tbuckley/cabot-search huggingface dataset:
Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: the role of mucosal strengthening
Authors: Thomas Hueso, Kenneth Ekpe, Camille Mayeur, Anna Gatse, Marie Joncquel-Chevallier Curt, Guillaume Gricourt, Christophe Rodriguez, Charles Burdet, Guillaume Ulmann, Christel Neut, Salah-Eddine Amini, Patricia Lepage, Bruno Raynard, Christophe Willekens, Jean-Baptiste Micol, Stéphane De Botton, Ibrahim Yakoub-Agha, Frédéric Gottrand, Jean-Luc Desseyn, Muriel Thomas, Paul-Louis Woerther, David Seguy
Journal: Gut Microbes (2020)

Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except for Escherichia coli and Enterococcus spp., which became dominant. Both the α and β-diversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase of E. coli and Enterococcus spp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved α-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients' outcome.
WASh multicentre randomised controlled trial: water-assisted sigmoidoscopy in English NHS bowel scope screening
Authors: Matthew D Rutter, Rachel Evans, Zoe Hoare, Christian Von Wagner, Jill Deane, Shiran Esmaily, Tony Larkin, Rhiannon Edwards, Seow Tien Yeo, Llinos Haf Spencer, Emily Holmes, Brian P Saunders, Colin J Rees, Zacharias P Tsiamoulos, Iosif Beintaris
Journal: Gut (2020)

The English Bowel Cancer Screening Programme invites 55 year olds for a sigmoidoscopy (Bowel Scope Screening (BSS)), aiming to resect premalignant polyps, thus reducing cancer incidence. A national patient survey indicated higher procedural pain than anticipated, potentially impacting on screening compliance and effectiveness. We aimed to assess whether water-assisted sigmoidoscopy (WAS), as opposed to standard CO2 technique, improved procedural pain and detection of adenomatous polyps.The WASh (Water-Assisted Sigmoidoscopy) trial was a multicentre, single-blind, randomised control trial for people undergoing BSS. Participants were randomised to either receive WAS or CO2 from five sites across England. The primary outcome measure was patient-reported moderate/severe pain, as assessed by patients on a standard Likert scale post procedure prior to discharge. The key secondary outcome was adenoma detection rate (ADR). The costs of each technique were also measured.1123 participants (50% women, mean age 55) were randomised (561 WAS, 562 CO2). We found no difference in patient-reported moderate/severe pain between WAS and CO2 (14% in WAS, 15% in CO2; p=0.47). ADR was 15% in the CO2 arm and 11% in the WAS arm (p=0.03); however, it remained above the minimum national performance standard in both arms. There was no statistical difference in mean number of adenomas nor overall polyp detection rate. There was negligible cost difference between the two techniques.In the context of enema-prepared unsedated screening sigmoidoscopies performed by screening-accredited endoscopists, no difference in patient-reported pain was seen when using either a CO2 or WAS intubation technique.ISRCTN81466870.
Visit-to-Visit Hemoglobin A1c Variability Is Associated With the Risk of Lower-Extremity Amputation in Patients With Type 2 Diabetes
Authors: Yuxin Fan, Yun Shen, Jian Zhou, Lizheng Shi, Elizabeth Nauman, Peter T. Katzmarzyk, Eboni G. Price-Haywood, Ronald Horswell, San Chu, Alessandra N. Bazzano, Gang Hu
Journal: Diabetes Care (2020)

Patients with diabetes have a 10-fold higher risk of lower-extremity amputation (LEA) than people without diabetes (1). LEA is associated with the greatest reduction in quality of life and the greatest increase in mortality and medical costs in all diabetes complications. Previous studies suggested that the mean hemoglobin A1c (HbA1c) level was associated with an increased LEA risk among patients with type 2 diabetes (2). However, emerging evidence indicates that long-term glycemic variability evaluated by clinical visit-to-visit HbA1c variability may be a better predictor of diabetes complications (3). So far, the definitions of long-term HbA1c variability are inconsistent. In most studies, standard deviation of serial HbA1c measurements (HbA1c SD) and the intrapersonal coefficient of variation of HbA1c (HbA1c CV) are often used to represent HbA1c variability. In the current study, we added a new marker—HbA1c variability score (HVS) (4)—which is more easily applied to clinical practice.

