W., Hinoue, T., Schultz, N., Ramirez, R., Hansel, D., Hoadley, K. A., Kim, W. Y., Damrauer, J. S., Baylin, S. B., Mungall, A. J., Robertson, A. G., Chu, A., Kwiatkowski, D. J., Sougnez, C., Cibulskis, K., Lichtenstein, L., Sivachenko, A., Stewart, C., Lawrence, M. S., Getz, G., Lander, E., Gabriel, S. B., Creighton, C. J., Donehower, L., Cherniack, A. D., Kim, J., Carter, S. L., Saksena, G., Schumacher, S. E., Sougnez, C., Freeman, S. S., Jung, J., Pedamallu, C. S., Bhatt, A. S., Pugh, T., Getz, G., Beroukhim, R., Gabriel, S. B., Meyerson, M., Mungall, A. J., Robertson, A. G., Chu, A., Ally, A., Balasundaram, M., Butterfield, Y. S., Dhalla, N., Hirst, C., Holt, R. A., Jones, S. J., Lee, D., Li, H. I., Marra, M. A., Mayo, M., Moore, R. A., Schein, J. E., Sipahimalani, P., Tam, A., Thiessen, N., Wong, T., Wye, N., Bowlby, R., Chuah, E., Guin, R., Jones, S. J., Marra, M. A., Hinoue, T., Shen, H., Bootwalla, M. S., Triche, T., Lai, P. H., Van den Berg, D. J., Weisenberger, D. J., Laird, P. W., Hansel, D., Hoadley, K. A., Balu, S., Bodenheimer, T., Damrauer, J. S., Hoyle, A. P., Jefferys, S. R., Meng, S., Mose, L. E., Simons, J. V., Soloway, M. G., Wu, J., Kim, W. Y., Parker, J. S., Hayes, D. N., Roach, J., Buda, E., Jones, C. D., Mieczkowski, P. A., Tan, D., Veluvolu, U., Waring, S., Auman, J. T., Perou, C. M., Wilkerson, M. D., Santoso, N., Parfenov, M., Ren, X., Pantazi, A., Hadjipanayis, A., Seidman, J., Kucherlapati, R., Lee, S., Yang, L., Park, P. J., Baylin, S. B., Xu, A. W., Protopopov, A., Zhang, J., Bristow, C., Mahadeshwar, H. S., Seth, S., Song, X., Tang, J., Zeng, D., Chin, L., Guo, C., Weinstein, J. N., Akbani, R., Broom, B. M., McConkey, D., Casasent, T. D., Liu, W., Ju, Z., Motter, T., Peng, B., Ryan, M., Wang, W., Verhaak, R. G., Su, X., Yang, J., Lorenzi, P. L., Yao, H., Zhang, N., Zhang, J., Mills, G. B., Kim, J., Noble, M. S., Cho, J., DiCara, D., Frazer, S., Gehlenborg, N., Heiman, D. I., Lin, P., Liu, Y., Stojanov, P., Voet, D., Zhang, H., Zou, L., Chin, L., Getz, G., Bernard, B., Kreisberg, D., Reynolds, S., Rovira, H., Shmulevich, I., Ramirez, R., Schultz, N., Gao, J., Jacobsen, A., Aksoy, B. A., Antipin, Y., Ciriello, G., Dresdner, G., Gross, B., Lee, W., Reva, B., Shen, R., Sinha, R., Sumer, S. O., Weinhold, N., Ladanyi, M., Sander, C., Benz, C., Carlin, D., Haussler, D., Ng, S., Paull, E. O., Stuart, J., Zhu, J., Liu, Y., Zhang, W., Taylor, B. S., Lichtenberg, T. M., Zmuda, E., Barr, T., Black, A. D., George, M., Hanf, B., Helsel, C., McAllister, C., Ramirez, N. C., Tabler, T. R., Weaver, S., Wise, L., Bowen, J., Gastier-Foster, J. M., Weinstein, J. N., Lerner, S., Jian, W., Tello, S., Ittman, M., Castro, P., McClenden, W. D., Morgan, M., Gibbs, R., Liu, Y., Saller, C., Tarvin, K., DiPiero, J. M., Owens, J., Bollag, R., Li, Q., Weinberger, P., Czerwinski, C., Huelsenbeck-Dill, L., Iacocca, M., Petrelli, N., Rabeno, B., Swanson, P., Shelton, T., Curley, E., Gardner, J., Mallery, D., Penny, R., Nguyen Van Bang, N. V., Phan Thi Hanh, P. T., Kohl, B., Xuan Van Le, X. V., Bui Duc Phu, B. D., Thorp, R., Nguyen Viet Tien, N. V., Le Quang Vinh, L. Q., Sandusky, G., Burks, E., Christ, K., Gee, J., Holway, A., Moinzadeh, A., Sorcini, A., Sullivan, T., Al-Ahmadie, H. A., Bajorin, D. F., Bochner, B. H., Garcia-Grossman, I. R., Regazzi, A. M., Solit, D. B., Rosenberg, J. E., Reuter, V. E., Koppie, T., Boice, L., Rathmell, W. K., Thorne, L., Bastacky, S., Davies, B., Dhir, R., Gingrich, J., Hrebinko, R., Maranchie, J., Nelson, J., Parwani, A., Bshara, W., Gaudioso, C., Morrison, C., Alexopoulou, V., Bartlett, J., Engel, J., Kodeeswaran, S., Antic, T., O'Donnell, P. H., Smith, N. D., Steinberg, G. D., Egea, S., Gomez-Fernandez, C., Herbert, L., Jorda, M., Soloway, M., Beaver, A., Carter, S., Kapur, P., Lewis, C., Lotan, Y., Robinson, B., Hansel, D., Guo, C., Bondaruk, J., Czerniak, B., Akbani, R., Broom, B. M., Liu, Y., Zhang, W., Weinstein, J. N., Lerner, S., Morgan, M., Kim, J., Cherniack, A. D., Freeman, S. S., Pedamallu, C. S., Noble, M. S., Kwiatkowski, D. J., Al-Ahmadie, H. A., Bajorin, D. F., Bochner, B. H., Solit, D. B., Rosenberg, J. E., Reuter, V. E., Koppie, T., Robinson, B., Skinner, E., Ramirez, R., Schultz, N., Hansel, D., Kim, W. Y., Guo, C., Bondaruk, J., Aldape, K., Czerniak, B., Jensen, M. A., Kahn, A. B., Pihl, T. D., Pot, D. A., Srinivasan, D., Wan, Y., Ferguson, M. L., Zenklusen, J. C., Davidsen, T., Demchok, J. A., Shaw, K. R., Sheth, M., Tarnuzzer, R., Wang, Z., Yang, L., Hutter, C., Ozenberger, B. A., Sofia, H. J., Eley, G. 2014; 507 (7492): 315-322
View details for DOI 10.1038/nature12965

