tbuckley/cabot-search huggingface dataset:
Epithelial Mesenchymal Transition in Tumor Metastasis
Authors: Vivek Mittal
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes. Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli. Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance. Given these attributes, the complex biological process of EMT has been heralded as a key hallmark of carcinogenesis, and targeting EMT pathways constitutes an attractive strategy for cancer treatment. However, demonstrating the necessity of EMT for metastasis in vivo has been technically challenging, and recent efforts to demonstrate a functional contribution of EMT to metastasis have yielded unexpected results. Therefore, determining the functional role of EMT in metastasis remains an area of active investigation. Studies using improved lineage tracing systems, dynamic in vivo imaging, and clinically relevant in vivo models have the potential to uncover the direct link between EMT and metastasis. This review focuses primarily on recent advances in and emerging concepts of the biology of EMT in metastasis in vivo and discusses future directions in the context of novel diagnostic and therapeutic opportunities.
Wnt9a Promotes Renal Fibrosis by Accelerating Cellular Senescence in Tubular Epithelial Cells
Authors: Congwei Luo, Shan Zhou, Zhanmei Zhou, Yahong Liu, Li Yang, Jiafeng Liu, Yunfang Zhang, Hongyan Li, Youhua Liu, Fan Fan Hou, Lili Zhou
Journal: Journal of the American Society of Nephrology (2018)

Cellular senescence is associated with renal disease progression, and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. However, the underlying mechanism is unknown. We assessed the potential role of Wnt9a in tubular cell senescence and renal fibrosis. Compared with tubular cells of normal subjects, tubular cells of humans with a variety of nephropathies and those of several mouse models of CKD expressed high levels of Wnt9a that colocalized with the senescence-related protein p16 INK4A . Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16 INK4A . Furthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation of β -catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16 INK4A expression and senescence-associated β -galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosis in vivo and impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16 INK4A in the IRI mouse model. In a human proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a remarkably upregulated levels of senescence-related p16 INK4A , p19 ARF , p53, and p21 and decreased the phosphorylation of retinoblastoma protein. Wnt9a also induced senescent tubular cells to produce TGF- β 1, which promoted proliferation and activation in normal rat kidney fibroblasts. Thus, Wnt9a drives tubular senescence and fibroblast activation. Furthermore, the Wnt9a–TGF- β pathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the pathogenesis of renal fibrosis.
Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group
Authors: Hans Wildiers, Konstantinos Tryfonidis, Lissandra Dal Lago, Peter Vuylsteke, Giuseppe Curigliano, Simon Waters, Barbara Brouwers, Sevilay Altintas, Nathan Touati, Fatima Cardoso, Etienne Brain
Journal: The Lancet Oncology (2018)
Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes
Authors: David S Williams, Dmitri Mouradov, Robert N Jorissen, Marsali R Newman, Elham Amini, David K Nickless, Julie A Teague, Catherine G Fang, Michelle Palmieri, Marie J Parsons, Anuratha Sakthianandeswaren, Shan Li, Robyn L Ward, Nicholas J Hawkins, Ian Faragher, Ian T Jones, Peter Gibbs, Oliver M Sieber
Journal: Gut (2018)

Objective Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. Design A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF / KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. Results Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; P multivariate &lt;0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; P multivariate =0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/ BRAF wt / KRAS wt , pMMR/ BRAF mut / KRAS wt , pMMR/ BRAF wt / KRAS mut ) and transcriptomic (CMS 1-4) subtypes. Conclusion TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.
The characteristics of 76 atypical neurofibromas as precursors to neurofibromatosis 1 associated malignant peripheral nerve sheath tumors
Authors: Christine S Higham, Eva Dombi, Aljosja Rogiers, Sucharita Bhaumik, Steven Pans, Steve E J Connor, Markku Miettinen, Raf Sciot, Roberto Tirabosco, Hilde Brems, Andrea Baldwin, Eric Legius, Brigitte C Widemann, Rosalie E Ferner
Journal: Neuro-Oncology (2018)

