tbuckley/cabot-search huggingface dataset:
Integrated microbiome and metabolome analysis reveals a novel interplay between commensal bacteria and metabolites in colorectal cancer
Authors: Yongzhi Yang, Biswapriya B Misra, Lei Liang, Dexi Bi, Wenhao Weng, Wen Wu, Sanjun Cai, Huanlong Qin, Ajay Goel, Xinxiang Li, Yanlei Ma
Journal: Theranostics (2019)

Rationale: Colorectal cancer (CRC) is a malignant tumor with the third highest morbidity rate among all cancers. Driven by the host's genetic makeup and environmental exposures, the gut microbiome and its metabolites have been implicated as the causes and regulators of CRC pathogenesis. We assessed human fecal samples as noninvasive and unbiased surrogates to catalog the gut microbiota and metabolome in patients with CRC. Methods: Fecal samples collected from CRC patients (CRC group, n = 50) and healthy volunteers (H group, n = 50) were subjected to microbiome (16S rRNA gene sequencing) and metabolome (gas chromatography-mass spectrometry, GC-MS) analyses. The datasets were analyzed individually and integrated for combined analysis using various bioinformatics approaches. Results: Fecal metabolomic analysis led to the identification of 164 metabolites spread across 40 metabolic pathways in both groups. In addition, there were 42 and 17 metabolites specific to the H and CRC groups, respectively. Sequencing of microbial diversity revealed 1084 operational taxonomic units (OTUs) across the two groups, and there was less species diversity in the CRC group than in the H group. Seventy-six discriminatory OTUs were identified for the microbiota of H volunteers and CRC patients. Integrated analysis correlated CRC-associated microbes with metabolites, such as polyamines (cadaverine and putrescine). Conclusions: Our results provide substantial evidence of a novel interplay between the gut microbiome and metabolome (i.e., polyamines), which is drastically perturbed in CRC. Microbe-associated metabolites can be used as diagnostic biomarkers in therapeutic explorations.
Fitness Landscape of the Fission Yeast Genome
Authors: Leanne Grech, Daniel C Jeffares, Christoph Y Sadée, María Rodríguez-López, Danny A Bitton, Mimoza Hoti, Carolina Biagosch, Dimitra Aravani, Maarten Speekenbrink, Christopher J R Illingworth, Philipp H Schiffer, Alison L Pidoux, Pin Tong, Victor A Tallada, Robin Allshire, Henry L Levin, Jürg Bähler
Journal: Molecular Biology and Evolution (2019)

The relationship between DNA sequence, biochemical function, and molecular evolution is relatively well-described for protein-coding regions of genomes, but far less clear in noncoding regions, particularly, in eukaryote genomes. In part, this is because we lack a complete description of the essential noncoding elements in a eukaryote genome. To contribute to this challenge, we used saturating transposon mutagenesis to interrogate the Schizosaccharomyces pombe genome. We generated 31 million transposon insertions, a theoretical coverage of 2.4 insertions per genomic site. We applied a five-state hidden Markov model (HMM) to distinguish insertion-depleted regions from insertion biases. Both raw insertion-density and HMM-defined fitness estimates showed significant quantitative relationships to gene knockout fitness, genetic diversity, divergence, and expected functional regions based on transcription and gene annotations. Through several analyses, we conclude that transposon insertions produced fitness effects in 66-90% of the genome, including substantial portions of the noncoding regions. Based on the HMM, we estimate that 10% of the insertion depleted sites in the genome showed no signal of conservation between species and were weakly transcribed, demonstrating limitations of comparative genomics and transcriptomics to detect functional units. In this species, 3'- and 5'-untranslated regions were the most prominent insertion-depleted regions that were not represented in measures of constraint from comparative genomics. We conclude that the combination of transposon mutagenesis, evolutionary, and biochemical data can provide new insights into the relationship between genome function and molecular evolution.
Time for early predictive biosignatures to personalize the clinical approach of advanced tumor patients?
