tbuckley/cabot-search huggingface dataset:
Association of intratumoral FoxP3 T-regulatory lymphocytes and perineural invasion in colorectal adenocarcinoma.
Authors: Lynn Messersmith, Grant Williams, Jamie Lombardo, Annelies Hickerson, Jessica Campf, Robert Brady, Ryan Collins, George Earl Peoples, Guy T. Clifton
Journal: Journal of Clinical Oncology (2019)

51 Background: In colorectal cancer, higher densities of lymphocytes in the tumor microenvironment (TME) have been associated with better clinical outcomes. FoxP3+ regulatory T-cells (Tregs) are a subset of lymphocytes that play an immunosuppressive role in the TME. However, the impact of Tregs in the TME in colon cancer prognosis is more controversial. We evaluated the densities of FoxP3+ Tregs at multiple locations in matched endoscopic biopsies and resection specimens from patients with colonic adenocarcinoma to assess concordance of Treg densities between locations, and the association with prognostic factors. Methods: Patients with banked, matched endoscopic biopsies and surgically resected colon adenocarcinoma specimens from a single institution from 2006-2016 were selected for evaluation. Paraffin embedded tissue samples were cut and stained with FoxP3 immunohistochemical stain. The densities of FoxP3 positive cells were counted within a 1 mm 2 area at the center of the tumor and at the invasive margin. The densities of FoxP3 positive lymphocytes were compared between the center and invasive margin, and to prognostic factors. Results: 107 matched endoscopic biopsies and surgical resection specimens were evaluated. A moderate-strong correlation was noted in levels of FoxP3+ cells between endoscopic biopsies and resected specimens at the center of the tumor (r= 0.68) and invasive margin (r=0.69). Higher FoxP3 densities were associated with a decreased rate of perineural invasion (P= 0.040). Levels of Tregs in endoscopic biopsies were correlated with the levels in the larger tumor of resected colon adenocarcinoma specimens. There was a weak correlation between increased density of Tregs and lower anatomic stage (R 2 = 0.05). Conclusions: Tregs are a potential biomarker that can be evaluated in neoadjuvant immunomodulatory therapies in clinical trials to assess for response. Moreover, Treg levels are associated with perineural invasion, a predictive factor for decreased response to chemotherapy, underscoring the potential for immunomodulatory therapies in colorectal adenocarcinoma.
The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF
Authors: Jessica Vetters, Mary J. van Helden, Sigrid Wahlen, Simon J. Tavernier, Arne Martens, Farzaneh Fayazpour, Karl Vergote, Manon Vanheerswynghels, Kim Deswarte, Justine Van Moorleghem, Sofie De Prijck, Nozomi Takahashi, Peter Vandenabeele, Louis Boon, Geert van Loo, Eric Vivier, Bart N. Lambrecht, Sophie Janssens
Journal: The Journal of Experimental Medicine (2019)

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20−/− cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20−/− cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.
Single-Cell Analysis Reveals a Preexisting Drug-Resistant Subpopulation in the Luminal Breast Cancer Subtype
Authors: Marta Prieto-Vila, Wataru Usuba, Ryou-u Takahashi, Iwao Shimomura, Hideo Sasaki, Takahiro Ochiya, Yusuke Yamamoto
Journal: Cancer Research (2019)

Drug resistance is a major obstacle in the treatment of breast cancer. Surviving cells lead to tumor recurrence and metastasis, which remains the main cause of cancer-related mortality. Breast cancer is also highly heterogeneous, which hinders the identification of individual cells with the capacity to survive anticancer treatment. To address this, we performed extensive single-cell gene-expression profiling of the luminal-type breast cancer cell line MCF7 and its derivatives, including docetaxel-resistant cells. Upregulation of epithelial-to-mesenchymal transition and stemness-related genes and downregulation of cell-cycle-related genes, which were mainly regulated by LEF1, were observed in the drug-resistant cells. Interestingly, a small number of cells in the parental population exhibited a gene-expression profile similar to that of the drug-resistant cells, indicating that the untreated parental cells already contained a rare subpopulation of stem-like cells with an inherent predisposition toward docetaxel resistance. Our data suggest that during chemotherapy, this population may be positively selected, leading to treatment failure. SIGNIFICANCE: This study highlights the role of breast cancer intratumor heterogeneity in drug resistance at a single-cell level.
A Composite Hydrogel Scaffold Permits Self‐Organization and Matrix Deposition by Cocultured Human Glomerular Cells
Authors: Jack Tuffin, Madeline Burke, Thomas Richardson, Timothy Johnson, Moin A. Saleem, Simon Satchell, Gavin I. Welsh, Adam Perriman
Journal: Advanced Healthcare Materials (2019)