Neurofibromatosis 1 (NF1) leads to the development of benign and malignant peripheral nerve sheath tumors (MPNST). MPNST have been described to develop in preexisting benign plexiform neurofibromas (PN) and have a poor prognosis. Atypical neurofibromas (ANF) were recently described as precursor lesions for MPNST, making early detection and management of ANF a possible strategy to prevent MPNST. We aimed to clinically characterize ANF and identify management approaches. We analyzed clinical, imaging, and pathology findings of all patients with NF1 and ANF at 3 institutions. Sixty-three patients had 76 ANF (32M/31F; median age 27.1 y). On MRI, most ANF appeared as distinct nodular lesions and were 18F-fluorodeoxyglucose (FDG) avid. Forty-six ANF were associated with pain, 19 with motor weakness, 45 were palpable or visible, and 13 had no clinical signs. Completely resected ANF (N = 57) have not recurred (median follow-up, 4.1 y; range, 0–14 y). Four ANF transformed into MPNST and 17 patients had a history of MPNST in a different location than was their ANF. Growth of distinct nodular lesions, pain, and FDG-PET avidity should raise concern for ANF in NF1. Patients with ANF are at greater risk for development of MPNST. Complete resection of ANF may prevent development of MPNST.
Hot Tea Consumption and Its Interactions With Alcohol and Tobacco Use on the Risk for Esophageal Cancer
Authors: Canqing Yu, Haijing Tang, Yu Guo, Zheng Bian, Ling Yang, Yiping Chen, Aiyu Tang, Xue Zhou, Xu Yang, Junshi Chen, Zhengming Chen, Jun Lv, Liming Li
Journal: Annals of Internal Medicine (2018)

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: Although consumption of tea at high temperatures has been suggested as a risk factor for esophageal cancer, an association has not been observed consistently, and whether any relationship is independent of alcohol and tobacco exposure has not been evaluated. Objective: To examine whether high-temperature tea drinking, along with the established risk factors of alcohol consumption and smoking, is associated with esophageal cancer risk. Design: China Kadoorie Biobank, a prospective cohort study established during 2004 to 2008. Setting: 10 areas across China. Participants: 456 155 persons aged 30 to 79 years. Those who had cancer at baseline or who reduced consumption of tea, alcohol, or tobacco before baseline were excluded. Measurements: The usual temperature at which tea was consumed, other tea consumption metrics, and lifestyle behaviors were self-reported once, at baseline. Outcome was esophageal cancer incidence up to 2015. Results: During a median follow-up of 9.2 years, 1731 incident esophageal cancer cases were documented. High-temperature tea drinking combined with either alcohol consumption or smoking was associated with a greater risk for esophageal cancer than hot tea drinking alone. Compared with participants who drank tea less than weekly and consumed fewer than 15 g of alcohol daily, those who drank burning-hot tea and 15 g or more of alcohol daily had the greatest risk for esophageal cancer (hazard ratio [HR], 5.00 [95% CI, 3.64 to 6.88]). Likewise, the HR for current smokers who drank burning-hot tea daily was 2.03 (CI, 1.55 to 2.67). Limitation: Tea consumption was self-reported once, at baseline, leading to potential nondifferential misclassification and attenuation of the association. Conclusion: Drinking tea at high temperatures is associated with an increased risk for esophageal cancer when combined with excessive alcohol or tobacco use. Primary Funding Source: National Natural Science Foundation of China and National Key Research and Development Program.
Abstract 20549: Advanced Glycation End Product Modification of Laminin Alters Kir4.1 Expression in Retinal Glia Cells
Authors: Kayla M Thompson, Qianyi Luo, Ashay D Bhatwadekar
Journal: Circulation (2016)

