tbuckley/cabot-search huggingface dataset:
Co-evolutionary Signals Identify<i>Burkholderia pseudomallei</i>Survival Strategies in a Hostile Environment
Authors: Claire Chewapreecha, Johan Pensar, Supaksorn Chattagul, Maiju Pesonen, Apiwat Sangphukieo, Phumrapee Boonklang, Chotima Potisap, Sirikamon Koosakulnirand, Edward J Feil, Susanna Dunachie, Narisara Chantratita, Direk Limmathurotsakul, Sharon J Peacock, Nick P J Day, Julian Parkhill, Nicholas R Thomson, Rasana W Sermswan, Jukka Corander
Journal: Molecular Biology and Evolution (2021)

Abstract The soil bacterium Burkholderia pseudomallei is the causative agent of melioidosis and a significant cause of human morbidity and mortality in many tropical and subtropical countries. The species notoriously survives harsh environmental conditions but the genetic architecture for these adaptations remains unclear. Here we employed a powerful combination of genome-wide epistasis and co-selection studies (2,011 genomes), condition-wide transcriptome analyses (82 diverse conditions), and a gene knockout assay to uncover signals of “co-selection”—that is a combination of genetic markers that have been repeatedly selected together through B. pseudomallei evolution. These enabled us to identify 13,061 mutation pairs under co-selection in distinct genes and noncoding RNA. Genes under co-selection displayed marked expression correlation when B. pseudomallei was subjected to physical stress conditions, highlighting the conditions as one of the major evolutionary driving forces for this bacterium. We identified a putative adhesin (BPSL1661) as a hub of co-selection signals, experimentally confirmed a BPSL1661 role under nutrient deprivation, and explored the functional basis of co-selection gene network surrounding BPSL1661 in facilitating the bacterial survival under nutrient depletion. Our findings suggest that nutrient-limited conditions have been the common selection pressure acting on this species, and allelic variation of BPSL1661 may have promoted B. pseudomallei survival during harsh environmental conditions by facilitating bacterial adherence to different surfaces, cells, or living hosts.
Hybrid Cardiac Magnetic Resonance/Fluorodeoxyglucose Positron Emission Tomography to Differentiate Active From Chronic Cardiac Sarcoidosis
Authors: Simon Greulich, Sergios Gatidis, Christoph Gräni, Ron Blankstein, Andreas Glatthaar, Katharina Mezger, Karin A.L. Müller, Tatsiana Castor, Heiko Mahrholdt, Maik Häntschel, Jürgen Hetzel, Helmut Dittmann, Konstantin Nikolaou, Meinrad Gawaz, Christian la Fougère, Patrick Krumm
Journal: JACC. Cardiovascular imaging (2021)

The purpose of this study was to investigate the diagnostic value of simultaneous hybrid cardiac magnetic resonance (CMR) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for detection and differentiation of active (aCS) from chronic (cCS) cardiac sarcoidosis. Late gadolinium enhancement (LGE) CMR and FDG-PET are both established imaging techniques for the detection of CS. However, there are limited data regarding the value of a comprehensive simultaneous hybrid CMR/FDG-PET imaging approach that includes CMR mapping techniques. Forty-three patients with biopsy-proven extracardiac sarcoidosis (median age: 48 years, interquartile range: 37-57 years, 65% male) were prospectively enrolled for evaluation of suspected CS. After dietary preparation for suppression of myocardial glucose metabolism, patients were evaluated on a 3-T hybrid PET/MR scanner. The CMR protocol included T1 and T2 mapping, myocardial function, and LGE imaging. We assumed aCS if PET and CMR (ie, LGE or T1/T2 mapping) were both positive (PET+/CMR+), cCS if PET was negative but CMR was positive (PET−/CMR+), and no CS if patients were CMR negative regardless of PET findings. Among the 43 patients, myocardial glucose uptake was suppressed successfully in 36 (84%). Hybrid CMR/FDG-PET revealed aCS in 13 patients (36%), cCS in 5 (14%), and no CS in 18 (50%). LGE was present in 14 patients (39%); T1 mapping was abnormal in 10 (27%) and T2 mapping abnormal in 2 (6%). CS was diagnosed based on abnormal T1 mapping in 4 out of 18 CS patients (22%) who were LGE negative. PET FDG uptake was present in 17 (47%) patients. Comprehensive simultaneous hybrid CMR/FDG-PET imaging is useful for the detection of CS and provides additional value for identifying active disease. Our results may have implications for enhanced diagnosis as well as improved identification of patients with aCS in whom anti-inflammatory therapy may be most beneficial.
Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma
Authors: Sixue Liu, Hannah M. Knochelmann, Shirley H. Lomeli, Aayoung Hong, Mary Richardson, Zhentao Yang, Raymond J. Lim, Yan Wang, Camelia Dumitras, Kostyantyn Krysan, Cynthia Timmers, Martin J. Romeo, Carsten Krieg, Elizabeth C. O’Quinn, Joshua D. Horton, Steve M. Dubinett, Chrystal M. Paulos, David M. Neskey, Roger S. Lo
Journal: Cell Reports Medicine (2021)

Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma
Organoid Models for Infectious Disease
Authors: Sarah E. Blutt, Mary K. Estes
Journal: Annual Review of Medicine (2021)

Infectious diseases affect individual health and have widespread societal impacts. New ex vivo models are critical to understand pathogenesis, host response, and features necessary to develop preventive and therapeutic treatments. Pluripotent and tissue stem cell-derived organoids provide new tools for the study of human infections. Organoid models recapitulate many characteristics of in vivo disease and are providing new insights into human respiratory, gastrointestinal, and neuronal host-microbe interactions. Increasing culture complexity by adding the stroma, interorgan communication, and the microbiome will improve the use of organoids as models for infection. Organoid cultures provide a platform with the capability to improve human health related to infectious diseases.
Structural requirements for interleukin 13 to bind IL13R-alpha2, a tumor associated receptor
Authors: A. B. Madhankumar, Waldemar Debinski
Journal: Cancer Research (2004)

4674  We have found that a vast majority of patients with high-grade astrocytoma (HGA) over-express IL13R-alpha2, a receptor (R) for an immune regulatory cytokine, interleukin 13 (IL13). The other receptor for IL13, IL13/4R, is shared with IL4, transduces intracellular signaling and is expressed comparably in both vital organs and human malignancies. In addition, IL13R-alpha2 can be induced in normal cells otherwise not-expressing this tumor-restricted receptor in response to IL13 alone. The cytokine also stimulates a signaling cascade in cancer cells that leads to further activation of oncogenic pathways. Thus, in the development of diagnostics/therapeutics the ligand should be deprived of any ability to bind and activate IL13/4R, unlike IL13, and bind tighter the IL13R-alpha2. Our laboratory documented that residues at positions 105, 106, and 109 in alpha-helix D of IL13 contribute to the binding of IL13 to IL13R-alpha2. We began to determine the structural requirements of IL13 to interact with IL13R-alpha2. In the Conolly’s algorithm surface analysis we found Lys-105 and Arg-109 lay one above the other with a depression in between the residues while Lys-106 lies farther away. It is plausible that the receptor-binding pocket for IL13R-alpha2 encompasses this specific region. Next, we analyzed the structural side-chain changes at position 105 upon substitution with various amino acids. We noted a proximity between the side chain −NH2 group of Lys-105 and −C (NH2)=NH- group of Lys-109, and we suggest that such orientation may in fact favor the residues to anchor the receptor site coordinately. All position 105 mutants of IL13 studied, namely IL13.K105E, IL13.K105D, IL13.K105A and IL13.K105L do not to have the extended side-chain and none of them competes for the IL13R-alpha2 binding. Accordingly, a mutant of IL13, IL13K105R, has the arginine side chain protruding in parallel to that of Lys-109 and competes for the IL13R-alpha2 sites even better than the wild type IL13. Another possible explanation for Arg-105 substitution enabling preserved or even better binding to IL13R-alpha2 is that the epsilon-N-group in Arg has a restricted rotation due to the partial double bond character due to resonance, and Arg is able to interact better with the backbone carbonyl oxygens providing structural rigidity to the protein. We suggest that in IL13.K105R, Arg increases the rigidity of the protein and influences the overall electrostatic potential of the protein surface. We thus propose that a positively-charged polar residue with an extended side-chain orientation at position 105 in the alpha-helix D region in IL13 may be crucial for its anchoring property towards the HGA-associated receptor. This knowledge should allow us to generate other IL13 mutants/peptidomimetics of desired characteristics for future development of specific tumor targeting molecules.
Polyamino acid calcified nanohybrids induce immunogenic cell death for augmented chemotherapy and chemo-photodynamic synergistic therapy
Authors: Wei Qiu, Mengyun Liang, Yuan Gao, Xuelian Yang, Xingyao Zhang, Xiaoli Zhang, Peng Xue, Yuejun Kang, Zhigang Xu
Journal: Theranostics (2021)