Abstract 3D scaffolds provide cells with a spatial environment that more closely resembles that of in vivo tissue, when compared to 2D culture on a plastic substrate. However, many scaffolding materials commonly used in tissue engineering tend to exhibit anisotropic morphologies that exhibit a narrow range of fiber diameters and pore sizes, which do not recapitulate extracellular matrices. In this study, a fibrin hydrogel is formed within the interstitial spaces of an electrospun poly(glycolic) acid (PGA) monolith to generate a composite, bimodal scaffold for the coculture of kidney glomerular cell lines. This new scaffold exhibits multiple fiber morphologies, containing both PGA microfibers (14.5 ± 2 µm) and fibrin gel nanofibers (0.14 ± 0.09 µm), which increase the compressive Young's modulus beyond that of either of the constituents. The composite structure provides an enhanced 3D environment that increases proliferation and adhesion of immortalized human podocytes and glomerular endothelial cells. Moreover, the micro/nanoscale fibrous morphology promotes motility and reorganization of the glomerular cells into glomerulus‐like structures, resulting in the deposition of organized collagen IV; the primary component of the glomerular basement membrane (GBM).
Comparison of Injured Older Adults Included in vs Excluded From Trauma Registries With 1-Year Follow-up
Authors: Craig D. Newgard, Aaron Caughey, K. John McConnell, Amber Lin, Elizabeth Eckstrom, Denise Griffiths, Susan Malveau, Eileen Bulger
Journal: JAMA Surgery (2019)

<h3>Importance</h3> Trauma registries are the primary data mechanism in trauma systems to evaluate and improve the care of injured patients. Research has suggested that trauma registries may miss high-risk older adults, who commonly experience morbidity and mortality after injury. <h3>Objective</h3> To compare injured older adults who were included in with those excluded from trauma registries, with a focus on patients with serious injuries, requiring major surgery, or dying after injury. <h3>Design, Setting, and Participants</h3> This cohort study included all injured adults 65 years and older transported by 44 emergency medical services agencies to 51 trauma and nontrauma centers in 7 counties in Oregon and Washington from January 1, 2011, to December 31, 2011, with follow-up through December 31, 2012. Record linkage was used to match emergency medical services records with state trauma registries, state discharge databases, state death registries, and Medicare claims. Data were analyzed from August to November 2018. <h3>Exposures</h3> Inclusion in vs exclusion from a trauma registry. <h3>Main Outcomes and Measures</h3> Mortality up to 12 months, including time to death and causes of death. <h3>Results</h3> Of 8161 included patients, 5579 (68.4%) were women, and the mean (SE) age was 82.2 (0.10) years. A total of 1720 older adults (21.1%) were matched to a trauma registry record. Seriously injured patients not captured by trauma registries ranged from 18% (7 of 38 patients with abdominal-pelvic Abbreviated Injury Scale score of 3 or greater) to 80.0% (1792 of 2241 patients with extremity Abbreviated Injury Scale score of 3 or greater), while 68 of 186 patients requiring major nonorthopedic surgery (36.6%) and 1809 of 2325 patients requiring orthopedic surgery (77.8%) were not included in trauma registries. Of patients with serious injuries or undergoing major surgery missed by trauma registries (range by injury and procedure type, 36.0% to 57.1%), 36.4% (39.3% when excluding serious extremity injuries and orthopedic procedures) were treated at trauma centers, particularly level III through V hospitals. When registry and nonregistry groups were tracked over 12 months, 93 of 188 in-hospital deaths (49.5%) and 1531 of 1887 total deaths (81.1%) occurred in the nonregistry cohort. <h3>Conclusions and Relevance</h3> In their current form, trauma registries are ineffective in capturing, tracking, and evaluating injured older adults, although mortality following injury is frequently due to noninjury causes. High-risk injured older adults are not included in registries because of care in nontrauma hospitals, restrictive registry inclusion criteria, and being missed by registries in trauma centers.
Tumor-specific circulating cell-free DNA (cfDNA) to predict clinical outcome in BRAF V600 mutation-positive melanoma patients (pts) treated with the MEK inhibitor trametinib (T) or chemotherapy (C).
Authors: Dirk Schadendorf, Keith Flaherty, Peter Hersey, Paul D. Nathan, Claus Garbe, Mohammed M. Milhem, Lev V. Demidov, Jessica Cecile Hassel, Piotr Rutkowski, Peter Mohr, Reinhard Dummer, Uwe Trefzer, James M. G. Larkin, Jochen Utikal, Michelle Casey, Ademi Santiago-Walker, Laurie Jill Sherman, Anne-Marie Martin, Frank S. Wu, Caroline Robert
Journal: Journal of Clinical Oncology (2013)

