tbuckley/cabot-search huggingface dataset:
Ascites, or Fluid in the Belly, in Patients With Cancer
Authors: Arjun Gupta, Ramy Sedhom, Muhammad S. Beg
Journal: JAMA Oncology (2019)

Ascites, or Fluid in the Belly, in Patients With CancerWhat Is Ascites?Ascites (uh-SIGH-tees) refers to excess fluid in the abdomen.This fluid collects in the space within the walls of the abdomen, between the abdominal organs.It is common in patients with liver disease and cirrhosis, though patients with cancer can also develop ascites.
Interleukin 31 in insect bite hypersensitivity—Alleviating clinical symptoms by active vaccination against itch
Authors: Florian Olomski, Victoria Fettelschoss, Sigridur Jonsdottir, Katharina Birkmann, Franziska Thoms, Eliane Marti, Martin F. Bachmann, Thomas M. Kündig, Antonia Fettelschoss‐Gabriel
Journal: Allergy (2019)

Insect bite hypersensitivity (IBH) is the most common seasonal pruritic allergic dermatitis of horses occurring upon insect bites. In recent years, a major role for IL-31 in allergic pruritus of humans, monkeys, dogs, and mice was acknowledged. Here, we investigate the role of IL-31 in IBH of horses and developed a therapeutic vaccine against equine IL-31 (eIL-31).IL-31 levels were quantified in allergen-stimulated peripheral blood mononuclear cells (PBMCs) and skin punch biopsies of IBH lesions and healthy skin from IBH-affected and healthy horses. The vaccine consisted of eIL-31 covalently coupled to a virus-like particle (VLP) derived from cucumber mosaic virus containing a tetanus toxoid universal T-cell epitope (CuMVTT). Eighteen IBH-affected horses were recruited and immunized with 300 μg of eIL-31-CuMVTT vaccine or placebo and IBH severity score was recorded.IL-31 was increased in PBMCs and exclusively detectable in skin lesions of IBH-affected horses. Vaccination against eIL-31 reduced delta clinical scores when compared to previous untreated IBH season of the same horses and to placebo-treated horses in the same year. The vaccine was well tolerated without safety concerns throughout the study.TH2-derived IL-31 is involved in IBH pathology and accordingly the immunotherapeutic vaccination approach targeting IL-31 alleviated clinical scores in affected horses.
Abstract C29: Development of a circulating tumor DNA assay in pancreas cancer
Authors: Dan King, Mari Olsen, George Fisher, Max Diehn, Ash Alizadeh
Journal: Cancer Research (2019)

Abstract Pancreas cancer is the third most common cause of cancer-related death, owing in part to high rates of unresectable disease at time of diagnosis and poor long-term response to chemotherapy. Biomarkers are needed to sensitively identify and monitor disease burden, and to measure response to therapy. The CA19-9 tumor marker lacks sufficient positive or negative predictive value to guide treatment decisions, and digital droplet PCR (ddPCR) assessment of circulating KRAS mutations suffers poor sensitivity on account of only assessing a single DNA locus. We hypothesize that a multitargeted circulating tumor DNA assay can outperform CA19-9 and ddPCR as biomarker for the detection and monitoring of pancreas cancer. Our lab has developed the cancer personalized profiling by deep sequencing (CAPP-Seq) method, which combines high-depth sequencing with several strategies of error-suppression to identify minute amounts of tumor DNA circulating in patients’ blood. The development of our CAPP-Seq targeted sequencing panel hinged primarily on capturing regions of the genome known to be recurrently mutated in pancreatic ductal adenocarcinoma (PDAC), based on The Cancer Genome Atlas project. These regions contain mutations in KRAS, TP53, SMAD4, and by a long-tail of mutations in many other genes for which we contributed approximately 200 kb of selector space. In addition to recurrent SNVs, we also contributed approximately 35 kb for recurrent copy number variant locations, 10 kb for recurrent noncoding variants, and 20 kb for regions with aberrant expression patterns in PDAC based on TCGA RNA-sequencing data. This purpose of this study is to employ CAPP-Seq in two pancreas cancer cohorts: patients who underwent resection at Stanford and had blood drawn before and after surgical resection (n=30), and a cohort of patients with metastatic disease who are undergoing chemotherapy with blood draws at multiple time-points (n=20). The former cohort will assess prediction of recurrence based on ctDNA level, and the latter will assess patients with early development of resistance to chemotherapy. Before assessing this ctDNA detection assay in patients with pancreas cancer, we first evaluated the CAPP-Seq approach on two healthy research subjects and achieved on average 4000x de-duplicated sequencing depth, for a theoretical limit of detection of 0.03% circulating tumor fraction. We next sequenced samples from 7 patients with resectable disease and 8 with metastatic disease, with results expected in early July. Citation Format: Dan King, Mari Olsen, George Fisher, Max Diehn, Ash Alizadeh. Development of a circulating tumor DNA assay in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C29.
BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging
Authors: Volkan Turan, Kutluk Oktay
Journal: Human Reproduction Update (2019)

Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. BRCA1 and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated (ATM)-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and ATM-mediated DNA DSB repair in ovarian aging.Although there are several competing or complementary theories, given the growing evidence tying BRCA function and ATM-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality.We searched for published articles in the PubMed database containing key words, BRCA, BRCA1, BRCA2, Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own.Laboratory studies provided robust and reproducible evidence that BRCA1 function and ATM-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for BRCA1 and other ATM-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related ATM-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging.The existing data suggest that the BRCA-related ATM-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.
Rechallenge with ifosfamide-containing regimen as salvage option for patients with metastatic soft tissue sarcomas progressing after multiple pretreatments.
Authors: Mathias Hoiczyk, Petra Kuschel, Florian Grabellus, Mareike Geffken, Marit Ahrens, Martin H. Schuler, Sebastian Bauer
Journal: Journal of Clinical Oncology (2012)

10046 Background: Ifosfamide (I) is commonly used in first or second-line treatment of locally advanced or metastatic soft tissue sarcomas (STS). The clinical efficacy of a rechallenge with ifosfamide (IR) or I-containing regimen (ICR) is unclear. We conducted a retrospective analysis of our institutional database (n=1354) of pts who received IR or ICR. Methods: 66 STS pts were identified, who had received more than one I-based regimen. Ifosfamide retreatment was given in neoadjuvant (n=26), adjuvant (n=18) or metastatic settings (n=22) and most patient were pretreated with doxorubicin (D; 94%). PFS was determined from first administration of IR until disease progression, OS from R until last follow-up or death. ORR (RECIST) was assessed to determine the clinical benefit rate (CBR) defined as CR, PR plus SD. Covariates were age, gender, histology, pretreatment, dose intensity, response and toxicity. Results: Median age at time of first I was 45y (range: 17-74, 44% f 56% m). Median time from diagnosis until first ICR treatment was 4mo. Median time from first I until IR, which was given as median 3 rd -line treatment (2-9 lines), was 17 mo. Histologies were 12 leiomyo-, 11 lipo- 13 pleomorphic,14 synovial, 4 rhabdomyosarcomas and 12 other subtypes. Pts received a median of I 9.6 g/m²/cycle and a median of 4 cycles. I was given as monotherapy (38%) or in combination (D: 45%, other 17%). Overall median PFS was 5mo with PFS-rates of 63% at 12 and 25% at 24 wks. Median PFS was 6 mo for ICR and 2 mo for IR. The median OS was 36 mo from time of first diagnosis of metastases or locally advanced disease. ORR was 29% for I/D combination (CBR 70%) and 12 % for I monotherapy (CBR: 52%). 22 pts received a second IR with a median of 2 cycles (27% PR; CBR:77%; 69% combinations). Most common toxicities for IR/ICR were neutropenia (42%), encephalopathy (21%) and neutropenic fever (18%). Dose reductions were necessary in 18% of pts and treatment was stopped in 8% due to toxicity. No significant cardiotoxicity was observed. Conclusions: Patients with soft tissue sarcomas who had at least disease stabilization after initial ifosfamide-based therapy may derive substantial clinical benefit from a rechallenge.
Detection rates during colonoscopy: What matters most?
Authors: Michael Bretthauer
Journal: Endoscopy (2019)

