tbuckley/cabot-search huggingface dataset:
Lymphoid tissue fibrosis is associated with impaired vaccine responses
Authors: Cissy Kityo, Krystelle Nganou Makamdop, Meghan Rothenberger, Jeffrey G. Chipman, Torfi Hoskuldsson, Gregory J. Beilman, Bartosz Grzywacz, Peter Mugyenyi, Francis Ssali, Rama S. Akondy, Jodi Anderson, Thomas E. Schmidt, Thomas Reimann, Samuel P. Callisto, Jordan Schoephoerster, Jared Schuster, Proscovia Muloma, Patrick Ssengendo, Eirini Moysi, Constantinos Petrovas, Ray Lanciotti, Lin Zhang, Maria T. Arévalo, Benigno Rodriguez, Ted M. Ross, Lydie Trautmann, Rafick-Pierre Sekaly, Michael M. Lederman, Richard A. Koup, Rafi Ahmed, Cavan Reilly, Daniel C. Douek, Timothy W. Schacker
Journal: Journal of Clinical Investigation (2018)

Vaccine responses vary by geographic location. We have previously described how HIV-associated inflammation leads to fibrosis of secondary lymph nodes (LNs) and T cell depletion. We hypothesized that other infections may cause LN inflammation and fibrosis, in a process similar to that seen in HIV infection, which may lead to T cell depletion and affect vaccine responses. We studied LNs of individuals from Kampala, Uganda, before and after yellow fever vaccination (YFV) and found fibrosis in LNs that was similar to that seen in HIV infection. We found blunted antibody responses to YFV that correlated to the amount of LN fibrosis and loss of T cells, including T follicular helper cells. These data suggest that LN fibrosis is not limited to HIV infection and may be associated with impaired immunologic responses to vaccines. This may have an impact on vaccine development, especially for infectious diseases prevalent in the developing world.
Bhlhe40 is an essential repressor of IL-10 during <i>Mycobacterium tuberculosis</i> infection
Authors: Jeremy P. Huynh, Chih-Chung Lin, Jacqueline M. Kimmey, Nicholas N. Jarjour, Elizabeth A. Schwarzkopf, Tara R. Bradstreet, Irina Shchukina, Oleg Shpynov, Casey T. Weaver, Reshma Taneja, Maxim N. Artyomov, Brian T. Edelson, Christina L. Stallings
Journal: The Journal of Experimental Medicine (2018)

The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40-/- mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.
Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy: A TRYPHAENA Substudy
Authors: Michail Ignatiadis, Gert Van den Eynden, Salgado Roberto, Marco Fornili, Yacine Bareche, Christine Desmedt, Françoise Rothé, Marion Maetens, David Venet, Esther Holgado, Virginia McNally, Astrid Kiermaier, Heidi M Savage, Timothy R Wilson, Javier Cortes, Andreas Schneeweiss, Karen Willard-Gallo, Elia Biganzoli, Christos Sotiriou
Journal: JNCI Journal of the National Cancer Institute (2018)

There is an urgent requirement to identify biomarkers to tailor treatment in human epidermal growth factor receptor 2 (HER2)-amplified early breast cancer treated with trastuzumab/pertuzumab-based chemotherapy.Among the 225 patients randomly assigned to trastuzumab/pertuzumab concurrently or sequentially with an anthracycline-containing regimen or concurrently with an anthracycline-free regimen in the Tryphaena trial, we determined the percentage of tumor-infiltrating lymphocytes (TILs) at baseline in 213 patients, of which 126 demonstrated a pathological complete response (pCR; ypT0/is ypN0), with 28 demonstrating event-free survival (EFS) events. We investigated associations between baseline TIL percentage and either pCR or EFS after adjusting for clinicopathological characteristics using logistic and Cox regression models, respectively. To understand TIL biology, we evaluated associations between baseline TILs and baseline tumor gene expression data (800 gene set by NanoString) in a subset of 173 patients. All statistical tests were two-sided.Among the patients with measurable TILs at baseline, the median level was 14.1% (interquartile range = 7.1%-32.4%). After adjusting for clinicopathological characteristics, baseline percentage TIL was not associated with pCR (adjusted odds ratio [aOR] for every 10-percentage unit increase in TILs = 1.12, 95% confidence interval [CI] = 0.95 to 1.31, P = .17). At a median follow-up of 4.7 years, for every increase in baseline TILs of 10%, there was a 25% reduction in the hazard for an EFS event (aOR = 0.75, 95% CI = 0.56 to 1.00, P = .05) after adjusting for baseline clinicopathological characteristics and pCR. Additionally, genes associated with epithelial-mesenchymal transition, angiogenesis, and T-cell inhibition such as SNAIL1, ZEB1, NOTCH3, and B7-H3 were statistically significantly inversely correlated with percentage TIL.Baseline TIL percentage provides independent prognostic information in patients treated with trastuzumab/pertuzumab-based neoadjuvant chemotherapy. However, further validation is required.
Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β
Authors: Hsi-Min Hsiao, Ramiro Fernandez, Satona Tanaka, Wenjun Li, Jessica H. Spahn, Stephen Chiu, Mahzad Akbarpour, Daniel Ruiz-Perez, Qiang Wu, Cem Turam, Davide Scozzi, Tsuyoshi Takahashi, Hannah P. Luehmann, Varun Puri, G.R. Scott Budinger, Alexander S. Krupnick, Alexander V. Misharin, Kory J. Lavine, Yongjian Liu, Andrew E. Gelman, Ankit Bharat, Daniel Kreisel
Journal: Journal of Clinical Investigation (2018)