Monotherapy for cancer treatment is limited by unstable efficacy and uncontrollable toxic side effects, while the multifunctional nanoplatform with complex preparation process cannot avoid the potential toxicity of each functional component.
Preoperative Stress Testing Before Elective Arthroplasty
Authors: Ravi Chopra, Kieran Patel, Michael W. Rich
Journal: JAMA Internal Medicine (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Evaluation of the antitumor efficacy and pharmacodynamics of the histone deacetylase inhibitor depsipeptide on childhood cancer models in vivo
Authors: Claire L. Graham, Chandra Tucker, Franklin C. Harwood, Lorina Dudkin, Jeremy Creech, Edward Favours, Peter J. Houghton
Journal: Cancer Research (2005)

4119  Histone acetyltransferases and histone deacetylases (HDACs) control the acetylation state of histones and other proteins regulating transcription and protein function. A number of structurally diverse HDAC inhibitors have been developed as cancer therapeutic agents and have been shown to cause differentiation, cell cycle arrest or apoptosis. Depsipeptide is a natural tetrapeptide that was isolated from Chromobacterium violaceum No. 968. We have evaluated depsipeptide against 39 independently derived childhood tumors (9 brain tumors, 11 kidney cancers, 9 rhabdomyosarcomas, 3 neuroblastomas, and 7 osteosarcomas) growing in scid mice as xenografts. Western Blot analysis was performed to determine the acetylation state of histones (H2A, H2B, H3 and H4), protein levels of p53, pp53 (ser15), p21cip1 and cleaved PARP following administration of depsipeptide. The MTD was 4.4 mg/kg administered q7dx3iv (repeated q21dx2). Of 39 tumors evaluated, three were considered sensitive (2 stable disease, IRS56 and BT35, and 1 complete response, BT27). We have compared pharmacodynamic changes in these sensitive tumors and contrasted the pattern of histone acetylation (H2A, H2B, H3 and H4) with that in three resistant tumors (GBM2, SKNEP and WT10). Sensitive and resistant tumors followed a similar pattern of histone acetylation; maximal increases in histone acetylation occurred at 8hr and were elevated for 96hr. BT35 tumors showed the highest levels of histone acetylation and therefore more genes involved in growth arrest may be transcribed. To investigate the putative role of p53 in sensitivity to depsipeptide, total p53 and phospho-p53 (Ser15) were determined in control and treated tumors. In two sensitive tumor lines, IRS56 and BT27, there was no detectable p53 in the controls but an increase was observed maximal at 8 hr associated with induction of p21cip1 after treatment; no pp53 (Ser15) was detected. BT35, GBM2, SKNEP and WT10 tumors had stable p53, GBM2 and SKNEP tumors also had pp53, throughout the time course studied suggesting that these tumors have mutant p53. Cleaved PARP was detected in all of the tumors; the highest levels were detected 24 hours after treatment. Our results demonstrate that depsipeptide does inhibit its target in vivo i.e. causes increased histone acetylation, however this does not correlate with drug sensitivity. The magnitude and duration of acetylation may be an important factor in whether a tumor responds, as may be the p53 status of the tumor. Altogether, determining whether depsipeptide would work on a given tumor seems to be multifactorial, which is understandable as depsipeptide can have multiple effects in a cell. Supported by CA23099 and ALSAC.
FP10.01 The Efficacy of Immunotherapy in non-Small Cell Lung Cancer Patients with Uncommon Mutations: a Real World Research from Single Site
Authors: Y. Cheng, Y. Zhang, Y. Liu, X. Liu, C. Zhang, X. Zuo, X. Zhang, Q. Wang, J. Zhu, H. Jiang, Y. Wang, Y. Zhang, Y. Xin, Y. Chen, Z. Chen, H. Liu, C. Zhang, S. Qin, J. Ren, L. Hao, H. Ding
Journal: Journal of Thoracic Oncology (2021)
Coordinate-Based Network Mapping of Brain Structure in Major Depressive Disorder in Younger and Older Adults: A Systematic Review and Meta-Analysis
Authors: Peter Zhukovsky, John A.E. Anderson, Gillian Coughlan, Benoit H. Mulsant, Andrea Cipriani, Aristotle N. Voineskos
Journal: American Journal of Psychiatry (2021)

