tbuckley/cabot-search huggingface dataset:
Letter to the Editor: Focal Adhesion Kinase/β‐Catenin Network May Act as a Regulator of Hepatocellular Carcinoma Epigenetics
Authors: Ilaria Romito, Nadia Panera, Giuseppe D’Ermo, Anna Alisi
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: We read with interest the very valuable article recently published by Na and colleagues1 that deciphered the crucial role of focal adhesion kinase (FAK)/β‐catenin (CAT) network in hepatocarcinogenesis. To unveil this mechanism, the authors overexpressed FAK alone, constitutively active CAT alone, or a combination of both in the livers of C57BL6 mice. FAK overexpression or CAT mutation were not sufficient to induce hepatocellular carcinoma (HCC), whereas combined FAK/CAT led to hepatocarcinogenesis in mice. Na et al.1 also demonstrated that FAK activity was crucial for development of FAK/CAT‐dependent HCC. The authors found that many genes closely related to hepatocarcinogenesis were enriched in FAK/CAT‐induced HCCs, including genes involved in oxidative phosphorylation, fatty acid metabolism, adipogenesis, mechanistic target of rapamycin complex 1 signaling, G2/M checkpoint, mitotic spindle formation, and cholesterol homeostasis. Interestingly, in the liver samples of FAK/CAT mice, the authors revealed a significant increase of the CAT binding to the promoter of androgen receptor (AR) with respect to the control samples. AR has been reported as a direct transcriptional target of CAT/transcription factor 4.2 Moreover, AR signaling was found to be crucial in the initiation of carcinogen‐related or hepatitis B virus–related HCC.3 In the model proposed by Na et al.,1 FAK overexpression was able to increase the phosphorylation level of CAT, thereby increasing the transcription of the AR gene. The authors suggested that in this way, the AR gene was able to increase its targets, such as enhancer of zeste homolog 2 (EZH2). Accordingly, we have reported that FAK silencing down‐regulated the expression of the pro‐oncogene EZH2, thus reducing its activity on Histone 3 trimethylation at lysine 27 (H3K27me3) levels at the promoter of the NOTCH2 gene.4 However, contrary to Na et al., we also suggested4 the existence of a more direct interaction between FAK and EZH2 that may promote epigenetic changes occurring in hepatocarcinogenesis. This hypothesis is certainly plausible, as Na et al.1 reported that only 34.8% of human HCC tissues with protein tyrosine kinase 2 gene amplification co‐occurred with CAT mutations. In view of this, a FAK/CAT‐driven HCC model will not only be useful for further clinical studies but also contribute to the discovery of other FAK signaling networks that hide new epigenetic targets and might be druggable.
Neurologic, vascular, and endocrine morbidity following childhood exposure to low and moderate doses of ionizing radiation.
Authors: Siegal Sadetzki, Angela Chetrit, Ben Boursi, Fabienne Sikron
Journal: Journal of Clinical Oncology (2013)