Ischemia-reperfusion injury, a form of sterile inflammation, is the leading risk factor for both short-term mortality following pulmonary transplantation and chronic lung allograft dysfunction. While it is well recognized that neutrophils are critical mediators of acute lung injury, processes that guide their entry into pulmonary tissue are not well understood. Here, we found that CCR2+ classical monocytes are necessary and sufficient for mediating extravasation of neutrophils into pulmonary tissue during ischemia-reperfusion injury following hilar clamping or lung transplantation. The classical monocytes were mobilized from the host spleen, and splenectomy attenuated the recruitment of classical monocytes as well as the entry of neutrophils into injured lung tissue, which was associated with improved graft function. Neutrophil extravasation was mediated by MyD88-dependent IL-1β production by graft-infiltrating classical monocytes, which downregulated the expression of the tight junction-associated protein ZO-2 in pulmonary vascular endothelial cells. Thus, we have uncovered a crucial role for classical monocytes, mobilized from the spleen, in mediating neutrophil extravasation, with potential implications for targeting of recipient classical monocytes to ameliorate pulmonary ischemia-reperfusion injury in the clinic.
Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis
Authors: Antoine Bouquegneau, Charlotte Loheac, Olivier Aubert, Yassine Bouatou, Denis Viglietti, Jean–Philippe Empana, Camilo Ulloa, Mohammad Hassan Murad, Christophe Legendre, Denis Glotz, Annette M. Jackson, Adriana Zeevi, Stephan Schaub, Jean–Luc Taupin, Elaine F. Reed, John J. Friedewald, Dolly B. Tyan, Caner Süsal, Ron Shapiro, E. Steve Woodle, Luis G. Hidalgo, Jacqueline O’Leary, Robert A. Montgomery, Jon Kobashigawa, Xavier Jouven, Patricia Jabre, Carmen Lefaucheur, Alexandre Loupy
Journal: PLoS Medicine (2018)

Background Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients' access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations. Methods and findings To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55–3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05–6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection. Conclusions In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification. Trial registration National Clinical Trial protocol ID: NCT03438058.
Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells
Authors: Anandani Nellan, Christopher Rota, Robbie Majzner, Cynthia M. Lester-McCully, Andrea M. Griesinger, Jean M. Mulcahy Levy, Nicholas K. Foreman, Katherine E. Warren, Daniel W. Lee
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Standard-of-care therapies for treating pediatric medulloblastoma have long-term side effects, even in children who are cured. One emerging modality of cancer therapy that could be equally effective without such side effects would be chimeric antigen receptor (CAR) T cells. Knowing that human epidermal growth factor receptor 2 (HER2) is overexpressed in many medulloblastomas and has been used as a CAR T target before, we sought to evaluate the efficacy of more sophisticated anti-HER2 CAR T cells, as well as the feasibility and efficacy of different routes of delivering these cells, for the treatment of pediatric medulloblastoma. <h3>Methods</h3> Daoy, D283 and D425 medulloblastoma cell lines were characterized by flow cytometry to evaluate HER2 expression. Anti-tumor efficacy of HER2-BBz-CAR T cells in vitro was performed using cytokine release and immune cytotoxicity assays compared to control CD19 CAR T cells. In vivo, Daoy and D283 tumor cells were orthotopically implanted in the posterior fossa of NOD.Cg-<i>Prkdc</i><sup><i>scid</i></sup><i>Il2rg</i><sup><i>tm1Wjl</i></sup>/SzJ (NSG) mice and treated with regional or intravenous HER2-BBz-CAR T cells or control CD19 CAR T cells. Non-human primates (NHPs) bearing ventricular and lumbar reservoirs were treated with target autologous cells bearing extracellular HER2 followed by autologous HER2-CAR T cells intraventricularly. Cerebrospinal fluid and blood were collected serially to measure the persistence of delivered cells and cytokines. <h3>Results</h3> HER2-BBz-CAR T cells effectively clear medulloblastoma orthotopically implanted in the posterior fossa of NSG mice via both regional and intravenous delivery in xenograft models. Intravenous delivery requires a log higher dose compared to regional delivery. NHPs tolerated intraventricular delivery of autologous cells bearing extracellular HER2 followed by HER2-BBz-CAR T cells without experiencing any systemic toxicity. <h3>Conclusions</h3> HER2-BBz-CAR T cells show excellent pre-clinical efficacy in vitro and in mouse medulloblastoma models, and their intraventricular delivery is feasible and safe in NHPs. A clinical trial of HER2-BBz-CAR T cells directly delivered into cerebrospinal fluid should be designed for patients with relapsed medulloblastoma.
Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges
Authors: Luiza Bagno, Konstantinos E. Hatzistergos, Wayne Balkan, Joshua M. Hare
Journal: Molecular Therapy (2018)