9020 Background: Tumor-derived cfDNA in the blood is a potential alternative source to derive tumor mutation (mut) status and could be a useful biomarker of therapeutic response. Data from METRIC (NCT01245062), an open-label randomized Phase III study evaluating the efficacy and safety of T vs C, were used to assess: correlation between baseline tumor and cfDNA BRAF muts; correlation between baseline cfDNA levels and tumor burden (i.e., the sum of target lesion diameters); and efficacy based on baseline cfDNA BRAF mut status. Methods: BRAF mut status was established for 322 pts using an allele-specific PCR assay in tumor samples. Baseline plasma samples were available for 305/322 pts. cfDNA BRAF mut status was evaluated by Inostics GmBH using BEAMing technology. Spearman correlation coefficients were used to determine the association between cfDNA fraction (mut DNA molecules &gt; 0.01%) and baseline tumor burden. A Cox proportional hazards model was used to assess the association between cfDNA mut status and progression-free survival (PFS). Results: The overall agreement between tumor and cfDNA BRAF V600E and V600K mut status was 77%, and 96% respectively. V600E or V600K cfDNA mut fraction did not correlate with baseline tumor burden (R=0.38 and 0.23, respectively). Benefit of T vs C was observed regardless of cfDNA BRAF mut status (HR= 0.42, 0.41, 0.47 for V600E, V600K, and not detectable (cfDNA ND) subgroups). Interestingly, cfDNA ND pts had longer PFS vs cfDNA V600E/K pts, independent of treatment (HR=0.37 for cfDNA ND vs V600E/K, p=&lt;0.0001). For T cfDNA ND median PFS was not reached (n=52), however the first quartile was 4.5 months; for V600E (n=127) and V600K (n=21) median PFS was 3.5 and 4.4 months, respectively. For C median PFS was 3.5, 1.4, and 1.5 months for cfDNA ND (n=28), V600E (n=69), and V600K (n=7), respectively. Similarly, higher response rates were seen in cfDNA ND pts vs cfDNA V600E/K pts across both treatment arms. Conclusions: Free circulating DNA can be used to detect BRAF V600 muts. cfDNA mut fraction was not linked to tumor burden. The absence of circulating BRAF mut DNA in BRAF V600 pts may be a marker of a better outcome. Clinical trial information: NCT01245062.
Diagnosis and Management of Primary Hyperparathyroidism Across the Veterans Affairs Health Care System
Authors: Elizabeth A. Alore, James W. Suliburk, David J. Ramsey, Nader N. Massarweh, Courtney J. Balentine, Hardeep Singh, Samir S. Awad, Konstantinos I. Makris
Journal: JAMA Internal Medicine (2019)