1599 Background: While the association between exposure to ionizing radiation and cancer is well known, its possible role in the development of other diseases e.g. in the vascular, neurologic and endocrine systems is limited and inconsistent. The aim of this study was to assess the effect of childhood exposure to low and moderate doses of radiation on the development of chronic diseases (other than cancer) based on a large cohort followed for 55 years. Methods: The study population included an exposed group of 13,158 individuals treated with ionizing radiation for tinea capitis and a comparison group of 16,225 unexposed subjects. The mean dose to the head and the thyroid gland were 1.5 Gy and 0.094 Gy respectively and the mean age at exposure was 7.1±3.1y. Data on the outcome variables was obtained through computer linkage of the study database with the largest health care provider registry in Israel. Results: Of the study population, 64% were found to be insured in this heath provider (66.8% among the irradiated and 63.6% among the unexposed group). The two study groups did not differ in current age (mean 62.1+4.5 y), gender, marital status, smoking and BMI. Compared to the unexposed group, the irradiated group demonstrated a significantly (p&lt;0.001 ) increased prevalence of epilepsy (1.8% vs. 2.8%), CVA (6.4% vs. 8%), diabetes (26.5 % vs. 28.2%), hyperthyroidism (8.1% vs. 9.4%), hyper/hypo-parathyroidism (0.6% vs. 1.2%) and depression (8.1% vs. 9.4%), respectively. There was no statistical difference between the groups in the prevalence of dementia and Parkinson's disease. Multivariate models accounting for different variables of interest (e.g. age at exposure, gender, SES) will be presented. Conclusions: These results have practical implications for primary prevention and early detection of therapeutic and diagnostic radiation associated morbidity.
Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial
Authors: Halidou Tinto, Walter Otieno, Samwel Gesase, Hermann Sorgho, Lucas Otieno, Edwin Liheluka, Innocent Valéa, Valentine Sing'oei, Anangisye Malabeja, Daniel Valia, Anne Wangwe, Emilia Gvozdenovic, Yolanda Guerra Mendoza, Erik Jongert, Marc Lievens, François Roman, Lode Schuerman, John Lusingu
Journal: The Lancet Infectious Diseases (2019)
Prostate Magnetic Resonance Imaging, with or Without Magnetic Resonance Imaging-targeted Biopsy, and Systematic Biopsy for Detecting Prostate Cancer: A Cochrane Systematic Review and Meta-analysis
Authors: Frank-Jan H. Drost, Daniel Osses, Daan Nieboer, Chris H. Bangma, Ewout W. Steyerberg, Monique J. Roobol, Ivo G. Schoots
Journal: European Urology (2019)
The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation
Authors: Yinyin Li, Yi Shen, Ke Jin, Zhenke Wen, Wenqiang Cao, Bowen Wu, Ru Wen, Lu Tian, Gerald J. Berry, Jorg J. Goronzy, Cornelia M. Weyand
Journal: Cell Metabolism (2019)
Autoimmune receptor encephalitis in mice induced by active immunization with conformationally stabilized holoreceptors
Authors: Brian E. Jones, Kenneth R. Tovar, April Goehring, Farzad Jalali-Yazdi, Nana J. Okada, Eric Gouaux, Gary L. Westbrook
Journal: Science Translational Medicine (2019)

Autoimmunity to membrane proteins in the central nervous system has been increasingly recognized as a cause of neuropsychiatric disease. A key recent development was the discovery of autoantibodies to N-methyl-d-aspartate (NMDA) receptors in some cases of encephalitis, characterized by cognitive changes, memory loss, and seizures that could lead to long-term morbidity or mortality. Treatment approaches and experimental studies have largely focused on the pathogenic role of these autoantibodies. Passive antibody transfer to mice has provided useful insights but does not produce the full spectrum of the human disease. Here, we describe a de novo autoimmune mouse model of anti-NMDA receptor encephalitis. Active immunization of immunocompetent mice with conformationally stabilized, native-like NMDA receptors induced a fulminant encephalitis, consistent with the behavioral and pathologic characteristics of human cases. Our results provide evidence for neuroinflammation and immune cell infiltration as components of the autoimmune response in mice. Use of transgenic mice indicated that mature T cells and antibody-producing cells were required for disease induction. This active immunization model may provide insights into disease induction and a platform for testing therapeutic approaches.
Phase I/II trial of sorafenib combined with FOLFOX4 in untreated patients with advanced gastric adenocarcinoma: Phase I results.
Authors: Yihebali Chi, Jianliang Yang, Feng Du, Sheng Yang, Yongkun Sun, Yuankai Shi
Journal: Journal of Clinical Oncology (2012)