Authors: Nise Hitomi Yamaguchi, Manoela Tavares Arruda Spada, Rachel Ribeiro, Flavio Silverio, Paula Tamura, Fernando Moura, Aline Crisitna Conceicao Oliveira, Eivete Cordeiro, Fabiana Sequim Anciaes, Kleber Kobayashi, Silvio Donatangelo, Nivia Fernanda Oliveira
Journal: Journal of Clinical Oncology (2013)

e22176 Background: The Institute of Advances in Medicine is a private referral center in Brazil that treats patients with advanced disease, often after failure to previous lines of treatments. Predictive response assays allow physicians to make better informed choices when establishing the therapeutic strategy for each patient. Methods: 48 patients (21 male; 27 female), 54.5 y old (33-80y) with advanced disease were submitted to molecular diagnostic investigation using paraffin-embedded tumor samples from Brazil, shipped to Caris Target Now-US in accordance with the Brazilian Federal Sanitary Agency regulations. We have considered the samples diversity, different tumor sites, tissue availability and technical conservation. Results: More than 1920 IHC, FISH or CISH, RT-PCR, RFLP, sequencing and mutational analysis by PCR were performed, with a list of drugs with Potential Clinical Benefit (PCB) or Potential Lack of Benefit (PLB) for the 48 primary tumors: 11 colorectal, 9 breast, 6 NSCLC, 22 other sites. Drugs were listed in the PCB column that were usual drugs in first and second line treatments for their cancer types. However, many patients were classified with PLB with drugs that they had used before and were not active. These data were analyzed for Performance Status, Previous Treatments actually given and current commercially available anticancer agents, such as chemotherapeutic and new molecular targeted agents to help the decision for future treatments. Conclusions: When the test was performed, patients had already been treated (and had had disease progression) with drugs that were listed as potentially lacking benefit. Time is ripen for testing tumors prior to beginning clinical treatment, since it may provide a better understanding of the tumor biology and the probable clinical response, making it possible to distinguish which therapeutic schedule is preferable. The present availability of reliable predictive assays for assessing tumor sensitiveness (or lack of it) to anticancer drugs makes it imperative to change guidelines. The ever growing health costs in the public health systems around the world may also benefit from such strategy since only drugs with a potential for response will be chosen.
Tracheostomy prevalence at Skilled Nursing Facilities
Authors: F. Pereira, A.Maia Silva, I.Machado Vaz, S. Viamonte, J.C. Winck
Journal: Pulmonology (2019)

The incidence of chronically ill subjects with prolonged mechanical ventilation has significantly increased over the last decade. Many patients get discharge to Skilled Nursing Facilities with an artificial airway, which do not have the means to properly progress on weaning. In Portugal this prevalence is unknown. Our aim was to establish the prevalence of tracheostomized patients at SNF in the North of Portugal, characterizing these units and its population, in a cross-sectional study, through an online questionnaire answered on the same day. Of the 75 SNF, 30 answered: 13 long-term, 2 medium-term, 2 short-term, 12 had beds of both medium and long-term and 1 had the three typologies. 33 had tracheostomy ventilation (prevalence 3.36%), all admitted at long-term units, the majority transferred from previous hospital admission (n = 27, 90%). Only one was under mechanical ventilation. The most frequent reason for tracheostomy placement was acute respiratory failure (n = 10, 33.3%). The most commonly presented cannula was the fenestrated non-cuffed (n = 17, 59%). Only 4 were performing occlusion training, 21 needed frequent secretion suctioning and 1 used the mechanical in-exsufflation. Regarding motor function, 16 (53.3%) were unable to achieve sitting balance and 20 (66.7%) had no orthostatic balance or walking ability. 14 (46.7%) had percutaneous endoscopic gastrostomy. Although low response rate may induce some bias, this study revealed a significant prevalence of tracheostomized patients at SNF. These facilities do not have the resources to safely and effectively progress on ventilatory weaning. It is essential to establish new referral criteria and create specialized weaning units.
Sex Differences in 20-Hydroxyecdysone Hormone Levels Control Sexual Dimorphism in Bicyclus anynana Wing Patterns
Authors: Shivam Bhardwaj, Kathleen L Prudic, Ashley Bear, Mainak Dasgupta, Bethany R Wasik, Xiaoling Tong, Wei Fun Cheong, Markus R Wenk, Antónia Monteiro
Journal: Molecular Biology and Evolution (2017)

In contrast to the important role of hormones in the development of sexual traits in vertebrates (Cox RM, Stenquist DS, Calsbeek R. 2009. Testosterone, growth and the evolution of sexual size dimorphism. J Evol Biol. 22(8):1586-1598.), the differentiation of these traits in insects is attributed almost exclusively to cell-autonomous mechanisms controlled by members of the sex determination pathway (Verhulst EC, van de Zande L. 2015. Double nexus - doublesex is the connecting element in sex determination. Brief Funct Genomics 14(6):396-406.), such as doublesex. Although hormones can shape the development of sexual traits in insects, variation in hormone levels are not conclusively known to cause dimorphism in these traits (Prakash A, Monteiro A. 2016. Molecular mechanisms of secondary sexual trait development in insects. Curr Opin Insect Sci. 17:40-48.). Here, we show that butterflies use sex-specific differences in 20-hydroxyecdysone hormone titers to create sexually dimorphic wing ornaments. Females of the dry season (DS) form of Bicyclus anynana display a larger sexual ornament on their wings than males, whereas in the wet season form both sexes have similarly sized ornaments (Prudic KL, Jeon C, Cao H, Monteiro A. 2011. Developmental plasticity in sexual roles of butterfly species drives mutual sexual ornamentation. Science 331(6013):73-75.). High levels of circulating 20-hydroxyecdysone during larval development in DS females and wet season forms cause proliferation of the cells fated to give rise to this wing ornament, and results in sexual dimorphism in the DS forms. This study advances our understanding of how the environment regulates sex-specific patterns of plasticity of sexual ornaments and conclusively shows that hormones can play a role in the development of secondary sexual traits in insects, just like they do in vertebrates.
