tbuckley/cabot-search huggingface dataset:
The prognostic value of a Methylome-based Malignancy Density Scoring System to predict recurrence risk in early-stage Lung Adenocarcinoma
Authors: Lu Yang, Jing Zhang, Guangjian Yang, Haiyan Xu, Jing Lin, Lin Shao, Junling Li, Changyuan Guo, Yanru Du, Lei Guo, Xin Li, Han Han-Zhang, Chenyang Wang, Shannon Chuai, Junyi Ye, Qiaolin Kang, Hao Liu, Jianming Ying, Yan Wang
Journal: Theranostics (2020)

Current NCCN guidelines do not recommend the use of adjuvant chemotherapy for stage IA lung adenocarcinoma patients with R0 surgery.However, 25% to 40% of patients with stage IA disease experience recurrence.Stratifying patients according to the recurrence risk may tailor adjuvant therapy and surveillance imaging for those with a higher risk.However, prognostic markers are often identified by comparing high-risk and low-risk cases which might introduce bias due to the widespread interpatient heterogeneity.Here, we developed a scoring system quantifying the degree of field cancerization in adjacent normal tissues and revealed its association with disease-free survival (DFS).Methods: We recruited a cohort of 44 patients with resected stage IA lung adenocarcinoma who did not receive adjuvant therapy.Both tumor and adjacent normal tissues were obtained from each patient and subjected to capture-based targeted genomic and epigenomic profiling.A novel methylome-based scoring system namely malignancy density ratio (MD ratio) was developed based on 39 patients by comparing tumor and corresponding adjacent normal tissues of each patient.A MD score was then obtained by Wald statistics.The correlations of MD ratio, MD score, and genomic features with clinical outcome were investigated.Results: Patients with a high-risk MD ratio showed a significantly shorter postsurgical DFS compared with those with a low-risk MD ratio (HR=4.47,P=0.01).The MD ratio was not associated with T stage (P=1), tumor cell fraction (P=0.748)nor inflammatory status (p=0.548).Patients with a high-risk MD score also demonstrated an inferior DFS (HR=4.69,P=0.039).In addition, multivariate analysis revealed EGFR 19 del (HR=5.39,P=0.012) and MD score (HR= 7.90, P=0.01) were independent prognostic markers. Conclusion:The novel methylome-based scoring system, developed by comparing the signatures between tumor and corresponding adjacent normal tissues of individual patients, largely minimizes the bias of interpatient heterogeneity and reveals a robust prognostic value in patients with resected lung adenocarcinoma.
Questions on a Randomized Clinical Trial of Stellate Ganglion Block for Patients With Posttraumatic Stress Disorder—Reply
Authors: Kristine L. Rae Olmsted, Bradford B. Walters, Dennis Wallace
Journal: JAMA Psychiatry (2020)

In Reply On behalf of our coauthors, we thank Dr Stein for his interest in our study, “Effect of Stellate Ganglion Block Treatment on Posttraumatic Stress Disorder Symptoms: A Randomized Clinical Trial.”1 We are pleased to have the opportunity to address his questions.
Patterns of Daily Physical Activity across the Spectrum of Visual Field Damage in Glaucoma Patients
Authors: Jian-Yu E, Jennifer A. Schrack, Aleksandra Mihailovic, Amal A. Wanigatunga, Sheila K. West, David S. Friedman, Laura N. Gitlin, Tianjing Li, Pradeep Y. Ramulu
Journal: Ophthalmology (2020)
Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort
Authors: Byoung Chul Cho, Amaury Daste, Alain Ravaud, Sébastien Salas, Nicolas Isambert, Edward McClay, Ahmad Awada, Christian Borel, Laureen S Ojalvo, Christoph Helwig, P Alexander Rolfe, James L Gulley, Nicolas Penel
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β)RII receptor (a TGF-β ‘trap’) fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN). Methods In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or &lt;6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg intravenously every 2 weeks. The primary endpoint was confirmed best overall response (BOR; Response Evaluation Criteria for Solid Tumors (RECIST) 1.1) per independent review committee (IRC); other endpoints included BOR per investigator and safety. Results As of August 24, 2018, 32 patients had received bintrafusp alfa (median follow-up 86.4 weeks; range 2–97). Per IRC, the confirmed objective response rate (ORR) was 13% (95% CI 4% to 29%; 4 partial responses (PR)); 4 patients had stable disease (SD) (disease control rate 25%; 95% CI 12% to 43%). Per investigator, there were 5 PRs (ORR, 16%), including 2 patients who developed delayed PRs after initial disease increase (total clinical response rate 22%). Responses (ORRs) were observed in patients with PD-L1-positive (12%), PD-L1-negative (17%; 73-10 antibody for immunohistochemistry), human papillomavirus (HPV)-positive (33%) and HPV-negative tumors (5%). Grade 3 treatment-related adverse events (TRAEs) were reported in 11 patients (34%), with no grade 4 TRAEs or treatment-related deaths. Conclusions Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with heavily pretreated advanced SCCHN. Activity in HPV-positive tumors is favorable compared with historical data from PD-L1 inhibitors and is being further investigated in an ongoing study of HPV-associated tumors. Trial registration number NCT02517398 .
Characterization of the rate, predictors, and thrombotic complications of thrombocytosis in iron deficiency anemia
Authors: Andrew B. Song, David J. Kuter, Hanny Al‐Samkari
Journal: American Journal of Hematology (2020)