Administration of mesenchymal stem cells (MSCs) to diseased hearts improves cardiac function and reduces scar size. These effects occur via the stimulation of endogenous repair mechanisms, including regulation of immune responses, tissue perfusion, inhibition of fibrosis, and proliferation of resident cardiac cells, although rare events of transdifferentiation into cardiomyocytes and vascular components are also described in animal models. While these improvements demonstrate the potential of stem cell therapy, the goal of full cardiac recovery has yet to be realized in either preclinical or clinical studies. To reach this goal, novel cell-based therapeutic approaches are needed. Ongoing studies include cell combinations, incorporation of MSCs into biomaterials, or pre-conditioning or genetic manipulation of MSCs to boost their release of paracrine factors, such as exosomes, growth factors, microRNAs, etc. All of these approaches can augment therapeutic efficacy. Further study of the optimal route of administration, the correct dose, the best cell population(s), and timing for treatment are parameters that still need to be addressed in order to achieve the goal of complete cardiac regeneration. Despite significant progress, many challenges remain.
RCGP calls for national campaign to tackle loneliness
Authors: Abi Rimmer
Journal: BMJ (2018)

Loneliness is a public health epidemic, and a national campaign is needed to raise awareness of the issue, the Royal College of General Practitioners (RCGP) has said.

The college has published an action plan setting out how loneliness may be tackled and warns that, along with social isolation, it may be as bad for patients as chronic health conditions.1

As part of the action plan the college highlighted a need to “encourage everyone to take action to tackle loneliness by checking on their neighbours and getting involved in their local …
Prognostic Significance of Molecular Markers and Targeted Regimens in the Management of Acute Myeloid Leukemia
Authors: Martin Tallman
Journal: Journal of the National Comprehensive Cancer Network (2018)

<section class="abstract"><p id="P1">The diagnosis, staging, and treatment of acute myeloid leukemia (AML) has evolved based on identification of important genetic alterations and drugs to target those genes. Cytogenetic abnormalities play a major role in managing AML. Achieving minimal residual disease is an increasingly important milestone. Four new targeted therapies are now available for the treatment of AML. </section>
Small Bowel Obstruction
Authors: Ioana Baiu, Mary T. Hawn
Journal: JAMA (2018)

Small Bowel ObstructionA small bowel obstruction is a blockage in the small intestine.Small bowel obstructions are usually caused by scar tissue, hernia, or cancer.In the United States, most obstructions occur as a result of prior surgeries.The bowel often forms bands of scar (called adhesions) after being handled during an operation.The more surgeries that involve the bowel, the more scars are likely to form.If the bowel becomes trapped in adhesions, it may lead to a small bowel obstruction.In severe cases, the blood supply might be compromised, and the bowel tissues might die.This is a life-threatening situation.
Clinicians' Perspectives on Providing Emergency-Only Hemodialysis to Undocumented Immigrants
Authors: Lilia Cervantes, Sara Richardson, Rajeev Raghavan, Nova Hou, Romana Hasnain-Wynia, Matthew K. Wynia, Catherine Kleiner, Michel Chonchol, Allison Tong
Journal: Annals of Internal Medicine (2018)