Untreated primary hyperparathyroidism impairs quality of life and incurs substantial costs. Parathyroidectomy is a low-risk, high-success, definitive intervention.To determine the appropriateness of diagnostic evaluation for primary hyperparathyroidism in patients with hypercalcemia and the use of parathyroidectomy for the treatment of primary hyperparathyroidism across the Veterans Affairs (VA) health care system.A retrospective cohort study of veterans with hypercalcemia and primary hyperparathyroidism was conducted from January 1, 2000, through September 30, 2015, using the VA Corporate Data Warehouse, a national electronic health record-based repository. The study included 371 370 veterans with chronic hypercalcemia and 47 158 veterans with biochemical evidence of primary hyperparathyroidism diagnosed by hypercalcemia, elevated serum parathyroid hormone levels, and near-normal serum creatinine levels. Statistical analysis was performed from April 21, 2017, to April 10, 2019.The proportion of veterans with hypercalcemia who have parathyroid hormone levels evaluated, the proportion of veterans with hyperparathyroidism who are treated surgically, and the factors associated with parathyroidectomy using generalized linear latent and mixed model regression.Of 371 370 patients with chronic hypercalcemia, 86 887 (23.4%) received further testing with parathyroid hormone level. Of 47 158 patients meeting diagnostic criteria for primary hyperparathyroidism (42 737 men [90.6%] and 4421 women [9.4%]; mean [SD] age, 67.3 [11.8] years), 6048 (12.8%) underwent parathyroidectomy. Of 5793 patients with primary hyperparathyroidism presenting with a serum calcium level more than 1 mg/dL above the upper limit of normal, 1501 (25.9%) underwent parathyroidectomy. There was a decreasing trend in the use of parathyroidectomy over time. Factors positively associated with parathyroidectomy were nephrolithiasis (odds ratio [OR], 2.23; 95% CI, 1.90-2.61) and non-Hispanic white race/ethnicity (OR, 1.31; 95% CI, 1.17-1.46), while age (OR, 0.95; 95% CI, 0.95-0.96), Elixhauser Comorbidity Index score (OR, 0.76; 95% CI, 0.72-0.80), decreased estimated glomerular filtration rate (OR, 0.52; 95% CI, 0.45-0.60), and diagnosis of osteoporosis (OR, 0.65; 95% CI, 0.52-0.80) were inversely related to surgery.From this study's findings, parathyroid hormone level is infrequently tested in patients with hypercalcemia, suggesting underdiagnosis of primary hyperparathyroidism. Patients meeting diagnostic criteria for primary hyperparathyroidism are undertreated with recommended parathyroidectomy. Similar gaps have previously been observed in non-VA care of primary hyperparathyroidism, suggesting the need for a systematic evaluation of barriers to diagnosis and treatment that informs intervention design.
Beyond a gut feeling: How the immune system impacts the effect of gut microbiota in neurodevelopment
Authors: Atiqah Azhari, Farouq Azizan, Gianluca Esposito
Journal: Behavioral and Brain Sciences (2019)

Abstract Hooks et al. posit that gastrointestinal microbes alter the end state of development indirectly. Here, we present the immune system as the link that facilitates communication between the gut and the brain. Illustrating the case of autism spectrum disorder, we explicate the role of the immune system in responding to microbial dysbiosis by inducing an inflammatory state that affects neurodevelopment. We propose two models: directly, within the infant, and indirectly, via maternal and infant systems.
Nuclear factor of activated T-cells, NFATC1, governs FLT3ITD-driven hematopoietic stem cell transformation and a poor prognosis in AML
Authors: Maria Solovey, Ying Wang, Christian Michel, Klaus H. Metzeler, Tobias Herold, Joachim R. Göthert, Volker Ellenrieder, Elisabeth Hessmann, Stefan Gattenlöhner, Andreas Neubauer, Dinko Pavlinic, Vladimir Benes, Oliver Rupp, Andreas Burchert
Journal: Journal of Hematology & Oncology (2019)