The adenoma detection rate (ADR) is defined as the percentage of patients undergoing colonoscopy who have one or more adenomas detected [1] [2]. ADR has been the hallmark of high quality colonoscopy since a landmark study from Poland published in the New England Journal of Medicine in 2010 established the relationship between an individual endoscopist’s ADR and their patient’s risk of colorectal cancer (CRC) after colonoscopy (so-called interval cancer) [1]. The association of endoscopist’s ADR with CRC was confirmed by a large US cohort in 2014, and extended by establishing its importance also for CRC mortality [2].
Abstract B21: Pharmacologic activation of G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma
Authors: Christopher Natale, Jinyang Li, Tzvete Dentchev, Brian Capell, John Seykora, Ben Stanger, Todd Ridky
Journal: Cancer Research (2019)

Abstract LNS8801 is a novel, orally bioavailable, small-molecule agonist of the G Protein Coupled Estrogen Receptor (GPER) being developed for the treatment of pancreatic ductal adenocarcinoma (PDAC) and other advanced cancers. Women have a lower incidence and improved clinical outcomes for most cancer types, including PDAC. The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that PDAC lacks classic nuclear estrogen receptors. Here we used murine syngeneic tumor models and human xenografts to determine that agonizing GPER on tumor cells inhibits PDAC. Systemically administered GPER agonists were well tolerated, induced tumor regression, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. Complete responses, observed with the GPER agonist alone or in combination with PD-1 targeted immune therapy, were associated with durable immune memory that protected against tumor rechallenge. Activation of GPER depleted c-Myc and programmed death ligand 1 (PD-L1) and increased tumor cell immunogenicity. These data, coupled with the wide tissue distribution of GPER and previous work showing that GPER activation inhibits other cancer types, suggest that GPER agonists may be useful against a range of cancers that are not classically considered sex hormone responsive, and that arise in tissues outside of the reproductive system. Citation Format: Christopher Natale, Jinyang Li, Tzvete Dentchev, Brian Capell, John Seykora, Ben Stanger, Todd Ridky. Pharmacologic activation of G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B21.
Abstract I04: Regulatory T-cell depletion causes compensatory immune suppression and accelerates pancreatic carcinogenesis
Authors: Yaqing Zhang, Jenny Lazarus, Nina Steele, Ho-Joon Lee, Wei Yan, Cristopher J. Halbrook, Rosa Menjivar, Samantha B. Kemp, Veerin Sirihoracai, Eileen S. Carpenter, Anna C. Nevison, Alekya Vinta, Michelle A. Anderson, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano
Journal: Cancer Research (2019)