The association of thrombocytosis with iron deficiency anemia (IDA) is well-recognized, but data describing the rate, predictors, and risk of thrombotic complications associated with IDA-related thrombocytosis are limited. We queried an institutional patient data repository containing comprehensive chart data for over 6 million patients to identify IDA patients with and without thrombocytosis and thrombotic events over a 40-year time period (1979 to 2019). Demographics, hematological parameters, thrombosis history, and other medical history were collected. Fidelity of query data was assessed via detailed manual chart review of 700 patients, including confirmation of ferritin and hematologic parameters in addition to temporal and clinical association of thrombocytosis. Our queries identified 36 327 cases of IDA of which 15 022 had thrombocytosis. Following assessment for data integrity, we observed a thrombocytosis rate of 32.6% in patients with IDA. The rate of thrombosis was calculated to be 7.8% in patients with IDA and 15.8% in patients with IDA and thrombocytosis. Platelet mass index at time of peak thrombocytosis was significantly higher than at baseline and was strongly negatively correlated with hemoglobin at peak thrombocytosis. A multivariable model demonstrated a significant predictive relationship between decreasing hemoglobin and increasing platelet count at peak thrombocytosis. In conclusion, we observed reactive thrombocytosis in one-third of IDA patients, and a 2-fold thrombosis risk in patients with IDA and thrombocytosis compared with patients with IDA alone. Given the global burden of untreated and undertreated IDA, adequate IDA treatment may reduce thrombotic complications and associated morbidity and mortality.
Abstract A06: Synthetic peptides derived from the cell adhesion molecule Nectin-4 inhibit the formation of ovarian cancer 3D spheroids
Authors: Kristin L.M. Boylan, Rory D. Manion, Heena Shah, Amy P.N. Skubitz
Journal: Clinical Cancer Research (2020)

Abstract A unique aspect of ovarian cancer progression is the collection of ascites fluid in the abdominal cavity, which contains free-floating tumor cells in the form of single cells and also multicellular aggregates or spheroids. Spheroids are more resistant to standard chemotherapy due in part to their slow proliferation rate and also to the protection afforded by the tight cell aggregation. Agents that prevent spheroid formation have the potential to improve chemotherapeutic response. Our previous work on the function of the cell surface adhesion molecule Nectin-4 in ovarian cancer demonstrates that it plays a key role in the formation of ovarian cancer spheroids. We also showed that synthetic peptides derived from the amino acid sequences of Nectin-4 and its binding partner Nectin-1 could inhibit cell adhesion in an in vitro assay. The purpose of this study was to further examine the role of Nectin-4 in the formation of ovarian cancer spheroids using live-cell digital microscopy to monitor spheroid formation over time. Synthetic peptides derived from the amino acid sequences of Nectin-4 and Nectin-1 were tested for their ability to alter the spheroid formation of two ovarian cancer cell lines. Several peptides disrupted ovarian cancer spheroid formation, warranting further investigation. For the peptide with the strongest inhibitory effect on spheroid formation, we tested scrambled versions of the peptide, which did not affect the formation of spheroids. This peptide also inhibited spheroid formation in a concentration-dependent manner and was not cytotoxic. These results suggest that Nectin-derived peptides could augment the effect of chemotherapy, as they would maintain the cancer cells as single cells or small aggregates that are more sensitive to chemotherapy. Citation Format: Kristin L.M. Boylan, Rory D. Manion, Heena Shah, Amy P.N. Skubitz. Synthetic peptides derived from the cell adhesion molecule Nectin-4 inhibit the formation of ovarian cancer 3D spheroids [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A06.
Class switching and high-affinity immunoglobulin G production by B cells is dispensable for the development of hypertension in mice
Authors: Yuhan Chen, Bethany L Dale, Matthew R Alexander, Liang Xiao, Mingfang Ao, Arvind K Pandey, Charles D Smart, Gwendolyn K Davis, Meena S Madhur
Journal: Cardiovascular Research (2020)