Diabetes alters neurotransmitter metabolism of the body increasing susceptibility to cardiovascular disorders. Retinal vascular dysfunction in diabetes is viewed as a change in the neurovascular unit which exhibits striking similarities with the neurovascular unit of the brain. Diabetic retinopathy (DR), a major cause of adult blindness is linked to a change in the retinal neurovascular unit, leading to dysfunction between the physical and biochemical relationship of neurons, glia, and retinal vasculature. Retinal glia, or Muller cells, span across the retina to maintain water homeostasis and potassium concentration via inwardly rectifying Kir4.1 channels. Diabetes is linked to an increase in Advance Glycation End products (AGEs) and a decrease in Kir4.1 expression, but no reports show how AGEs-linked to the basement membrane (BM) impact normal Kir4.1 expression. Laminin, a BM-component, is necessary for the expression of Kir4.1 in Muller cells. In this study, we hypothesized that AGE-modification of laminin is detrimental to Kir4.1 expression, thereby disrupting Muller cell function. The AGE-modified laminin-coated substrates were prepared by coating Petri-dishes in laminin (20 μg/mL) and methylglyoxal (MGO; 10, 100, 1000 μM) for seven days at 37°C. The rat Muller cells (rMC-1) were then propagated on AGE-modified laminin dishes for 24 hours. The expression of Kir4.1 and  Kcnj10  (gene for Kir4.1) was determined using immunofluorescence and qRT-PCR respectively. The immunofluorescence studies revealed a profound decrease in the Kir4.1 expression on AGE-modified substrates as compared to untreated laminin. The mRNA expression of  Kcnj10  exhibited a 3.4-fold decrease (p
PD-L1 checkpoint inhibition and anti-CTLA-4 whole tumor cell vaccination counter adaptive immune resistance: A mouse neuroblastoma model that mimics human disease
Authors: Priya Srinivasan, Xiaofang Wu, Mousumi Basu, Christopher Rossi, Anthony D. Sandler
Journal: PLoS Medicine (2018)

Background Adaptive immune resistance induces an immunosuppressive tumor environment that enables immune evasion. This phenomenon results in tumor escape with progression and metastasis. Programmed cell death-ligand 1 (PD-L1) expressed on tumors is thought to inhibit tumor-infiltrating lymphocytes (TILs) through programmed cell death 1 (PD1), enabling adaptive immune resistance. This study investigates the role of PD-L1 in both mouse and human neuroblastoma immunity. The consequence of PD-L1 inhibition is characterized in the context of an established whole tumor cell vaccine. Methods and findings A mouse model of neuroblastoma was investigated using an Id2 knockdown whole cell vaccine in combination with checkpoint inhibition. We show that immunogenic mouse neuroblastoma acquires adaptive immune resistance by up-regulating PD-L1 expression, whereas PD-L1 is of lesser consequence in nonimmunogenic neuroblastoma tumors. Combining PD-L1 checkpoint inhibition with whole tumor cell/anti-CTLA-4 vaccination enhanced tumor cell killing, cured mice with established tumors, and induced long-term immune memory (6 months). From an evaluation of patient neuroblastoma tumors, we found that the inflammatory environment of the mouse neuroblastoma mimicked human disease in which PD-L1 expression was associated directly with TILs and lower-risk tumors. High-risk patient tumors were lacking both TILs and PD-L1 expression. Although a correlation in immunity seems to exist between the mouse model and human findings, the mouse tumor model is induced and not spontaneously occurring, and furthermore, the number of both mouse and human correlates is limited. Conclusions This study demonstrates the role PD-L1 plays in neuroblastoma's resistance to immunity and defines the nonredundant effect of combination checkpoint inhibition with vaccine therapy in a mouse model. High-risk, nonimmunogenic human tumors display both diminished PD-L1 expression and adaptive immune resistance. Paradoxically, high-risk tumors may be more responsive to effective vaccine therapy because of their apparent lack of adaptive immune resistance.
Factor XII and uPAR upregulate neutrophil functions to influence wound healing
Authors: Evi X. Stavrou, Chao Fang, Kara L. Bane, Andy T. Long, Clément Naudin, Erdem Kucukal, Agharnan Gandhi, Adina Brett-Morris, Michele M. Mumaw, Sudeh Izadmehr, Alona Merkulova, Cindy C. Reynolds, Omar Alhalabi, Lalitha Nayak, Wen-Mei Yu, Cheng-Kui Qu, Howard J. Meyerson, George R. Dubyak, Umut A. Gurkan, Marvin T. Nieman, Anirban Sen Gupta, Thomas Renné, Alvin H. Schmaier
Journal: Journal of Clinical Investigation (2018)