Abstract In human patients and in mouse models, immunosuppressive regulatory T cells (Tregs) accumulate in pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Using a genetically engineered mouse model of pancreatic cancer, we determined that—unlike in other malignancies—Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumor progression. We show that Tregs are a key source of TGFb ligands both in human samples and in mouse models. Accordingly, their depletion reprograms the fibroblast population, exemplified by loss of smooth muscle actin expression and an increase in the myeloid-recruiting chemokines Ccl3, Ccl6, and Ccl8. Our findings point to a dual role of Tregs in pancreatic cancer, with their immune-suppressive function being balanced by their induction of a SMA-high (tumor-restraining) fibroblast phenotype. Further, our data point to a compensatory immunosuppression mechanism that confers resistance to Treg depletion in pancreatic cancer. Finally, blockade of the common CCL3/6/8 receptor CCR1 combined with Treg-depletion successfully inhibited tumorigenesis, a finding with potential therapeutic implications. Citation Format: Yaqing Zhang, Jenny Lazarus, Nina Steele, Ho-Joon Lee, Wei Yan, Cristopher J. Halbrook, Rosa Menjivar, Samantha B. Kemp, Veerin Sirihoracai, Eileen S. Carpenter, Anna C. Nevison, Alekya Vinta, Michelle A. Anderson, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano. Regulatory T-cell depletion causes compensatory immune suppression and accelerates pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I04.
Relationship between heart rate and outcomes in patients in sinus rhythm or atrial fibrillation with heart failure and reduced ejection fraction
Authors: Kieran F. Docherty, Li Shen, Davide Castagno, Mark C. Petrie, William T. Abraham, Michael Böhm, Akshay S. Desai, Kenneth Dickstein, Lars V. Køber, Milton Packer, Jean L. Rouleau, Scott D. Solomon, Karl Swedberg, Ali Vazir, Michael R. Zile, Pardeep S. Jhund, John J.V. McMurray
Journal: European Journal of Heart Failure (2019)
NTS Catecholamine Neurons Mediate Hypoglycemic Hunger via Medial Hypothalamic Feeding Pathways
Authors: Iltan Aklan, Nilufer Sayar Atasoy, Yavuz Yavuz, Tayfun Ates, Ilknur Coban, Fulya Koksalar, Gizem Filiz, Iskalen Cansu Topcu, Merve Oncul, Pelin Dilsiz, Utku Cebecioglu, Muhammed Ikbal Alp, Bayram Yilmaz, Deborah R. Davis, Karolina Hajdukiewicz, Kenji Saito, Witold Konopka, Huxing Cui, Deniz Atasoy
Journal: Cell Metabolism (2019)
Endoscopic Bipolar Electrocoagulation in Upper Gastrointestinal Bleeding
Authors: K. Hajiro, H. Yamamoto, H. Matsui, D. Tsujimura, T. Yamamoto, T. Hirooka, A. Todo
Journal: Endoscopy (1984)

A new endoscopically deliverable bipolar electrocoagulator has been developed, and employed clinically to treat upper gastrointestinal bleeding in 53 patients on 61 occasions. By direct application of the electrode to the bleeding vessels immediate hemostasis was achieved in 52 out of 53 bleeding vessels. Non-bleeding visible vessels were safely coagulated. Arrest of bleeding was permanent in 44 patients (83%), of whom 20 were candidates for emergency operation because of massive, continued or recurrent bleeding. Rebleeding after hemostasis by bipolar electrocoagulation was noted in 8 patients (15%); however, the majority of rebleeds were those with acute mucosal lesions who had serious underlying medical problems. Emergency operation was performed in 5 patients, and was averted in most patients after successful hemostasis by bipolar electrocoagulation. There were no complications related to the procedure. Bipolar electrocoagulation with our coagulator is a safe and easily applicable technique that is a promising addition to currently available endoscopic hemostatic methods.
Imidazoline Receptor System: The Past, the Present, and the Future
Authors: Pascal Bousquet, Alan Hudson, Jesús A. García-Sevilla, Jun-Xu Li
Journal: Pharmacological Reviews (2019)