e14606 Background: Sorafenib (Sor) is a potent inhibitor of multiple intracellular and cell surface kinases. FOLFOX4 was demonstrated to be an active and well-tolerated chemotherapy for advanced gastric adenocarcinoma (AGA). The phase I portion of the phase I/II study is designed to assess the maximum tolerated dose (MTD) of Sor combined with standard dose FOLFOX4, as well as safety, tolerance, and activity of the combination in patients (pts) with AGA. Methods: Pts with AGA with ECOG 0-1 and without prior chemotherapy or radiotherapy were eligible. Three patients per cohort were treated with FOLFOX4 [Oxaliplatin (85 mg/m 2 ), LV (200mg/m 2 ) and 5-FU (400 mg/m 2 ), followed by 5-FU continuously infusion (1200mg/ m 2 ) for 44h every 2 weeks, up to 8 cycles, along with escalating doses of Sor (200, 400, 600mg) PO BID, continuously. If one patient experienced DLT, three additional patients were entered at the same dose level. Dose escalation continued until DLTs were experienced in two or more out of six patients, which was then defined as the MTD. Radiographic responses were assessed every 6 weeks per RECIST v1.0. Results: Nine pts were enrolled. Median age was 59.3 yr (range 42.6-71.6). M/F: 6/3; ECOG PS 0/1: 2/7. One out of 6 pts experienced DLT (G3 HFSR) in dose level 1 (200 mg BID), and 2 out of 3pts experienced DLT in dose level 2 (400 mg BID). The Sor 200mg BID was therefore identified as the MTD when combined with FOLFOX4. Major toxicity of this combination include neutropenia (G3/4: 7/3), leucopenia (G3/4: 2/0), HFSR (G3/4: 2/0) and incomplete bowel obstruction (G3/4: 1/0). One patient experienced G4 ALT/AST elevation accompanied with G3 GGT/bilirubin elevation, which led to treatment discontinuation. Preliminary efficacy data in 9 evaluable pts included 1 complete response (CR), 6 partial responses (PR) and 1 stable disease (SD) as best response. Median time to progression was 6.6 months. Median overall survival was 12.2 months. Conclusions: The MTD of Sor when used in combination of FOLFOX4 in AGA is 200mg PO BID, and this combination regimen has a manageable toxicity profile and promising activity in AGA. This efficacy and safety profiles need to be confirmed in further phase II studies.
Post-axitinib systemic therapy in metastatic renal cell carcinoma (mRCC).
Authors: Housam Haddad, Brian I. Rini, Eric Jonasch, Nizar M. Tannir, Robert Dreicer, Jorge A. Garcia, Laura S. Wood, Paul Elson
Journal: Journal of Clinical Oncology (2012)

4609 Background: Axitinib is a potent and selective inhibitor of the VEGF receptor family with efficacy as a second-line therapy in mRCC. Evaluation of further systemic therapy following axitinib has not been previously reported. Methods: The medical records ofmRCCpatients (pts) treated at The Cleveland Clinic or MD Anderson Cancer Center who received axitinib were retrospectively reviewed. Patient characteristics including best response and duration of treatment on axitinib and each subsequent line of therapy were recorded. Results: Eighty-one patients were initially identified; 29 patients received at least one approved targeted agent following axitinib and are included in this analysis. The remainder of pts were excluded due to ongoing axitinib (n=16), lack of subsequent therapy (n=13), lost to follow up (n=11), received experimental agents post-axitinib (n=7) or were inevaluable (n=2). Three pts were excluded due to ≤ 21 days on axitinib. Pt characteristics at start of axitinib included 76% male, median age 59 (range, 44-78); 97% clear cell; 93% prior nephrectomy; 64% previously-treated. Pts were favorable (39%) or intermediate (60%) risk based on Heng criteria. Overall response rate to axitinib was 52% and median duration of treatment of 11.2 months (range, 1.1-90). Thirty eight percent of patients had new brain, bone, and/or liver metastases at disease progression on axitinib. For the first subsequent therapy post axitinib (n=25), pts were treated with tyrosine kinase inhibitors (72%) or mTOR inhibitors (28%). Overall 8% of pts achieved partial responses (one pt each to sunitinib and pazopanib) and 52% had a best response of stable disease. Estimated median duration of therapy was 4.4 months (range, 0.2-27.5+). Fifteen pts received a second post-axitinib targeted therapy with mTOR inhibitors (60%) or TKIs (40%). One patient (7%) achieved a partial response to pazopanib and 8 patients (53%) had a best response of SD. Estimated median treatment duration was 4.8 months (range, 0.7-19.1+). Conclusions: There are objective responses and stable disease to post-axitinib targeted therapies, consistent with previous series and trials in refractory RCC patients.
Targeting TGFβ Pathway in Adult Granulosa Cell Tumor: Opening Pandora's Box?
Authors: Luisa Bonilla, Amit M. Oza
Journal: Clinical Cancer Research (2019)