We collected data from electronic health records for patients with type 2 diabetes between 2013 and 2019 in the Louisiana Experiment Assessing Diabetes outcomes (LEAD) cohort study (5). We excluded patients who had LEA diagnosis before entry and within 2 years after the first date of diabetes diagnosis, those with incomplete baseline data, those who did not have at least four HbA1c tests within 2 …
Abstract 1773: Targeting HER2 and Src in HER2-driven ovarian and esophagogastric cancers
Authors: Neil T. Conlon, Keshia Kroh, John Crown, Denis M. Collins
Journal: Cancer Research (2020)

Abstract Background: Neratinib, an oral, irreversible pan-HER tyrosine kinase inhibitor, has exhibited clinical activity against HER2-mutant and HER2 over-expressing cancers. Our previous pre-clinical studies have shown that combining the multi-kinase inhibitor dasatinib with neratinib is highly synergistic in HER2-positive breast cancer. Therefore, the aim of this study was to examine the potential of combining neratinib and dasatinib in HER2 over-expressing/mutant esophagogastric (EG) and ovarian cancer. Methods: The prevalence of HER2 mutation and amplification levels in ovarian and EG cancers was determined using the AACR Project GENIE database. The anti-proliferative effects of neratinib and dasatinib were assessed by acid phosphatase assay in a panel of HER2-altered ovarian (Caov3, OVCAR8, IGROV-1) and EG (NCI-N87, OE19) cancers. Synergy was assessed using Combenefit software with the Loewe additivity model, with additivity and synergy &amp;gt; 0 and antagonism &amp;lt; 0. Western blotting was used to examine the basal expression of HER2 and downstream signalling activity and to investigate the signalling effects of drug treatment in HER2-mutant OVCAR8 cells. Results: HER2 was the most commonly amplified gene in EG cancers (14.1%) and was also amplified in 2.4% of ovarian cancers. HER2 mutations occurred in 6.1% of EG and 1.5% ovarian cancers. All five cell lines tested displayed nanomolar sensitivity to single agent neratinib or dasatinib (Table). The combination of neratinib and dasatinib was synergistic in all cell lines. The greatest synergy was observed with low concentrations of neratinib in EG cell lines. Synergistic interactions occurred across a range of concentrations with both drugs in ovarian cancer cell lines. Antagonism was not observed at any concentration tested. Neratinib plus dasatinib inhibited Src and MAPK activity in OVCAR8 cells. Neratinib and dasatinib in ovarian and EG cancersCell linesCancertypeNeratinib EC50 value (nM)Dasatinib EC50 value (nM)Combination effectNCI-N87Esophagogastric0.188979SynergismOE19Esophagogastric0.432284SynergismOVCAR8Ovarian16281SynergismIGROV-1Ovarian1706SynergismCaov3Ovarian13730Synergism Conclusions: These data suggest that the addition of dasatinib may enhance the anti-cancer effect of neratinib in HER2-driven ovarian and EG cancers and warrants further investigation. Citation Format: Neil T. Conlon, Keshia Kroh, John Crown, Denis M. Collins. Targeting HER2 and Src in HER2-driven ovarian and esophagogastric cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1773.
Abstract 1207: Custom next-generation sequencing primer designs for targeted sequencing of multi strain viral targets
Authors: Ratnesh Singh, Na Li, Zunping Luo, Anna McGeachy, Antonio F. Martinez Alcantara, Aren Ewing, Fiona C. Hyland
Journal: Cancer Research (2020)