Elevated serum immunoglobulins have been associated with experimental and human hypertension for decades but whether immunoglobulins and B cells play a causal role in hypertension pathology is unclear. In this study, we sought to determine the role of B cells and high-affinity class-switched immunoglobulins on hypertension and hypertensive end-organ damage to determine if they might represent viable therapeutic targets for this disease.
MULTI-PARAMETRIC LIVER MRI CAN DISCRIMINATE BETWEEN TREATMENT NAIVE AUTOIMMUNE HEPATITIS PATIENTS AND THOSE UNDER TREATMENT IN THE PAEDIATRIC KIDS 4 LIFE COHORT
Authors: E Gomez-Castaneda, K Janowski, A Dennis, A Kazimianec, E Shumbayawonda, M Pronicki, W Grajkowska, M Wozniak, P Pawliszak, E Jurkiewicz, M Kelly, S Neubauer, R Banerjee, P Socha
Journal: Hepatology (2019)
Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen–mismatched donors
Authors: Brian Kornblit, Barry E. Storer, Niels S. Andersen, Michael B. Maris, Thomas R. Chauncey, Effie W. Petersdorf, Ann E. Woolfrey, Mary E. D. Flowers, Rainer Storb, David G. Maloney, Brenda M. Sandmaier
Journal: Blood (2020)

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.
Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation
Authors: Jikai Cui, Jizhang Yu, Heng Xu, Yanqiang Zou, Hao Zhang, Shanshan Chen, Sheng Le, Jing Zhao, Lang Jiang, Jiahong Xia, Jie Wu
Journal: Theranostics (2020)

Background: The immune checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4), induced upon T cell activation but degraded quickly, has been targeted in the clinical therapy of advanced cancers and autoimmune diseases. However, whether inhibiting CTLA-4 degradation ameliorates transplant rejection remains unknown. Methods: The CTLA-4 expression in activated murine T cells treated with the inhibitors mediating protein degradation was detected by flow cytometry (FCM). CD45.1 mice, which received TEa T cells and underwent heart transplantation, were administrated with the inhibitor. Subsequently, CTLA-4 expression of TEa T cells was analyzed. Murine skin and heart transplantation models were built, then the survival and histopathology of the allografts, and T cell subsets in the spleens of each group were compared. Results: Chloroquine (CQ) was identified as an inhibitor of CTLA-4 degradation, which augmented both surface and total CTLA-4 expression in T cells. It considerably prolonged the skin and heart allograft survival time and reduced the infiltration of inflammatory cells in allografts. Besides decreasing the frequencies of the CD4+ and CD8+ effector T cells, especially IFN-γ producing T cells, CQ also increased the proportion of regulatory T cells in the spleen. The CTLA-4 blockade abrogated the benefits of CQ on the survival of heart allografts. Moreover, CQ enhanced CTLA-4 expression in activated human T cells and reduced the secretion of IFN-γ in human mixed lymphocyte reaction. Conclusion: Targeting CTLA-4 degradation provides a novel means to prevent transplant rejection and induce transplant tolerance.
A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone
Authors: Julie N Graff, Tomasz M Beer, Joshi J Alumkal, Rachel E Slottke, William L Redmond, George V Thomas, Reid F Thompson, Mary A Wood, Yoshinobu Koguchi, Yiyi Chen, Emile Latour, Raymond C Bergan, Charles G Drake, Amy E Moran
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Checkpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response. Methods We evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens. Results Five (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression. Conclusions Pembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects. Trial registration number clinicaltrials.gov ( NCT02312557 ).
Characteristics of late transplant‐associated thrombotic microangiopathy in patients who underwent allogeneic hematopoietic stem cell transplantation
Authors: Cihan Heybeli, Meera Sridharan, Hassan B. Alkhateeb, Jose C. Villasboas Bisneto, Francis K. Buadi, Dong Chen, David Dingli, Angela Dispenzieri, Morie A. Gertz, Ronald S. Go, Shahrukh K. Hashmi, Suzanne R. Hayman, William J. Hogan, David J. Inwards, Saad S. Kenderian, Shaji K. Kumar, Mark R. Litzow, Luis F. Porrata, Martha Q. Lacy, Ivana N. Micallef, M. M. Patnaik, Mithun V. Shah, Nelson Leung
Journal: American Journal of Hematology (2020)