Abstract Adult granulosa cell tumor (AGCT) is a rare malignancy characterized by FOXL2 (C134W) mutation, an inherent component of the TGFβ pathway. Activin A, a TGFβ superfamily member, is a driver of this activity and is a potential target in AGCT. See related article by Tao et al., p. 5458
Edoxaban Versus Warfarin in Patients With Atrial Fibrillation and History of Liver Disease
Authors: Arman Qamar, Elliott M. Antman, Christian T. Ruff, Francesco Nordio, Sabina A. Murphy, Laura T. Grip, Norton J. Greenberger, Ophelia Q.P. Yin, Youngsook Choi, Hans J. Lanz, Michele F. Mercuri, Eugene Braunwald, Robert P. Giugliano
Journal: Journal of the American College of Cardiology (2019)
Outcomes with rituximab plus bendamustine (R-Benda), dexamethasone, rituximab, cyclophosphamide (DRC), and bortezomib, dexamethasone, rituximab (BDR) as primary therapy in patients with Waldenstrom macroglobulinemia (WM).
Authors: Jithma P. Abeykoon, Saurabh Zanwar, Stephen M. Ansell, Shaji Kumar, Carrie A. Thompson, Thomas Matthew Habermann, Thomas E. Witzig, Francis Buadi, Ronald S. Go, Wilson I. Gonsalves, Nelson Leung, Angela Dispenzieri, Taxiarchis Kourelis, Martha Lacy, Rahma M. Warsame, David James Inwards, S. Vincent Rajkumar, Robert A. Kyle, Morie A. Gertz, Prashant Kapoor
Journal: Journal of Clinical Oncology (2019)

7509 Background: Waldenstrom macroglobulinemia (WM) is a rare lymphoma for which scant comparative data exist to guide frontline therapy. Herein, we compare 3 commonly used regimens in WM: R-Benda, DRC, and BDR in frontline setting. Methods: Patients (Pts) with active WM seen at Mayo Clinic between 2000 &amp; 2018 who received R-Benda, DRC or BDR as primary therapy were included in this retrospective study. Response rates were assessed by Consensus Criteria. All time to event analyses were performed from the frontline therapy, using Kaplan-Meier method. Results: The study included 172 pts with active WM (R-Benda, n=67, DRC, n=75, BDR, n=30).The median follow-up for the entire cohort was 3.7 years (y) (95% CI 3.7-3.0). Baseline characteristics, including IPSS, and time to frontline therapy from WM diagnosis were similar across the 3 cohorts. Clinically relevant endpoints are shown in the Table. Hematologic and non-hematologic toxicities were similar across the 3 groups. Grade 3 neuropathy requiring treatment discontinuation was encountered in 13% pts treated with BDR. 56 pts received subsequent salvage therapy [(10% in R-Benda arm, 44% in DRC arm, &amp; 53% in BDR arm]; 29% pts in the R-Benda arm and 30% pts in DRC arm received a PI-based regimen while 69% pts in the BDR arm received alkylator-rituximab based therapy. Conclusions: Outcomes (MRR, TTNT and EFS) with frontline R-Benda are superior in comparison to frontline DRC or BDR in patients with WM. Clinically relevant endpoints are not significantly different with DRC vs. BDR. The toxicity profile across the 3 groups was comparable. [Table: see text]
Patients with Chronic Lymphocytic Leukemia Belonging to the B-Cell Receptor Stereotypy Subset #2 Have Long Progression Free Survival after Chemo- or Chemoimmunotherapy in the HOVON68 Trial
Authors: Fie Juhl Vojdeman, Lone Bredo Pedersen, Doreen Te Raa, Vesa Juvonen, Yvette Norden, Geir Erland Tjønnfjord, Eva Kimby, Maija Itälä-Remes, Anton W Langerak, Ludo M. Evers, Thorsten Zenz, Marinus H.J. Van Oers, Christian H. Geisler, Arnon P. Kater, Carsten Utoft Niemann
Journal: Blood (2017)
Development and Validation of a Deep Learning Algorithm for Mortality Prediction in Selecting Patients With Dementia for Earlier Palliative Care Interventions
Authors: Liqin Wang, Long Sha, Joshua R. Lakin, Julie Bynum, David W. Bates, Pengyu Hong, Li Zhou
Journal: JAMA Network Open (2019)