Objective: Structural neuroimaging findings in younger and older adults with major depressive disorder (MDD) are highly heterogeneous, possibly as a result of methodological limitations, lack of distinction between MDD and late-life depression (LLD), or clinical moderators. Using a novel meta-analytic network mapping approach, the authors sought to identify the circuits affected in different clinical subtypes of MDD. Methods: The authors identified all voxel-based and surface-based morphometry studies published through October 2020 that compared younger adults with MDD or older adults with LLD to nonpsychiatric control participants. An activation likelihood estimation (ALE) analysis and a novel coordinate-based network mapping approach were used to identify brain circuits affected in MDD and LLD. Meta-regressions examined the impact of age at onset in older patients with LLD and treatment with antidepressants in younger patients with MDD. Results: The authors analyzed 145 comparisons from 143 articles, including a total of 14,318 participants (MDD: N=6,362; LLD: N=535; control subjects: N=7,421). Significant ALE results confirmed previous findings implicating the left and right parahippocampus and anterior cingulate in MDD and the anterior cingulate in LLD. In contrast, coordinate-based network mapping showed differences in the frontoparietal, dorsal attention, and visual networks both in MDD and LLD. Meta-regressions showed that late onset was significantly associated with widespread structural abnormalities in LLD, and treatment with antidepressants showed a significant association with abnormalities in the anterior cingulate (Brodmann’s area 32) and dorsolateral prefrontal cortex (Brodmann’s area 9) in MDD. Conclusions: These findings help to clarify the shared circuitry of depression across the adult lifespan and highlight some unique circuitry relevant to late-onset depression, which may explain some of the risk for cognitive decline and dementia.
Gut bacterial metabolites modulate endoplasmic reticulum stress
Authors: Xiaobo Ke, Kwontae You, Matthieu Pichaud, Henry J. Haiser, Daniel B. Graham, Hera Vlamakis, Jeffrey A. Porter, Ramnik J. Xavier
Journal: Genome biology (2021)

Abstract Background The endoplasmic reticulum (ER) is a membranous organelle that maintains proteostasis and cellular homeostasis, controlling the fine balance between health and disease. Dysregulation of the ER stress response has been implicated in intestinal inflammation associated with inflammatory bowel disease (IBD), a chronic condition characterized by changes to the mucosa and alteration of the gut microbiota. While the microbiota and microbially derived metabolites have also been implicated in ER stress, examples of this connection remain limited to a few observations from pathogenic bacteria. Furthermore, the mechanisms underlying the effects of bacterial metabolites on ER stress signaling have not been well established. Results Utilizing an XBP1s-GFP knock-in reporter colorectal epithelial cell line, we screened 399 microbiome-related metabolites for ER stress pathway modulation. We find both ER stress response inducers (acylated dipeptide aldehydes and bisindole methane derivatives) and suppressors (soraphen A) and characterize their activities on ER stress gene transcription and translation. We further demonstrate that these molecules modulate the ER stress pathway through protease inhibition or lipid metabolism interference. Conclusions Our study identified novel links between classes of gut microbe-derived metabolites and the ER stress response, suggesting the potential for these metabolites to contribute to gut ER homeostasis and providing insight into the molecular mechanisms by which gut microbes impact intestinal epithelial cell homeostasis.
Associations between cesarean delivery and child mortality: A national record linkage longitudinal study of 17.8 million births in Brazil
Authors: Enny S. Paixao, Christian Bottomley, Julia M. Pescarini, Kerry L. M. Wong, Luciana L. Cardim, Rita de Cássia Ribeiro Silva, Elizabeth B. Brickley, Laura C. Rodrigues, Flavia Jôse Oliveira Alves, Maria do Carmo Leal, Maria da Conceicao N. Costa, Maria Gloria Teixeira, Maria Yury Ichihara, Liam Smeeth, Mauricio L. Barreto, Oona M. R. Campbell
Journal: PLoS Medicine (2021)