Acute myeloid leukemia (AML) patients with a high allelic burden of an internal tandem duplication (ITD)-mutated FMS-like Tyrosine Kinase-3 (FLT3) have a dismal outcome. FLT3ITD triggers the proliferation of the quiescent hematopoietic stem cell (HSC) pool but fails to directly transform HSCs. While the inflammatory transcription factor nuclear factor of activated T-cells 2 (NFAT2, NFATC1) is overexpressed in AML, it is unknown whether it plays a role in FLT3ITD-induced HSC transformation. We generated a triple transgenic mouse model, in which tamoxifen-inducible Cre-recombinase targets expression of a constitutively nuclear transcription factor NFATC1 to FLT3ITD positive HSC. Emerging genotypes were phenotypically, biochemically, and also transcriptionally characterized using RNA sequencing. We also retrospectively analyzed the overall survival of AML patients with different NFATC1 expression status. We find that NFATC1 governs FLT3ITD-driven precursor cell expansion and transformation, causing a fully penetrant lethal AML. FLT3ITD/NFATC1-AML is re-transplantable in secondary recipients and shows primary resistance to the FLT3ITD-kinase inhibitor quizartinib. Mechanistically, NFATC1 rewires FLT3ITD-dependent signaling output in HSC, involving augmented K-RAS signaling and a selective de novo recruitment of key HSC-transforming signaling pathways such as the Hedgehog- and WNT/B-Catenin signaling pathways. In human AML, NFATC1 overexpression is associated with poor overall survival. NFATC1 expression causes FLT3ITD-induced transcriptome changes, which are associated with HSC transformation, quizartinib resistance, and a poor prognosis in AML.
Antibiotic treatment prior to immune checkpoint inhibitor therapy as a tumor-agnostic predictive correlate of response in routine clinical practice.
Authors: David James Pinato, Sarah Howlett, Diego Ottaviani, Heather Urus, Aisha Patel, Takashi Mineo, Cathryn Brock, Danielle Power, Olivia Hatcher, Alison Falconer, Manasi Ingle, Anna Brown, Dorothy M. Gujral, Sarah Partridge, Naveed Sarwar, Michael Gonzalez, Maggie Bendle, Conrad R. Lewanski, Thomas Newsom-Davis, Mark Bower
Journal: Journal of Clinical Oncology (2019)

147 Background: Antibiotic therapy (ATB) may impair efficacy of immune checkpoint inhibitors (ICPI) through modulation of gut microbiota. Evidence is however limited to trial participants with non-small cell (NSCLC) and renal cell carcinoma (RCC). In this multi-centre study, we validated the impact of ATB in patients (pts) treated with ICPI in routine practice, irrespective of tumour site. Methods: We analysed a prospective dataset of pts treated with ICPI in 2 centres. We documented timing and duration of ATB administered within 1 month prior to ICPI treatment (pATB) or concurrently (cATB) until ICPI cessation. We evaluated response and overall survival (OS) across ATB+/-. Results: We enrolled 196 pts with NSCLC (n=119), Melanoma (n=38) and other histotypes (n=39). Most pts were male (n=137, 70%) with performance status 0-1 (n=159, 84%) and a median number of 2 metastatic sites (range 0-7). Pts received mostly anti-PD-1/PD-L1 ICPI (n=189, 96%) as first-line metastatic therapy (n=120, 62%). Twenty-nine patients (15%) received pATB with penicillins (n=22, 75%) for ≤7 days (n=26, 89%). Sixty-eight pts (35%) received penicillin-based (n=49, 72%) cATB for ≤7 days (n=39, 88%). Respiratory infections were the commonest indication for both pATB (n=16, 55%) and cATB (n=38, 85%). pATB (p&lt;0.001) but not cATB (p=0.76) was associated with worse OS (26 vs. 2 months, Hazard Ratio 7.4, 95% CI 4.2-12.9) and increased likelihood of primary refractoriness to ICPI (44% vs 81%, p&lt;0.001). pATB consistently worsened OS in NSCLC (26 vs. 2.5 months, p&lt;0.001), melanoma (14 vs 3.9 months, p&lt;0.001) and other tumours (11 vs 1.1 months, p&lt;0.001). In multi-variable analyses pATB (p&lt;0.001, HR 3.4, 95% CI 1.9-6.1) and response to ICPI (p&lt;0.001, HR 8.2, 95% CI 4.0-16.9) predicted for OS independent of histotype, tumour burden, PS. Conclusions: This study suggests pATB to exert an independent detrimental effect on response and survival in unselected pts treated with ICPI in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICPI treatment.
Inter-individual variation shapes the human microbiome
Authors: Emily F. Wissel, Leigh K. Smith
Journal: Behavioral and Brain Sciences (2019)

Abstract The target article suggests inter-individual variability is a weakness of microbiota-gut-brain (MGB) research, but we discuss why it is actually a strength. We comment on how accounting for individual differences can help researchers systematically understand the observed variance in microbiota composition, interpret null findings, and potentially improve the efficacy of therapeutic treatments in future clinical microbiome research.