Imidazoline receptors historically referred to a family of nonadrenergic binding sites that recognize compounds with an imidazoline moiety, although this has proven to be an oversimplification. For example, none of the proposed endogenous ligands for imidazoline receptors contain an imidazoline moiety but they are diverse in their chemical structure. Three receptor subtypes (I<sub>1</sub>, I<sub>2</sub>, and I<sub>3</sub>) have been proposed and the understanding of each has seen differing progress over the decades. I<sub>1</sub> receptors partially mediate the central hypotensive effects of clonidine-like drugs. Moxonidine and rilmenidine have better therapeutic profiles (fewer side effects) than clonidine as antihypertensive drugs, thought to be due to their higher I<sub>1</sub>/<i>α</i><sub>2</sub>-adrenoceptor selectivity. Newer I<sub>1</sub> receptor agonists such as LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3<i>H</i>-pyrrol-2-yl)-amine hydrochloride] have little to no activity on <i>α</i><sub>2</sub>-adrenoceptors and demonstrate promising therapeutic potential for hypertension and metabolic syndrome. I<sub>2</sub> receptors associate with several distinct proteins, but the identities of these proteins remain elusive. I<sub>2</sub> receptor agonists have demonstrated various centrally mediated effects including antinociception and neuroprotection. A new I<sub>2</sub> receptor agonist, CR4056 [2-phenyl-6-(1<i>H</i>-imidazol-1yl) quinazoline], demonstrated clear analgesic activity in a recently completed phase II clinical trial and holds great promise as a novel I<sub>2</sub> receptor–based first-in-class nonopioid analgesic. The understanding of I<sub>3</sub> receptors is relatively limited. Existing data suggest that I<sub>3</sub> receptors may represent a binding site at the Kir6.2-subtype ATP-sensitive potassium channels in pancreatic <i>β</i>-cells and may be involved in insulin secretion. Despite the elusive nature of their molecular identities, recent progress on drug discovery targeting imidazoline receptors (I<sub>1</sub> and I<sub>2</sub>) demonstrates the exciting potential of these compounds to elicit neuroprotection and to treat various disorders such as hypertension, metabolic syndrome, and chronic pain.
Abstract PR05: Autophagy facilitates immune evasion of pancreatic cancer through downregulation of MHC class I molecules
Authors: Keisuke Yamamoto, Anthony Venida, Doug E. Biancur, Miwako Yamamoto-Kakiuchi, Albert P. Sohn, Rushika M. Perera, Alec C Kimmelman
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy refractory to most therapies, including immune checkpoint blockade (ICB). Autophagy is a highly conserved self-degradation process that recycles cellular components. PDAC requires high levels of autophagy/lysosome function to meet their metabolic demand under nutrient-deprived conditions; however, little is known about substrates that are preferentially targeted and subsequent biologic impacts of their loss on PDAC pathogenesis. Here we found that cell surface expression of major histocompatibility complex class I (MHC-I) molecules, a critical component of antigen-presentation to CD8+ cytotoxic T lymphocytes (CTLs), is downregulated in PDAC cells though an autophagy-dependent pathway. Autophagy inhibition in PDAC cells restored surface MHC-I levels and improved antigen presentation, leading to enhanced antitumor T-cell response in syngeneic mouse models of PDAC, which was further enhanced by combination with ICB. Our findings indicate that elevated autophagy/lysosome function facilitates immune evasion of PDAC cells through selective targeting of MHC-I molecules and provide a rationale for the combination of autophagy inhibition and ICB as a therapeutic strategy against PDAC. This abstract is also being presented as Poster B61. Citation Format: Keisuke Yamamoto, Anthony Venida, Doug E. Biancur, Miwako Yamamoto-Kakiuchi, Albert P. Sohn, Rushika M. Perera, Alec C Kimmelman. Autophagy facilitates immune evasion of pancreatic cancer through downregulation of MHC class I molecules [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR05.
Cardio-Oncology in Israel
Authors: Zaza Iakobishvili, Dan Gilon
Journal: JACC CardioOncology (2019)

The tremendous success of anticancer treatment has brought us to a new reality that substantial proportions of patients with cancer are living longer and with a chronic disease. The absolute survival of patients with cancer increased from 34% in 1960 to 1969 to 62% in 2000 to 2009, with a prevalence
Injectable, scalable 3D tissue-engineered model of marrow hematopoiesis
Authors: Daniel Naveed Tavakol, Josefine Tratwal, Fabien Bonini, Martina Genta, Vasco Campos, Patrick Burch, Sylke Hoehnel, Amélie Béduer, Marco Alessandrini, Olaia Naveiras, Thomas Braschler
Journal: Biomaterials (2019)