Early palliative care interventions drive high-value care but currently are underused. Health care professionals face challenges in identifying patients who may benefit from palliative care.To develop a deep learning algorithm using longitudinal electronic health records to predict mortality risk as a proxy indicator for identifying patients with dementia who may benefit from palliative care.In this retrospective cohort study, 6-month, 1-year, and 2-year mortality prediction models with recurrent neural networks used patient demographic information and topics generated from clinical notes within Partners HealthCare System, an integrated health care delivery system in Boston, Massachusetts. This study included 26 921 adult patients with dementia who visited the health care system from January 1, 2011, through December 31, 2017. The models were trained using a data set of 24 229 patients and validated using another data set of 2692 patients. Data were analyzed from September 18, 2018, to May 15, 2019.The area under the receiver operating characteristic curve (AUC) for 6-month and 1- and 2-year mortality prediction models and the factors contributing to the predictions.The study cohort included 26 921 patients (16 263 women [60.4%]; mean [SD] age, 74.6 [13.5] years). For the 24 229 patients in the training data set, mean (SD) age was 74.8 (13.2) years and 14 632 (60.4%) were women. For the 2692 patients in the validation data set, mean (SD) age was 75.0 (12.6) years and 1631 (60.6%) were women. The 6-month model reached an AUC of 0.978 (95% CI, 0.977-0.978); the 1-year model, 0.956 (95% CI, 0.955-0.956); and the 2-year model, 0.943 (95% CI, 0.942-0.944). The top-ranked latent topics associated with 6-month and 1- and 2-year mortality in patients with dementia include palliative and end-of-life care, cognitive function, delirium, testing of cholesterol levels, cancer, pain, use of health care services, arthritis, nutritional status, skin care, family meeting, shock, respiratory failure, and swallowing function.A deep learning algorithm based on patient demographic information and longitudinal clinical notes appeared to show promising results in predicting mortality among patients with dementia in different time frames. Further research is necessary to determine the feasibility of applying this algorithm in clinical settings for identifying unmet palliative care needs earlier.
Arginine-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a prospective diagnostic study
Authors: Bettina Winzeler, Nicole Cesana-Nigro, Julie Refardt, Deborah R Vogt, Cornelia Imber, Benedict Morin, Milica Popovic, Michelle Steinmetz, Clara O Sailer, Gabor Szinnai, Irina Chifu, Martin Fassnacht, Mirjam Christ-Crain
Journal: The Lancet (2019)
Targeted delivery of hyaluronic acid nanomicelles to hepatic stellate cells in hepatic fibrosis rats
Authors: Wenhao Li, Chuchu Zhou, Yao Fu, Tijia Chen, Xing Liu, Zhirong Zhang, Tao Gong
Journal: Acta Pharmaceutica Sinica B (2019)

Hepatic fibrosis is one kind of liver diseases with a high mortality rate and incidence. The activation and proliferation of hepatic stellate cells (HSCs) is the most fundamental reason of hepatic fibrosis. There are no specific and effective drug delivery carriers for the treatment of hepatic fibrosis at present. We found that when hepatic fibrosis occurs, the expression of CD44 receptors on the surface of HSCs is significantly increased. Based on this finding, we designed silibinin-loaded hyaluronic acid (SLB-HA) micelles to achieve the treatment of hepatic fibrosis. Meanwhile, we constructed liver fibrosis rat model using Sprague-Dawley rats. We demonstrated that HA micelles had specific uptake to HSCs in vitro while avoiding the distribution in normal liver cells and the phagocytosis of macrophages. Importantly, HA micelles showed a significant liver targeting effect in vivo, especially in fibrotic liver which highly expressed CD44 receptors. In addition, SLB-HA micelles could selectively kill activated HSCs, having an excellent anti-hepatic fibrosis effect in vivo and a significant sustained release effect, and also had a good biological safety and biocompatibility. Overall, HA micelles represented a novel nanomicelle system which showed great potentiality in anti-hepatic fibrosis drugs delivery.
Drug deaths: record number in Scotland prompts calls for urgent UK policy reform
Authors: Bryan Christie
Journal: BMJ (2019)

Radical change to official UK policies on drug use is being demanded as new figures show that Scotland has the highest number of drug related deaths in Europe and possibly the world.

