tbuckley/cabot-search huggingface dataset:
Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients
Authors: Silvia C. Formenti, Rachael E. Hawtin, Neha Dixit, Erik Evensen, Percy Lee, Judith D. Goldberg, Xiaochun Li, Claire Vanpouille-Box, Dörthe Schaue, William H. McBride, Sandra Demaria
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> We previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, <i>p</i> = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP). <h3>Methods</h3> The original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression. <h3>Results</h3> At baseline, a significantly higher level of expression (<i>p</i> &lt; 0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1<sup>+</sup> cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1<sup>+</sup> T cells and not in PD-1<sup>-</sup> T cells or in PD-1<sup>+</sup> T cells from HD. <h3>Conclusions</h3> Functional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy. <h3>Trial registration</h3> NCT01401062.
Why microbes, not microbiomes, are better causal explanations in gut-brain research
Authors: Kate E. Lynch
Journal: Behavioral and Brain Sciences (2019)

Abstract Much microbiota-gut-brain research focuses on the causal role of microbiomes as a whole, rather than their component parts: microbes. Hooks et al. find these whole-community explanations inadequate; however, they do not provide suggestions for better explanations. By appealing to proportionality – a criterion that can be used to develop more appropriate causal explanations – more accurate causal claims can be made.
A novel legumain DNA vaccine effectively eradicates neuroblastoma and induces long-term survival in vivo
Authors: Anja Woehler, Nicole Huebener, Stefan Fest, Alexander Stermann, Gerhard Gaedicke, Holger N Lode
Journal: Cancer Research (2008)

2868  Legumain, a member of the asparaginyl endopeptidase family, functions as a stress protein being upregulated under hypoxic conditions present during tumor growth. In fact, it is highly expressed in most human solid tumors and is known to promote cell migration, tissue invasion and metastasis. Neuroblastoma (NB), the most common solid extra cranial tumor in childhood, also expresses legumain. We therefore hypothesized that novel legumain DNA vaccines can break self-tolerance of the immune system and induce an anti-NB immune response.  In order to test this, we first evaluated the expression of legumain in human NB cell lines as well as in the murine NB cell line NXS2 and different tissues of healthy A/J mice by RT-PCR and western blot. We could show for the first time that Legumain is expressed in human and murine NB cells and therefore represents a suitable T cell antigen for active immunotherapy of NB. Second, we generated two novel DNA vaccines: one encoding for the whole murine legumain cDNA (mLGMN) and the second vaccine consisted of three mLGMN derived epitopes with high predicted binding affinity to MHC class I (mLGMN-Mini). Both constructs were cloned into the mammalian expression vector pCMV-F3Ub. This vector design provides for the expression of stably ubiquitinated fusion proteins facilitating their proteasomal degradation and subsequent antigen presentation. A/J mice (H2-KkDd) were vaccinated 3 times every 7 days by oral gavage of Salmonella typhimurium SL7207 (Aro-) carrying the vaccine constructs or empty vector controls. One week after the last vaccination mice were challenged subcutaneously (s.c.) with a lethal dose of NXS2 cells. Tumor growth and survival after surgical removal of s.c. tumors was monitored over time. Mice vaccinated with the LGMN DNA vaccines presented with significantly suppressed primary tumor growth and decreased tumor weights compared to empty vector controls. Moreover, the LGMN-minigene markedly induced long term survival in vaccinated mice in contrast to controls. We could also show effective target cell lysis of NXS2 cells mediated by splenocytes from LGMN minigene mice indicating the induction of CTLs. In conclusion, we could show for the first time that active immunotherapy with Legumain encoding DNA vaccines is highly effective against NB and therefore, it might be a promising adjuvant strategy against one of the most challenging childhood tumor.
Biomarkers to predict immune-related adverse events with checkpoint inhibitors.
Authors: Lia Head, Nicholas Gorden, Robert Van Gulick, Carol M. Amato, Ashley Frazer-Abel, William Robinson, V. Michael Holers, Wells A. Messersmith, S. Lindsey Davis
Journal: Journal of Clinical Oncology (2019)