View details for Web of Science ID 000333029000025
Sequence-Based Discovery of Bradyrhizobium enterica in Cord Colitis Syndrome NEW ENGLAND JOURNAL OF MEDICINE Bhatt, A. S., Freeman, S. S., Herrera, A. F., Pedamallu, C. S., Gevers, D., Duke, F., Jung, J., Michaud, M., Walker, B. J., Young, S., Earl, A. M., Kostic, A. D., Ojesina, A. I., Hasserjian, R., Ballen, K. K., Chen, Y., Hobbs, G., Antin, J. H., Soiffer, R. J., Baden, L. R., Garrett, W. S., Hornick, J. L., Marty, F. M., Meyerson, M. 2013; 369 (6): 517-528
Abstract

Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin.We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls.DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease.We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen. (Funded by the National Cancer Institute and others.)

View details for DOI 10.1056/NEJMoa1211115

View details for Web of Science ID 000322842000008

View details for PubMedID 23924002

View details for PubMedCentralID PMC3889161
NK-Cell and B-Cell Deficiency with a Thymic Mass NEW ENGLAND JOURNAL OF MEDICINE Ng, S., Fanta, C., Okam, M., Bhatt, A. S. 2011; 364 (6): 586-588
View details for Web of Science ID 000287139900041

View details for PubMedID 21306273
MT-SP1 proteolysis and regulation of cell-microenvironment interactions FRONTIERS IN BIOSCIENCE-LANDMARK Darragh, M. R., Bhatt, A. S., Craik, C. S. 2008; 13: 528-539
Abstract

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.

View details for DOI 10.2741/2698

View details for Web of Science ID 000255775700042

View details for PubMedID 17981566
Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bhatt, A. S., Welm, A., Farady, C. J., Vasquez, M., Wilson, K., Craik, C. S. 2007; 104 (14): 5771-5776
Abstract

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.

View details for DOI 10.1073/pnas.0606514104

View details for Web of Science ID 000245657600015

View details for PubMedID 17389401

View details for PubMedCentralID PMC1838401
Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers BIOCHEMICAL JOURNAL Herter, S., Piper, D. E., Aaron, W., Gabriele, T., Cutler, G., Cao, P., Bhattt, A. S., Choe, Y., CRAIK, C. S., Walker, N., Meininger, D., Hoey, T., Austin, R. J. 2005; 390: 125-136
Abstract

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.

View details for DOI 10.1042/BJ20041955

View details for Web of Science ID 000231492800014

View details for PubMedID 15839837
Adhesion signaling by a novel mitotic substrate of src kinases ONCOGENE Bhatt, A. S., Erdjument-Bromage, H., Tempst, P., CRAIK, C. S., Moasser, M. M. 2005; 24 (34): 5333-5343
Abstract

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.

View details for DOI 10.1038/sj.onc.1208582

View details for Web of Science ID 000231158500007

View details for PubMedID 16007225
Substrates of the prostate-specific serine protease prostase/KLK4 defined by positional-scanning peptide libraries PROSTATE Matsumura, M., Bhatt, A. S., Andress, D., Clegg, N., Takayama, T. K., CRAIK, C. S., Nelson, P. S. 2005; 62 (1): 1-13
Abstract

Prostase/KLK4 is a member of the human kallikrein (KLK) gene family that 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.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).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.These results identify potential KLK4 substrates that may serve to define the role of this protease in normal prostate physiology, and facilitate studies of the consequences of KLK4 expression in pathological conditions.

View details for DOI 10.1002/pros.20101

View details for Web of Science ID 000225704700001

View details for PubMedID 15389820
Quantitation of membrane type serine protease 1 (MT-SP1) in transformed and normal cells BIOLOGICAL CHEMISTRY Bhatt, A. S., Takeuchi, T., Ylstra, B., Ginzinger, D., Albertson, D., Shuman, M. A., CRAIK, C. S. 2003; 384 (2): 257-266
Abstract

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 nonquantitative 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.

View details for Web of Science ID 000181175000010

View details for PubMedID 12675519

Ami Bhatt

Assistant Professor of Medicine (Hematology) and of Genetics

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