Transplant-associated thrombotic microangiopathy (TA-TMA) has a wide range of presentations after hematopoietic stem-cell transplantation (HSCT). We retrospectively studied the risk factors and outcomes of patients with early (≤day 100) and late (>day 100) TA-TMA. Among the 1451 HSCT recipients, early TA-TMA occurred in 45 (3.1%) patients at a median of 27 (3-91) days, and late TA-TMA in 39 (2.7%) patients at a median of 303 (122-2595) days. Patients with early TA-TMA were more likely to have high blood calcineurin-inhibitor levels (P < .001) and acute graph-vs-host disease (GVHD, P < .001), while late TMA patients were more likely to have chronic GVHD (P < .001). The estimated median overall survival after onset of TMA for the entire cohort was 6 months. The estimated median overall survival was not reached in patients with an improvement of TMA vs 2 months in patients with no improvement (P < .001). In the early TMA group, older age (for every 10 years, HR 1.40; 95% CI 1.00-1.94; P = .049) and bacterial infection (HR 2.42; 95% CI 0.98-6.00; P = .056) were positively associated with mortality. Switching to MMF treatment (HR 0.40; 95% CI 0.16-0.99; P = .047) and improvement of TMA (HR 0.08; 95% CI 0.03-0.25; P < .001) were negatively associated with mortality in the multivariate analysis. In the late TMA group, the improvement of TMA was the only independent predictor associated with a lower risk of death (HR 0.05; 95% CI 0.02-0.19; P < .001). Mortality rates in both early and late TMA remain unacceptably high. Future studies are needed for early diagnosis, trigger identifications, and use of targeted treatments.
Injectable ECM hydrogel for delivery of BMSCs enabled full-thickness meniscus repair in an orthotopic rat model
Authors: Gang Zhong, Jun Yao, Xing Huang, Yixuan Luo, Meng Wang, Jinyu Han, Fei Chen, Yin Yu
Journal: Bioactive Materials (2020)

Meniscal injuries have poor intrinsic healing capability and are associated with the development of osteoarthritis. Decellularized meniscus extracellular matrix (mECM) has been suggested to be efficacious for the repair of meniscus defect. However, main efforts to date have been focused on the concentration, crosslinking density and anatomical region dependence of the mECM hydrogels on regulation of proliferation and differentiation of adult mesenchymal stem cells (MSCs) in vitro 2D or 3D culture. A systematic investigation and understanding of the effect of mECM on encapsulated MSCs response and integrative meniscus repair by in vivo rat subcutaneous implantation and orthotopic meniscus injury model will be highly valuable to explore its potential for clinical translation. In this study, we investigated the in situ delivery of rat BMSCs in an injectable mECM hydrogel to a meniscal defect in a SD rat model. Decellularized mECM retained essential proteoglycans and collagens, and significantly upregulated expression of fibrochondrogenic markers by BMSCs versus collagen hydrogel alone in vitro 3D cell culture. When applied to an orthotopic model of meniscal injury in SD rat, mECM is superior than collagen I scaffold in reduction of osteophyte formation and prevention of joint space narrowing and osteoarthritis development as evidenced by histology and micro-CT analysis. Taken together, these results indicate mECM hydrogel is a highly promising carrier to deliver MSCs for long-term repair of meniscus tissue, while preventing the development of osteoarthritis.
Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8
Authors: Takahide Ara, Daigo Hashimoto, Eiko Hayase, Clara Noizat, Ryo Kikuchi, Yuta Hasegawa, Kana Matsuda, Shoko Ono, Yoshihiro Matsuno, Ko Ebata, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Emi Yokoyama, Keitaro Matsuo, Junichi Sugita, Masahiro Onozawa, Ryu Okumura, Kiyoshi Takeda, Takanori Teshima
Journal: Science Translational Medicine (2020)

Goblet cells play a protective role against GVHD after allogeneic stem cell transplantation in a Lypd8-dependent manner.
David Oliver: Caring about language doesn’t mean we can’t care
Authors: David Oliver
Journal: BMJ (2020)

Back in February, the Daily Telegraph ’s Celia Walden used her column to mock the Royal College of Nursing’s (RCN) style guide on the correct terminology and formats to use in nursing communications.12

The piece was ostensibly light hearted, its tone gently ribbing what Walden saw as the RCN’s po-faced attitude. But it wasn’t hard to construe the meaning behind the joke—namely, that we’ve become far too obsessed with “woke” language and identity politics, that it’s distracting and detracting from the vital work of clinical care, and that staff have better things to worry about than putting their foot in it or getting into …
Thrombotic thrombocytopenic purpura masquerading as preclampsia with severe features at 13 weeks' gestation
Authors: Eric J. Avery, Sean P. Kenney, Benjamin D. Byers, Jennifer J. McIntosh, Christopher Hoover, Yizhi Jiang, Lijun Xia, Zhongxin Yu, James N. George
Journal: American Journal of Hematology (2020)