Background: In the United States, nearly half of undocumented immigrants with end-stage kidney disease receive hemodialysis only when they are evaluated in an emergency department and are found to have life-threatening renal failure ("emergency-only hemodialysis" [EOHD]). These patients experience psychosocial distress and much higher mortality than patients receiving regularly scheduled hemodialysis, but little is known about how providing EOHD affects the clinicians involved. Objective: To understand clinicians' experiences providing EOHD. Design: Qualitative study using semistructured interviews. Setting: A safety-net hospital in Denver, Colorado, and a safety-net system in Houston, Texas. Participants: Fifty interdisciplinary clinicians experienced in providing EOHD. Measurements: Interviews were analyzed using thematic analysis. Outcomes included themes and subthemes. Results: Four themes and 13 subthemes (in parentheses) were identified: 1) drivers of professional burnout (emotional exhaustion from witnessing needless suffering and high mortality, jeopardizing patient trust, detaching from patients, perceived lack of control over EOHD criteria, and physical exhaustion from overextending to bridge care), 2) moral distress from propagating injustice (altered care based on nonmedical factors, focus on volume at the expense of quality, and need to game the system), 3) confusing and perverse financial incentives (wasting resources, confusing financial incentives, and concerns about sustainability), and 4) inspiration toward advocacy (deriving inspiration from patients and strengthened altruism). Limitation: Whether the findings apply to other settings is unknown, and social desirability response bias might have reduced reporting of negative perceptions and experiences. Conclusion: Clinicians in safety-net settings who provide EOHD to undocumented patients describe experiencing moral distress and being driven toward professional burnout. The burden of EOHD on clinicians should inform discussions of systemic approaches to support provision of adequate care based on medical need. Primary Funding Source: Robert Wood Johnson Foundation and Doris Duke Charitable Foundation.
Cancer radiotheranostics targeting carbonic anhydrase-IX with <sup>111</sup>In- and <sup>90</sup>Y-labeled ureidosulfonamide scaffold for SPECT imaging and radionuclide-based therapy
Authors: Shimpei Iikuni, Masahiro Ono, Hiroyuki Watanabe, Yoichi Shimizu, Kohei Sano, Hideo Saji
Journal: Theranostics (2018)

Hypoxic cells dynamically translocate during tumor growth and after radiotherapy.The most desirable direction for therapy targeting hypoxic cells is combining imaging and therapy (theranostics), which may help realize personalized medicine.Here, we conducted cancer radiotheranostics targeting carbonic anhydrase-IX (CA-IX), which is overexpressed in many kinds of hypoxic cancer cells, using low-molecular-weight 111 In and 90 Y complexes with a bivalent ureidosulfonamide scaffold as the CA-IX-binding moiety ([ 111 In/ 90 Y]US2).Methods: The targeting ability of [ 111 In]US2 was evaluated by in vivo biodistribution study in CA-IX high-expressing (HT-29) tumor-bearing mice.In vivo imaging of HT-29 tumors was carried out using single photon emission computed tomography (SPECT).[ 90 Y]US2 was administered to HT-29 tumor-bearing mice to evaluate cancer therapeutic effects.Results: [ 111 In]US2 highly and selectively accumulated within HT-29 tumors (4.57% injected dose/g tumor at 1 h postinjection), was rapidly cleared from the blood pool and muscle after 4 h based on a biodistribution study, and visualized HT-29 tumor xenografts in mice at 4 h postinjection with SPECT.Radionuclide-based therapy with [ 90 Y]US2 significantly delayed HT-29 tumor growth compared with that of untreated mice (P = 0.02 on day 28, Student's t-test), without any critical hematological toxicity due to its rapid pharmacokinetics. Conclusion:These results indicate that cancer radiotheranostics with [ 111 In/ 90 Y]US2 provides a novel strategy of theranostics for cancer hypoxia.
Targeted Therapy for Patients With Metastatic Non–Small Cell Lung Cancer
Authors: Karen L. Reckamp
Journal: Journal of the National Comprehensive Cancer Network (2018)

Molecular testing is recommended for initial diagnosis in patients with non-small cell lung cancer (NSCLC), according to the updated NCCN Guidelines, because targeted therapies are available that can improve patient outcomes. Targeted therapies are currently approved for EGFR mutations, ALK and ROS1 gene rearrangements, and BRAF mutations, with the list of emerging "actionable" targets growing. The 2018 NCCN Guidelines for NSCLC incorporate new therapies, including the EGFR tyrosine kinase inhibitor osimertinib and the ALK inhibitor alectinib, as first-line preferences.
Moral externalization is an implausible mechanism for cooperation, let alone “hypercooperation”
Authors: Tim Johnson
Journal: Behavioral and Brain Sciences (2018)

Abstract To facilitate cooperation, moral externalization requires truthful and meticulous information about others’ moral commitments (Stanford target article, sect. 6). By definition, this information does not exist in the low-information environments where humans display their “hypercooperativeness.” Furthermore, collecting that information – if possible – entails costs that other mechanisms for correlated interaction avoid. Hence, moral externalization is an unlikely mechanism for cooperation, let alone “hypercooperation.”
Randomized controlled trials define shape of dose response for Pollinex Quattro Birch allergoid immunotherapy
Authors: M. Worm, T. Higenbottam, O. Pfaar, R. Mösges, W. Aberer, K. Gunawardena, D. Wessiepe, D. Lee, M. F. Kramer, M. Skinner, B. Lees, S. Zielen
Journal: Allergy (2018)

The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose.The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED50 ), a measure of potency.Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups.Increasing the cumulative dose of PQBirch 5.5-fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.