131 Background: Immune-related adverse events (IRAE) occur commonly with immune checkpoint inhibitor therapy for the treatment of cancer, although the specific event and severity can vary widely. Little is known regarding factors that may predict which patients will develop an IRAE. The goal of this study is to identify blood biomarkers predictive of IRAE associated with immune checkpoint inhibitor therapy. Methods: Blood samples collected from patients with melanoma prior to receiving therapy with immune checkpoint inhibitors were obtained from the University of Colorado Skin Cancer Biorepository. Testing for a panel of autoantibodies and cytokines (ANA, CCP 3.1, IL-1 beta, IL-2, IL-6, IL-10, IL-12, IP-10, MCP-1, TNF alpha, IFN alpha 2, IFN gamma) in serum samples from patients who had at least one documented IRAE was performed by Exsera BioLabs. Descriptive statistics were used to evaluate biomarker levels in relation to type, grade, and number of adverse events. Results: Pre-treatment samples from 45 patients were evaluated. Median age was 55; 26 were male and 19 were female. The most common IRAEs were colitis (n = 22), thyroid dysfunction (n = 21), and dermatitis (n = 20). Most IRAEs were grade 2 in severity, and the majority of patients (n = 36) experienced more than 1 IRAE. TNF alpha was elevated in 60% of patient samples, while IFN alpha 2 was elevated in 44%. Borderline ANA was detected in 27% of samples and ANA was positive in 11%. No samples had elevation of IL-2. Between 9% and 18% of samples had elevation of the other immune markers tested (IFN gamma, IL-1 beta, IL-6, IL-10, IL-12, and CCP 3.1). Elevation of TNF alpha and IFN alpha 2 were associated with higher grades of IRAEs. No associations between immune markers and the number or type of adverse events in an individual patient were noted. Results from 15 patients who did not have a documented IRAE on immune checkpoint inhibitor therapy are currently pending to confirm these findings are unique to patients developing IRAE. Conclusions: This preliminary data suggests that baseline elevations of TNF alpha and IFN alpha 2 may predict development of IRAEs with immune checkpoint inhibitor therapy. Results from samples from patients who did not develop an IRAE on therapy will be reported at the meeting.
Clinical Outcome and Prognostic Factors of Patients with Richter's Syndrome: Retrospective Multicenter Study of the Spanish Chronic Lymphocytic Leukemia (CLL) Study Group (GELLC)
Authors: Pau Abrisqueta, Julio Delgado, Miguel Alcoceba, Marcos González, Ana C Oliveira, Javier Loscertales, Jose Angel Hernandez-Rivas, Christelle Ferra, Raul Cordoba, Lucrecia Yañez, Angeles Medina, Cristina Motllo, Anna Varela, Francesc Bosch
Journal: Blood (2017)
Abstract 14853: Smoking and In-hospital Mortality in a Large Cohort of Chinese Patients With Acute Myocardial Infarction—Smoker’s Paradox Revisit
Authors: Chenxi Song, Rui Fu, Jingang Yang, Wei Li, Yang Wang, Xiaoxue Fan, Kefei Dou, Yuejin Yang
Journal: Circulation (2017)

Introduction: “Smoker’s paradox” refers to the phenomenon that among patients with acute myocardial infarction (AMI), smokers have lower in-hospital mortality rate compared with nonsmokers. Evidenc...
A phase I/II investigation of nivolumab and ABI-009 (<i>nab</i>-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma: Preliminary efficacy and safety results.
Authors: Erlinda Maria Gordon, Victoria S. Chua-Alcala, Katherine Kim, Rekha Baby, Nicole Angel, Doris Quon, Steven Wong, Sant P. Chawla
Journal: Journal of Clinical Oncology (2019)

11057 Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. This phase 1/2 study is aimed to investigate if ABI-009 a novel albumin-bound mTOR inhibitor is feasible and improve clinical outcomes in combination with nivolumab. Methods: Eligible patients with advanced UPS, LPS, CS, OS, or Ewing sarcoma are treated with the standard dose of nivolumab (240 mg given IV every 3 weeks, Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. Phase 1 portion is a dose-finding study using the 3+3 design. The starting dose of ABI-009 is 56 mg/m 2 , and sequentially escalating doses are 75 and 100 mg/m 2 . The primary endpoint is to identify the maximum-tolerated dose (MTD) of ABI-009 + nivolumab, secondary endpoints include disease control rate, progression-free survival (PFS), and overall survival (OS). Exploratory endpoints include correlation of PFS and OS with PD-L1 and other biomarkers. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: 9 patients were treated in Phase 1 (n = 3 each dose level); 5/9 patients had OS, 3/9 CS, and 1 had Ewing sarcoma. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m 2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1: Grade 3 treatment-related adverse events (TRAEs) included hyper dyslipidemia (n = 1), and hyperglycemia (n = 1). At Dose 2: Grade 3 TRAEs included increased ALT (n = 1). At Dose 3: Grade 3 TRAEs included hypophosphatemia (n = 1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. The median PFS at dose level 3 has not yet been reached. Conclusions: The MTD was not reached and Dose 3 (100 mg/m 2 ) has been designated as the phase 2 dose of ABI- 009, combinable with nivolumab. Enrollment to phase 2 is ongoing. Clinical trial information: NCT03190174.
Antimonene Nanoflakes: Extraordinary Photoacoustic Performance for High‐Contrast Imaging of Small Volume Tumors
Authors: Jingwen Yu, Xiu‐Hong Wang, Jinchao Feng, Xiaotong Meng, Xiangbao Bu, Yang Li, Na Zhang, Pu Wang
Journal: Advanced Healthcare Materials (2019)