Abstract 17544: T Regulatory Lymphocytes Function Increased, by Induction Of Ho-1, Improves Type-1 Cardio-Renal Syndrome
Authors: Paola Pesce, David Sacerdoti, Massimo Boldrin, Rita Rezzani, Nader G Abraham
Journal: Circulation (2012)

Rationale: Type-1 cardio-renal syndrome (CRS) is characterized by an acute kidney dysfunction due to renal arteriolar vasoconstriction following an acute worsening of cardiac function. It is well k...
S891 SUCCESSFUL TREATMENT OF INTESTINAL GRAFT‐VERSUS‐HOST DISEASE WITH FECAL MICROBIOTA TRANSPLANTATION
Authors: Y. Van Lier, M. Davids, N. Haverkate, P. de Groot, M. Donker, F. Heubel‐Moenen, E. Nur, S. Zeerleder, M. Nieuwdorp, B. Blom, M. Hazenberg
Journal: HemaSphere (2019)

Background: Disruption of the intestinal microbiome has a negative influence on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT). Decreased gut flora diversity with loss of commensals and pathobiont domination, is associated with an increased risk to develop graft‐versus‐host disease (GvHD). Fecal microbiota transplantation (FMT) has successfully been used to treat Clostridium difficile enteritis but the safety and efficacy of FMT in immunocompromised GvHD patients remains to be elucidated. Aims: 1. To assess the safety and effectiveness of FMT as treatment for GvHD patients in a prospective, single‐arm pilot study 2. To analyze the microbiome dynamics of GvHD patients receiving an FMT Methods: Fifteen patients with steroid‐refractory or steroid‐dependent intestinal GvHD received a single FMT from an unrelated, healthy donor via nasoduodenal infusion. Follow‐up included collection of blood and fecal samples prior to FMT and at 1, 4, 12 and 24 weeks after FMT as well as clinical follow‐up up to 6months. Results: FMT was well tolerated by all patients, there were no serious adverse events observed that could be attributed to FMT. Response evaluation at 4 weeks after FMT identified 11 participants with a complete response (CR), defined as resolution of all GvHD, without other interventions to alleviate symptoms. In 6 CR patients, the normalization of stool frequency and consistency was sustained throughout the whole period of follow‐up, with successful taper of immunosuppressants. Five other responders initially showed improvement of GvHD after FMT but relapsed upon prednisolone taper (CR/sf; complete responders with secondary failure). A durable response to FMT was associated with a better prognosis (Figure 1). Analysis of peripheral blood immune cell subsets did not reveal significant differences. Alpha diversity of fecal samples, analyzed by 16S ribosomal RNA sequencing, was low in patients pre‐FMT but improved upon response to treatment in CR and CR/sf patients. One week after FMT, the fecal microbial composition of CR patients resembled that of the donor the most, suggesting a better engraftment of fecal donor species in patients with persistent responses. Summary/Conclusion: This pilot study shows the potential of donor FMT to safely restore microbial diversity and improve symptoms of steroid‐refractory or steroid‐dependent GvHD patients. These encouraging data promote further investigation of this therapy in larger cohorts. image
AB0547 LUPUS ENTERITIS SERIES OF CASES IN DEVELOPING COUNTRY: FROM CLINICAL FINDINGS TO THERAPEUTIC MANAGEMENT
Authors: Gustavo Razo, Diego Felipe Garcia Rodriguez, David Alejandro Herrera Van Oostdam, Carlos Abud-Mendoza, Enrique Cuevas Orta, Alejandra Perez, Luis Gonzalo Hernandez
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The prevalence of lupus enteritis (LE) is 2% one of gastrointestinal manifestation of the involvement of the LES. The rapid onset of these symptoms requires determining the life-threatening conditions, but their detection becomes a challenge. We present a series of 6 cases of LE, the most clinical findings and limitations in our environment. <h3>Objectives:</h3> Our objective was to describe six cases of lupus enteritis, its diagnostic challenge in our country with limited resources, frequent clinical presentations and its management. <h3>Methods:</h3> We retrospectively reviewed