Coagulation factor XII (FXII) deficiency is associated with decreased neutrophil migration, but the mechanisms remain uncharacterized. Here, we examine how FXII contributes to the inflammatory response. In 2 models of sterile inflammation, FXII-deficient mice (F12-/-) had fewer neutrophils recruited than WT mice. We discovered that neutrophils produced a pool of FXII that is functionally distinct from hepatic-derived FXII and contributes to neutrophil trafficking at sites of inflammation. FXII signals in neutrophils through urokinase plasminogen activator receptor-mediated (uPAR-mediated) Akt2 phosphorylation at S474 (pAktS474). Downstream of pAkt2S474, FXII stimulation of neutrophils upregulated surface expression of αMβ2 integrin, increased intracellular calcium, and promoted extracellular DNA release. The sum of these activities contributed to neutrophil cell adhesion, migration, and release of neutrophil extracellular traps in a process called NETosis. Decreased neutrophil signaling in F12-/- mice resulted in less inflammation and faster wound healing. Targeting hepatic F12 with siRNA did not affect neutrophil migration, whereas WT BM transplanted into F12-/- hosts was sufficient to correct the neutrophil migration defect in F12-/- mice and restore wound inflammation. Importantly, these activities were a zymogen FXII function and independent of FXIIa and contact activation, highlighting that FXII has a sophisticated role in vivo that has not been previously appreciated.
Immune Checkpoint Inhibitors Restore Function of Lesion Infiltrating T Lymphocytes in Langerhans Cell Histiocytosis
Authors: Rikhia Chakraborty, Carl E. Allen, Amel Sengal, Amos S. Gaikwad, Harshal Abhyankar, Brooks Scull, Olive S. Eckstein, Miriam Merad, Kenneth L. McClain
Journal: Blood (2017)
Can we prescribe TMP/SMX prophylaxis without any concerns equally for all patients with rheumatic disease?
Authors: Yasuhiro Suyama, Masato Okada
Journal: Annals of the Rheumatic Diseases (2018)