A report from the National Records of Scotland states that last year saw a total of 1187 drug related deaths, the highest rate ever recorded and more than double the 574 deaths in 2008.1 For the first time more Scots died from drug related causes than from alcohol.

The number means that Scotland had 218 drug related deaths per million population, eclipsing the next …
MHC-1 genotype as a predictor of response to immunotherapy.
Authors: Aaron Goodman, Rachel Pyke, Shumei Kato, Ryosuke Okamura, Ethan Sokol, Garrett Michael Frampton, Vincent A. Miller, Hannah Carter, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2019)

149 Background: MHC-1 molecules present intracellular peptides on the surface of tumor cells for recognition by CD8+ cytotoxic T-cells. Cancers with a high tumor mutational burden (TMB) are more likely to respond to immune checkpoint blockade (ICB) due to the increased chance of having a mutated peptide presented by MHC-1. However, the interaction between TMB and patient-specific MHC-1 and ICB response is unknown. Methods: We analyzed 83 patients with diverse solid tumors treated with ICB for TMB and MHC-1 (tissue next generation sequencing (NGS) (Foundation Medicine)). TMB low vs high were defined as &lt;20 vs ≥20 mut/mb, respectively. Patient Harmonic-mean Best Rank (PHBR) (Marty et al. 2018) scores the ability of the MHC-I of an individual to bind and present a specific missense mutation. Patients were assigned the PHBR of their best presented missense driver mutation. PHBR low (strong presentation) vs high (weak presentation) were defined as &lt;1.01 vs ≥1.01 respectively (cutoff per a receiver operator curve). Overall response rate (ORR) (includes stable disease for ≥6 months) was determined (RECIST criteria). Results: The ORR, PFS, and OS for patients treated with ICB with PHBR low vs. high tumors was 72% vs 28% (P = 0.01), 6.3 vs 4.1 months (P = 0.03), and 37.1 vs 13.9 months (P = 0.25), respectively. The ORR, PFS, and OS for TMB low vs high was 36% vs 67% (P = 0.02), 4.3 vs 14.1 months (P = 0.01), and 12.0 months vs not reached (P = 0.03), respectively. The ORR, PFS, and OS for TMB high/PHBR high vs TMB high/PHBR low was 38% vs 85% (P &lt; 0.01), 3.9 vs 26.8 months (P &lt;0.01), and 17.1 vs not reached (P = 0.02), respectively Conclusions: MHC-1 genotype and the ability to present driver neo-antigens predicts which patients with TMB high will respond to ICB.[Table: see text]
Outcomes of T-Cell Depleted Haploidentical Peripheral Blood Stem Cell Transplantation for Adult Acute Leukemia: A Meta-Analysis
Authors: Seren Durer, Ceren Durer, Emmanuel Katsanis, Isin Yagmur Comba, Faiza Jamil, Shehroz Aslam, Zunairah Shah, Mustafa Nadeem Malik, Insija Ilyas Selene, Muhammad Asad Fraz, Jemin Aby Jose, Anum Qureshi, Muhammad Yasir, Saher Nasir Amin, Faiz Anwer
Journal: Blood (2018)
Reply to: Absence of evidence that Slc12a8 encodes a nicotinamide mononucleotide transporter
Authors: Alessia Grozio, Kathryn Mills, Jun Yoshino, Santina Bruzzone, Giovanna Sociali, Kyohei Tokizane, Hanyue Cecilia Lei, Yo Sasaki, Marie Migaud, Shin-ichiro Imai
Journal: Nature Metabolism (2019)