the medical records of 6 patients in our hospital with a diagnosis of SLE according to SLICC ACR 2010 criteria between 2017-2018 for suspicion of lupus enteritis. we discard infectious etiology. <h3>Results:</h3> We describe 6 cases, all the patients were woman with a mean age of 23.1 years and an average of 3.6 years until the presentation of enteritis. The clinical symptoms included mainly abdominal pain (100%), vomiting (50%), diarrhea (83%), nausea (50%) and fever (16%). The laboratory characteristics mainly reflect the high lupus activity: SLEDAI 23 pts. Low levels of complement (83%), anemia (50%). The homogeneous pattern predominated in 83%, antiDNA was quantified only in one patient due to a lack of resources, with high titers. The median level of CRP was 3.3 mg/dL. Only two patients (33%) presented class III lupus nephritis by biopsy. In CT, the sign of target shot was present in all cases. Only 1 patient could be biopsied with non-specific chronic colitis. All patients received corticosteroids as first-line treatment, with additional immunosuppressants with significant improvement. One patient died due to pulmonary complications. <h3>Conclusion:</h3> We should consider lupus enteritis as a possible initial digestive manifestation in patients with SLE. Its diagnosis requires a high index of suspicion, being the CT one of the fundamental pillars for the diagnosis. There is no consensus in the management, however, it was initiated with pulses of methylprednisolone, with limitations to request immunological studies and biological therapy due to economic implications.Finally, we emphasize the need for a prospective evaluation of this rare disease by encouraging the establishment of an international registry. <h3>References</h3> [1] Li Z, Xu D, Wang Z, et al. Gastrointestinal system involvement in systemic lupus erythematosus. Lupus 2017; 26: 1127–1138. [2] Yang C, Chen S, Gaut JP, Dehner LP. Smooth-muscle myopathy in systemic lupus erythematosus presenting with intestinal pseudo- obstruction. Am J Gastroenterol 2016; 111: 1501–1502 <h3>Disclosure of Interests:</h3> None declared
PB1827 LENALIDOMIDE AND RITUXIMAB COMBINED WITH CEP CHEMOTHERAPY (R2CEP) FOR PATIENTS WITH RELAPSED B-CELL LYMPHOMA.
Authors: S. Guidez, C. Gruchet, C. Tomowiak, A. Bobin, C. Debiais, A. Machet, V. Delwail
Journal: HemaSphere (2019)

Background: Patients with relapse or refractory (R/R) B-cell Non Hodgkin Lymphoma (B-NHL), especially DLBCL, have a poor prognostic mainly because of the difficulty of effective treatment. In patients relapsed after intensive chemotherapy or unfit patients, the treatment are not very effective and access to a clinical trial is not always possible. Aims: Based on the results of the combination of lenalidomide and rituximab in B-cell lymphoma, we combined this regimen with conventional CEP chemotherapy (cyclophosphamide, etoposide, and prednisone) in patients with R/R B-NHL most often DLCL. Methods: Thirteen patients were treated by R2CEP regimen from June 2017. The median age was 82 years (58-92). Eleven patients presented a DLBCL including 1 transformed follicular, 1 MCL and 1 follicular lymphoma. Patients had received an average of 2 prior lines of treatment (1-4) and presented for 11 of them an advanced stage (III-IV) at relapse. Patients were treated by R2CEP association with: rituximab 375 mg/m2 D1, cyclophosphamide 750 mg/m2 D1, etoposide 100 mg/m2 D1, prednisone 50 mg/m2 D1 to D5 and lenalidomide 10 mg by day D1 to D14, 21-days cycles for 6 cycles of treatment. Results: Five patients are still being treated. Two patients stopped the treatment for progression. Only one patient experienced an episode of febrile neutropenia. Seven patients achieved complete response. With a median follow up of 4.5 months (0.5-13.2), one patient died of lymphoma progression. Summary/Conclusion: In patients with R/R DLBCL lymphoma, the combination with lenalidomide-rituximab and CEP chemotherapy seems to be a well tolerated therapeutic option and our preliminary results seems to show an efficiency of this scheme. The results will be updated for the congress.