Abstract Photoacoustic imaging (PAI) has evolved to a stage that high‐performance exogeneous contrast agents are urgently needed for imminent biomedical and clinical applications. Given that a material meets the basic criteria of efficient photoacoustic conversion, high biocompatibility, and fast excretion, great effort has been devoted to evaluating various materials for developing advantageous contrast agents to explore the full potentials of PAI. One focus is through modification of the current agents to boost their PA performance; whilst the other focus is to develop novel agents. Antimonene (AM) has emerged as a promising candidate for next generation of electronics among 2D materials due to its outstanding properties. Herein, it is reported that liquid‐phase exfoliated antimonene exhibits extraordinary photoacoustic performance, which is not only more advantageous than other 2D materials, such as black phosphorus, graphene oxide, and transition metal dichalcogenides, but also superior to the commonly used PA contrast agents, such as ICG and gold nanorods. An insight analysis reveals that the unique thermal property of AM, including intrinsic low thermal conductivity and the morphology‐related high interfacial thermal conductivity, might interpret the high photothermal conversion efficiency, and thus the excellent photoacoustic performance. The prodigious performance allows sensitive monitoring of intracellular events and high‐quality in vivo tumor imaging.
Contributions of Rare Gene Variants to Familial and Sporadic FSGS
Authors: Minxian Wang, Justin Chun, Giulio Genovese, Andrea U. Knob, Ava Benjamin, Maris S. Wilkins, David J. Friedman, Gerald B. Appel, Richard P. Lifton, Shrikant Mane, Martin R. Pollak
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases. In this study, sequencing of 662 exomes from families with FSGS and 622 control exomes validated many known FSGS-causing genes. However, for some genes previously reported as FSGS related, they identified a number of purported “disease-causing” variants in controls at similar or higher frequencies. They also identified multiple additional candidate FSGS genes in which rare variants were more common among cases. Network analysis showed that their top-ranked genes were located significantly closer to known FSGS genes compared with a random gene set. These findings imply that genetic diagnosis in patients with FSGS is complicated by the nontrivial rate of variants in known FSGS genes among people without kidney disease. Background Over the past two decades, the importance of genetic factors in the development of FSGS has become increasingly clear. However, despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases. Methods To investigate mutations underlying FSGS, we sequenced 662 whole exomes from individuals with sporadic or familial FSGS. After quality control, we analyzed the exome data from 363 unrelated family units with sporadic or familial FSGS and compared this to data from 363 ancestry-matched controls. We used rare variant burden tests to evaluate known disease-associated genes and potential new genes. Results We validated several FSGS-associated genes that show a marked enrichment of deleterious rare variants among the cases. However, for some genes previously reported as FSGS related, we identified rare variants at similar or higher frequencies in controls. After excluding such genes, 122 of 363 cases (33.6%) had rare variants in known disease-associated genes, but 30 of 363 controls (8.3%) also harbored rare variants that would be classified as “causal” if detected in cases; applying American College of Medical Genetics filtering guidelines (to reduce the rate of false-positive claims that a variant is disease related) yielded rates of 24.2% in cases and 5.5% in controls. Highly ranked new genes include SCAF1 , SETD2 , and LY9 . Network analysis showed that top-ranked new genes were located closer than a random set of genes to known FSGS genes. Conclusions Although our analysis validated many known FSGS-causing genes, we detected a nontrivial number of purported “disease-causing” variants in controls, implying that filtering is inadequate to allow clinical diagnosis and decision making. Genetic diagnosis in patients with FSGS is complicated by the nontrivial rate of variants in known FSGS genes among people without kidney disease.
Successful Transition from Paediatric to Adult Care in Sickle Cell Disease: An Experience in a Belgian Center
Authors: Tracy Vandergraesen, Laurence Dedeken, Andre Efira, Phu Quoc Lê, Sophie Huybrechts, Safiatou Diallo, Christine Devalck, Catherine Heijmans, Marie-Agnes Azerad, Alina Ferster
Journal: Blood (2016)
Giant Melanotic Malignant Peripheral Nerve Sheath Tumor in the Pelvis
Authors: Entao Liu, Taotao Sun, Chao Liu, Siyun Wang, Shuxia Wang
Journal: Clinical Nuclear Medicine (2019)