Can we prescribe TMP/SMX prophylaxis without any concerns equally for all patients with rheumatic disease?We read with great interest the recent article by Park et al 1 and appreciate the authors' efforts to assess the benefit and safety of trimethoprim-sulfamethoxazole (TMP/SMX) as primary prophylaxis for pneumocystis pneumonia in patients with rheumatic diseases, exposed to prolonged high-dose glucocorticoids.However, we would like to point out one concern in the incidence of adverse drug reactions related to TMP/SMX prophylaxis.Despite its efficacy, TMP/SMX could induce adverse events that could cause some patients to discontinue prophylaxis and increase the risk for Pneumocystis jirovecii pneumonia.There could be a disease gap for the development of adverse events, and higher risk was indicated in patients with systemic lupus erythematosus (SLE) compared with other rheumatic diseases.In patients with SLE, the reaction rate was estimated to be up to 27.3%-53% 2-5 and anti-Ro/ SS-A antibody was especially warned to be a prognostic factor. 2 In addition, a prophylactic regimen is also important to assess safety.This is because adverse events requiring discontinuation of TMP/ SMX prophylaxis were higher in patients with usual prophylaxis of a single-strength TMP/SMX tablet daily compared with graded administration. 2 6For these reasons, detailed description revealing safety profiles based on individual diseases and prophylactic regimens would be required.In conclusion, we acknowledge the interesting results provided by the authors, confirming the safety and efficacy of TMP/SMX prophylaxis.However, we believe that evaluating safety in patients with SLE would guide the readers in having a better understanding regarding the TMP/SMX prophylaxis in patients with rheumatic diseases.
Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability
Authors: John M. Dawes, Greg A. Weir, Steven J. Middleton, Ryan Patel, Kim I. Chisholm, Philippa Pettingill, Liam J. Peck, Joseph Sheridan, Akila Shakir, Leslie Jacobson, Maria Gutierrez-Mecinas, Jorge Galino, Jan Walcher, Johannes Kühnemund, Hannah Kuehn, Maria D. Sanna, Bethan Lang, Alex J. Clark, Andreas C. Themistocleous, Noboru Iwagaki, Steven J. West, Karolina Werynska, Liam Carroll, Teodora Trendafilova, David A. Menassa, Maria Pia Giannoccaro, Ester Coutinho, Ilaria Cervellini, Damini Tewari, Camilla Buckley, M. Isabel Leite, Hendrik Wildner, Hanns Ulrich Zeilhofer, Elior Peles, Andrew J. Todd, Stephen B. McMahon, Anthony H. Dickenson, Gary R. Lewin, Angela Vincent, David L. Bennett
Journal: Neuron (2018)

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2−/−) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2−/− mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.
Abstract MP102: Family Caregiving is Associated with Increased Stroke Risk Among Strained Spouse Caregivers
Authors: Sindhu Lakkur, Virginia Howard, Suzanne Judd, William Haley, David Roth
Journal: Circulation (2016)

Background: As the American population ages, the number of family caregivers is expected to increase. Consequently, understanding the effects family caregiving has on the cardiovascular health of caregivers presents an important public health concern. Previous studies have observed associations between family caregiving and adverse cardiovascular health outcomes such as hypertension, coronary heart disease, and an increased Framingham Stroke Risk Score. However, the association between family caregiving and stroke risk is poorly understood. Hypothesis: We examined the association between family caregiving and risk of incident stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study to test the hypotheses that 1) family caregivers have higher risk of stroke compared to noncaregivers and 2) strained caregivers have higher risk of stroke compared to noncaregivers. Methods: The REGARDS study enrolled black and white participants, aged 45 and older, from 2003-2007. Participants were categorized as caregivers if they answered affirmatively to the baseline interview question, “Are you currently providing care on an on-going basis to a family member with a chronic illness or disability?” Caregivers were asked their relationship to the care recipient and the amount of perceived physical and mental strain they associated with care (none, some, a lot). Using a propensity score matching procedure based on 16 demographic, lifestyle, and stroke risk factors, caregivers (n=3,055) were individually matched with noncaregivers (n=3,055). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident stroke risk were calculated using Cox proportional hazards models. Results: During an average 8.5-year follow up period, 114 (3.73%) caregivers and 112 (3.67%) matched noncaregivers had an incident stroke. Caregivers did not have a higher risk of stroke compared to non-caregivers (HR=1.006, 95% CI=0.775, 1.306). The HRs (95% CIs) for incident stroke risk were 1.427 (0.938, 2.171) for caregivers reporting no caregiving strain, 0.918 (0.628, 1.341) for moderate strain, and 1.963 (0.977, 3.946) for high strain. Strained spouse caregivers who reported high or moderate strain had a 95% higher risk of stroke than matched noncaregivers (HR=1.958, 95% CI=1.002, 3.828). Conclusion: We observed that perceived caregiving strain, particularly among spouse caregiviers, is associated with increased risk of stroke. This group of caregivers may need targeted support. Further studies examining the nuanced effects of caregiver burden on cardiovascular health are required.