AB0198 THE ROLE OF LOW EXPRESSION OF MIR-127–3P IN THE PATHOGENESIS OF LUPUS NEPHRITIS
Authors: Yin Zhihua, Qu Bo, Ye Zhizhong
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Lupus nephritis (LN) is one of the most severe organ lesions in systemic lupus erythematosus (SLE). Overactivation of the type I interferon (IFN-I) signaling pathway is associated with the pathogenesis of LN. Overexpression of the IFN stimulated genes (ISGs) was found in the kidneys of LN patients, and the absence of the IFN receptor reduced nephritis in lupus prone mice. Abnormal expression of microRNA in renal tissue is involved in the pathogenesis of LN. <h3>Objectives</h3> We aimed to investigate the role of renal microRNA related to LN in the over-activation of the IFN signaling pathway of LN kidney. <h3>Methods</h3> The expression of microRNA was determined by Taqman method. Interferon stimulation response element (ISRE) -luciferase reporter gene assay and western blot assay were used to study the function of candidate microRNA in IFN signal transduction pathway. mRNA expression was measured by SYBR green method. Gene expression profile was detected by gene expression microarray. Antagomir and Agomir (chemically modified microRNA mimics and antagomir inhibitors) of candidate microRNAs were used for functional gain and functional loss experiments. <h3>Results</h3> Among differentially expressed renal microRNAs in LN, miR-127-3p was reduced in renal tissues of patients with LN. The miR-127-3p suppressed the fluorescase gene expression of ISRE induced by ISRE, and the phosphorylation of STAT1 and STAT2. By microarray analysis, we found that most ISG was inhibited by miR127-3p in IFN-stimulated Hela cells. The functional deletion of miR-127-3p enhanced the IFN response in human primary mesangial cells, which was manifested by enhanced ISRE mediated reporter gene expression, enhanced STAT2 phosphorylation and increased ISG expression. In addition, we found that JAK1, the upstream tyrosine kinase of STAT1 and STAT2, was a new target molecule for miR-127-3p. <h3>Conclusion</h3> Our study shows that miR-127-3p can inhibit IFN signal transduction by targeting JAK1. The decreased expression of miR-127-3p in the kidney is associated with an overactive IFN response in the renal tissue of patients with LN. Subsequent mouse model studies indicate the therapeutic potential of miR-127-3p in treating lupus associated organ damage. <h3>References</h3> [1] Han X, Wang Y, Zhang X, et al. MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I InterferonPathway on Renal Mesangial Cells. Arthritis Rheumatol. 2016 Sep;68(9):2232-43. [2] Wu L, Qin Y, Xia S, et al. Identification of Cyclin-Dependent Kinase 1 as a Novel Regulator of Type I Interferon Signaling in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2016 May;68(5):1222-32. <h3>Disclosure of Interests</h3> None declared
SP0206 LINKS BETWEEN SLEEP QUALITY AND IMMUNITY IN RMDS
Authors: Tanja Lange
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Summary:</h3> Sleep and the immune system are bi-directionally linked. An immune activation induces fatigue, sleepiness and changes in sleep architecture. These range from a deepening of sleep to severe sleep disturbances with shallow and fragmented sleep. Patients with rheumatic and musculoskeletal diseases (RMDs) often complain about feelings of debilitating fatigue, of problems initiating and maintaining sleep and of unrefreshing sleep. Chronic low-grade inflammation due to the RMD, disease symptoms such as pain, concurrent diseases such as depression and medication such as glucocorticoids are potential triggers of poor sleep. Often it is demanding to delineate the exact cause(s) of sleep impairments in patients with RMDs and attempts to improve sleep quality therefore often fail. However, as fatigue and sleep problems can substantially impair quality of life and as poor sleep may further aggravate RMDs and their symptoms it is key to unravel the pathophysiology of fatigue and poor sleep in these patients. A deeper understanding of sleep-immune interactions in RMDs will advance targeted interventions that presumably will encompass a combination of immunomodulatory drugs, chronopharmacology and cognitive behavioral therapy. <h3>References:</h3> [1] Besedovsky L, Lange T, Born J. Sleep and immune function (2012) Pflugers Arch 463(1):121-37. [2] Tan X, van Egmond L, Partinen M, Lange T, Benedict C. A narrative review of interventions for improving sleep and reducing circadian disruption in medical inpatients (2018) Sleep Med pii: S1389-9457(18)30314-9. [3] Lacourt TE, Vichaya EG, Chiu GS, Dantzer R, Heijnen CJ. The high costs of low-grade inflammation: persistent fatigue as a consequence of reduced cellular-energy availability and non-adaptive energy expenditure (2018) Front Behav Neurosci 12:78. <h3>Disclosure of Interests:</h3> None declared