Melanotic malignant peripheral nerve sheath tumor is an extremely rare tumor, which originates from the neural crest, and more than half the cases are associated with Carney complex (myxomas, spotty pigmentation, and endocrine abnormalities). Herein, we have presented a case of a melanotic malignant peripheral nerve sheath tumor, which is not associated with Carney complex. The patient underwent preoperative nonenhanced CT, contrast-enhanced CT, and F-FDG PET/CT scans, which showed a large pelvic tumor with heterogeneous enhancement and increased F-FDG uptake. Subsequently, the patient underwent complete resection of the tumor.
Chemoprevention of cancer with metformin: A meta-analysis.
Authors: Sara Gandini, Brandy M. Heckman-Stoddard, Matteo Puntoni, Barbara k Dunn, Leslie Ford, Bernardo Bonanni, Eva Szabo, Andrea De Censi
Journal: Journal of Clinical Oncology (2013)

1516 Background: Previous meta-analyses have shown that the anti-diabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiological studies. Here we update the meta-analyses of observational studies with a focus on confounders and biases. Methods: We identified 47 articles published between 1966 to August 2012 that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. Results: The analysis is based on a total of 32,647 cancer events and 1,198 cancer deaths. Cancer incidence was reduced by 34% (SRR=0.66, 95%CI: 0.42-1.03) in subjects taking metformin compared with other antidiabetic medications. Cancer mortality was reduced by 49% (SRR=0.51, 95%CI: 0.30-0.86). The SRR estimates for liver (SRR=0.40, 95%CI: 0.20-0.80) and lung cancer incidence (SRR=0.87, 95%CI: 0.83-0.93) were significant. Adjustment for BMI and exclusion of studies with time-related biases showed a significant reduction in cancer incidence of 26% (95%CI: 1% to 45%) or 10% (95%CI: 9% to 11%), respectively (Table). Breast cancer was significantly reduced by 24% (95%CI: 7% to 38%) in BMI-adjusted studies and the reduction remains significant in prospective studies and in studies without time-related biases. Conclusions: Metformin is a promising agent for cancer prevention, although it may not benefit all populations equally. Clinical trials are needed to determine if the observations seen in diabetic populations apply to pre-diabetic or non-diabetic populations and to optimize the benefit/risk ratio. [Table: see text]
Abstract P188: The Pooled Cohort Equations Over-predict Risk in Women With Hypertensive Disorders of Pregnancy, Even After Refitting the Model
Authors: Veerle Dam, N. C Onland-Moret, W. M Verschuren, Jolanda M Boer, Karel G Moons, Eric Boersma, Yvonne T van der Schouw
Journal: Circulation (2017)

Introduction: The AHA guidelines for the Prevention of Cardiovascular Disease (CVD) in Women describe hypertensive disorders of pregnancy (HDP) as a failed stress test, which might unmask early CVD. An abundance of prediction models for CVD risk is available for the general population, but their validity in women with HDP is not established. Hypothesis: The prognostic performance of the Pooled Cohort Equations (PCE) is lower in women with HDP compared to women without HDP and recalibrating and refitting the model will improve the prognostic performance. Methods: Data were used from 27,339 women out of the MORGEN and PROSPECT cohorts; we excluded those who had never been pregnant. In total, 5,358 answered the question: ‘Did you suffer from high blood pressure during pregnancy?’ with ‘Yes’; and 15,266 with ‘No’. Outcome definition was equal to that in the original PCE model. MORGEN and PROSPECT were analyzed separately, because of differences in characteristics (e.g. MORGEN is younger and has more current smokers) and observed risks. First, we calculated the 10-year predicted risk and compared this with the observed risk. Subsequently, the model was updated in three steps: by recalibrating the mean linear predictor, by additionally updating the baseline hazard, and by refitting the full model. The performance of all models was quantified by calibration (calibration plot, expected:observed ratio) and discrimination (c-statistic). Results: The Table shows that the original model over-predicts risk in all women, but more in women without HDP. Calibration plots improved most after refitting, which is confirmed by the expected:observed ratio, although the model still over-predicts. Refitting only improved discrimination in women with HDP, but not in women without HDP. Conclusion: The PCE over-predicts risk in women with and without HDP, even after refitting the model. Discrimination is overall quite good, except for MORGEN women without HDP. Especially in women with HDP the model discrimination benefits from refitting.
Lymphedema After Breast Cancer Treatment—Not Just the Surgeon’s Fault
Authors: John T. Vetto
Journal: JAMA Surgery (2019)

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