Abstract Viruses are infectious agents that can cause many diseases including cancers. A viral species is comprised of many strains each having a unique pathology. For example, over 170 types of HPV have been described, of which only 2 strains, HPV16 and HPV18, are implicated in 70% of cervical cancer cases. Accurate identification of viral strains is often critical and also facilitates research into their association with prognosis or response and personalized therapies. Currently, sequencing virus genes or genome requires complex procedures that involve purifying the virus particle and its genomes from the host genome. Whole genome sequencing is inefficient since viral genomes are orders of magnitude smaller than human genomes, and human DNA is orders of magnitude more abundant than viral DNA. In contrast, targeted next-generation sequencing allows focusing of sequencing and analysis to the region or species of interest using PCR based enrichment. We developed a viral design pipeline that accepts a multiple sequence alignment of the viral genomes or genomic regions of interest to identify and design primer pairs in conserved regions flanking the variable regions. The presence/absence of a set of 1 or more amplicons is used to precisely differentiate the many strains of a viral species. For whole genome sequencing, the complete viral genomic sequence is used as target to design unique and highly specific amplicons covering the whole genome for enrichment of the entire virus. All primers pass through rigorous quality checks to meet our sensitivity, specificity, and primer quality standards. We have successfully designed multi-strain Ion Ampliseq custom viral panels for HCV, HIV, CMV, Measles and Pestivirus. Some of these panels were designed with the objective of targeting a specific region on a virus genome; other panels were designed to enrich and sequence the whole virus genome. The panel primers were highly specific to the region of interest in the viral genomes and did not amplify the host genome. In conclusion, our custom Ion AmpliSeq viral panels enable the enrichment and amplification of the unique regions of interest in the viral genomes or the whole virus genome, avoiding the massive excess of the host genome. These panels allow precise identification of the virus species and strains for many applications including research, phylogenomic classification and comparative genomics. For Research Use Only. Not for use in diagnostic procedures Citation Format: Ratnesh Singh, Na Li, Zunping Luo, Anna McGeachy, Antonio F. Martinez Alcantara, Aren Ewing, Fiona C. Hyland. Custom next-generation sequencing primer designs for targeted sequencing of multi strain viral targets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1207.
Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection
Authors: Lara Labarta-Bajo, Steven P. Nilsen, Gregory Humphrey, Tara Schwartz, Karenina Sanders, Austin Swafford, Rob Knight, Jerrold R. Turner, Elina I. Zúñiga
Journal: The Journal of Experimental Medicine (2020)

Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. However, the causes of altered gut barrier remain mostly unknown. Using murine infection with lymphocytic choriomeningitis virus, we demonstrate that, in contrast to an acute viral strain, a persistent viral isolate leads to long-term viral replication in hematopoietic and mesenchymal cells, but not epithelial cells (IECs), in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. Type I IFN signaling caused tight junction dysregulation in IECs, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both type I IFN receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrates that infection with a virus that persistently replicates in the intestinal mucosa increases epithelial barrier permeability and reveals type I IFNs and CD8 T cells as causative factors of intestinal leakage during chronic infections.
Abstract 3807: Exposure to environmental chemicals leads to extensive branching and expression of cancer-promoting proteins in human mammary gland organoids
Authors: Johanna H. Hinrichs, Juliane Winkler, Pengyuan Liu, Nassim Ataii, Susan Fisher, Zena Werb
Journal: Cancer Research (2020)

Abstract Bisphenol A (BPA) is a chemical compound used as a plasticizer in a variety of plastic goods. Environmental chemicals like BPA haven been detected in the blood of women and girls. Yet, they are thought to interact with the endocrine system, thereby having carcinogenic effects on the tissue. While BPA is removed from many commercial products because of its potential carcinogenic effect, surprisingly little is known about its replacement chemicals, such as bisphenol S (BPS) and bisphenol F (BPF). In this study, we aim to link the exposure to those environmental chemicals to changes in human mammary gland morphology and to the underlying alterations at the protein level. We established organoid cultures from non-malignant primary human mammary gland tissue as advanced disease model. Human breast organoids were treated with physiological levels of various environmental chemicals, includingBPA, BPF, BPS, 17-β-estradiol (E2), or DMSO as vehicle control. Effects on organoid morphology were studied using brightfield and confocal microscopy. We analyzed relative protein abundances by quantitative mass spectrometry to define proteome changes between the different treatments. The exposure to the environmental chemicals as well as E2 resulted in altered branching morphology while organoid size was not affected. It is already known that BPA has oncogenic potential. Surprisingly, in our study, BPA has the least severe effects when compared to the other bisphenols. BSF or BPS treatment lead to more extensive branching and changed morphology.On protein level, each environmental chemical resulted in distinct protein profiles which show proteins alterations independent of endocrine signaling. Moreover, the exposure to the different bisphenols resulted in the upregulation of proteins which are involved in carcinogenesis, tumor progression and metastasis in various cancer types including breast cancer and thus may support tumor development. In this study, we identified BPS and BPF as potential carcinogens. Not only BPA, but also BPF and in particular BPS alter branching morphology of mammary organoids and influence various biological processes that are distinct from endocrine signaling. Our study highlights the desperate need of a thorough characterization of environmental chemicals to prevent the development of breast cancer caused by the exposure to potential harmful and carcinogenic substances. Citation Format: Johanna H. Hinrichs, Juliane Winkler, Pengyuan Liu, Nassim Ataii, Susan Fisher, Zena Werb. Exposure to environmental chemicals leads to extensive branching and expression of cancer-promoting proteins in human mammary gland organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3807.
Abstract 2517: Ectopic expression of miR-142-3p suppresses growth, migration, colony formation and induces apoptosis by down-regulating HMGA1, HMGA2, HMGB1 and HMGB3 in human cervical cancer cells
Authors: Priyanshu Sharma, Poonam Yadav, Devarajan Karunagaran
Journal: Cancer Research (2020)