Background There is an increasing use of cesarean delivery (CD) based on preference rather than on medical indication. However, the extent to which nonmedically indicated CD benefits or harms child survival remains unclear. Our hypothesis was that in groups with a low indication for CD, this procedure would be associated with higher child mortality and in groups with a clear medical indication CD would be associated with improved child survival chances. Methods and findings We conducted a population-based cohort study in Brazil by linking routine data on live births between January 1, 2012 and December 31, 2018 and assessing mortality up to 5 years of age. Women with a live birth who contributed records during this period were classified into one of 10 Robson groups based on their pregnancy and delivery characteristics. We used propensity scores to match CD with vaginal deliveries (1:1) and prelabor CD with unscheduled CD (1:1) and estimated associations with child mortality using Cox regressions. A total of 17,838,115 live births were analyzed. After propensity score matching (PSM), we found that live births to women in groups with low expected frequencies of CD (Robson groups 1 to 4) had a higher death rate up to age 5 years if they were born via CD compared with vaginal deliveries (HR = 1.25, 95% CI: 1.22 to 1.28; p &lt; 0.001). The relative rate was greatest in the neonatal period (HR = 1.39, 95% CI: 1.34 to 1.45; p &lt; 0.001). There was no difference in mortality rate when comparing offspring born by a prelabor CD to those born by unscheduled CD. For the live births to women with a CD in a prior pregnancy (Robson group 5), the relative rates for child mortality were similar for those born by CD compared with vaginal deliveries (HR = 1.05, 95% CI: 1.00 to 1.10; p = 0.024). In contrast, for live births to women in groups with high expected rates of CD (Robson groups 6 to 10), the child mortality rate was lower for CD than for vaginal deliveries (HR = 0.90, 95% CI: 0.89 to 0.91; p &lt; 0.001), particularly in the neonatal period (HR = 0.84, 95% CI: 0.83 to 0.85; p &lt; 0.001). Our results should be interpreted with caution in clinical practice, since relevant clinical data on CD indication were not available. Conclusions In this study, we observed that in Robson groups with low expected frequencies of CD, this procedure was associated with a 25% increase in child mortality. However, in groups with high expected frequencies of CD, the findings suggest that clinically indicated CD is associated with a reduction in child mortality.
Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward
Authors: Maria Rain Jennings, David Munn, John Blazeck
Journal: Journal for ImmunoTherapy of Cancer (2021)

Tumors accumulate metabolites that deactivate infiltrating immune cells and polarize them toward anti-inflammatory phenotypes. We provide a comprehensive review of the complex networks orchestrated by several of the most potent immunosuppressive metabolites, highlighting the impact of adenosine, kynurenines, prostaglandin E2, and norepinephrine and epinephrine, while discussing completed and ongoing clinical efforts to curtail their impact. Retrospective analyses of clinical data have elucidated that their activity is negatively associated with prognosis in diverse cancer indications, though there is a current paucity of approved therapies that disrupt their synthesis or downstream signaling axes. We hypothesize that prior lukewarm results may be attributed to redundancies in each metabolites' synthesis or signaling pathway and highlight routes for how therapeutic development and patient stratification might proceed in the future.
P40.03 Palliative Radiotherapy Decreased Circulating White Blood Cells in Patients With Stage IV Lung Cancer
Authors: Z. Liang, L. Ma, C. Zhao, F. Zhang, W. Xu, L. Xu, W. Chen, Z. Chen, J. Zha, Y. Han, Y. Qu, Q. Wang, J. Zhang, L. Yang, F.M. Kong
Journal: Journal of Thoracic Oncology (2021)