Abstract High Mobility Group (HMG) proteins are non-histone chromosomal proteins having molecular weight less than 30 kDa. Canonical HMG family of proteins include HMGA (A1 and A2), HMGB (B1, B2, B3, and B4) and HMGN (N1, N2, N3, N4 and N5). Overexpression of HMG proteins contributing to their oncogenic properties has been reported and thus inhibition of their expression is potentially a promising therapeutic strategy in different cancers. Earlier, our laboratory demonstrated that miR-214 downregulates HMGA1 and miR-34a downregulates HMGB1 leading to the suppression of growth, proliferative and invasive properties of human cervical and colorectal cancer cells. Prompted by these results, we tried to find a single miRNA which can target multiple HMG genes. To this end, TargetScan, miRWalk, and miRDB were used to find out miRNAs targeting more than one HMG gene. We found that miR-142-3p has its seed region binding sites in the 3'UTRs of HMGA1, HMGA2, HMGB1, and HMGB3. Survival analysis with OncoLnc server revealed that low miR-142-3p expression found in cervical cancer patients correlates with their poor survival. Strengthened by this classical miRNA-target inverse relationship, we hypothesized that miRNA-142-3p may act as a tumor suppressor by targeting multiple HMG genes in cervical cancer. Doxycycline-responsive miR-142-3p expression constructs were used to generate stable cell lines and functional assays were performed. Through dual-luciferase reporter assays, we demonstrate that all the four HMG genes are direct targets of miR-142-3p in four cervical cancer cell lines (HeLa, SiHa, C33A, and CaSki). We observed the downregulation of the HMG genes (through qRT-PCR) upon miR-142-3p overexpression in the stable cell lines. Also, a significant reduction in cell viability after 72 and 96 hours concurrent with the highest expression levels of miR-142-3p. In colony formation assay, colony-forming potential of the cell lines was found to be severely compromised upon miR-142-3p overexpression. The scratch assay was also performed and a slower rate of migration was observed in miR-142-3p overexpressing cells. Annexin V staining indicated that miR-142-3p induces cell death via apoptosis. These results suggest that miR-142-3p may act as a tumor suppressor in cervical cancer highlighting it as a potential candidate for miRNA replacement therapy. Citation Format: Priyanshu Sharma, Poonam Yadav, Devarajan Karunagaran. Ectopic expression of miR-142-3p suppresses growth, migration, colony formation and induces apoptosis by down-regulating HMGA1, HMGA2, HMGB1 and HMGB3 in human cervical cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2517.
Conditional Survival and Cure of Patients With Colon or Rectal Cancer: A Population-Based Study
Authors: Seyed M. Qaderi, Paul W. Dickman, Johannes H.W. de Wilt, Rob H.A. Verhoeven
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: The increasing number of colorectal cancer (CRC) survivors need survival estimates that account for the time already survived. The aim of this population-based study was to determine conditional survival, cure proportions, and time-to-cure (TTC) of patients with colon or rectal cancer. Materials and Methods: All patients with pathologic stage I–III CRC treated with endoscopy or surgery, diagnosed and registered in the Netherlands Cancer Registry between 1995 and 2016, and aged 18 to 99 years were included. Conditional survival was calculated for those diagnosed before and after 2007. Cure proportions were calculated using flexible parametric models. Results: A total of 175,384 patients with pathologic stage I (25%), II (38%), or III disease (37%) were included. Conditional 5-year survival of patients with stage I, II, and III colon cancer having survived 5 years was 98%, 94%, and 92%, respectively. For patients with stage I–III rectal cancer, this was 96%, 89%, and 85%, respectively. Statistical cure in patients with colon cancer was reached directly after diagnosis (stage I) to 6 years (stage III) after diagnosis depending on age, sex, and disease stage. Patients with rectal cancer reached cure 0.5 years after diagnosis (stage I) to 9 years after diagnosis (stage III). In 1995, approximately 42% to 46% of patients with stage III colon or rectal cancer, respectively, were considered cured, whereas in 2016 this percentage increased to 73% to 78%, respectively. Conclusions: The number of patients with CRC reaching cure has increased substantially over the years. This study’s results provide valuable insights into trends of CRC patient survival and are important for patients, clinicians, and policymakers.