tbuckley/cabot-search huggingface dataset:
A retrospective review of borderline resectable-locally advanced pancreatic adenocarcinoma (BR-LAPC) undergoing neoadjuvant chemotherapy followed by stereotactic body radiation therapy (SBRT) at the University of Colorado Cancer Center.
Authors: Claymore Joey Cuny, John Hoyle, Cindy L. O'Bryant, Cheryl Lauren Meguid, Christopher Hanyoung Lieu, Sarah Lindsey Davis, Wells A. Messersmith, Stephen Leong
Journal: Journal of Clinical Oncology (2018)

436 Background: Metastatic pancreatic chemotherapy regimens are often used as neoadjuvant treatment in the LAPC setting. The University of Colorado has a treatment paradigm for BR-LAPC which consists of 2-4 months of chemotherapy followed by SBRT then reevaluated for surgical resection. Methods: Retrospective analysis of patients with pathologically confirmed BR-LAPC who received all neoadjuvant treatment (chemotherapy and SBRT) with intention of undergoing surgical resection at the University of Colorado Cancer Center from 2012 to 2017. Baseline data collected includes demographics, comorbidities, disease characteristics and chemotherapy regimen FOLFIRINOX or Gemcitabine/Nab-Paclitaxel (GNP). The objective of the study is to describe the correlation of neoadjuvant regimens and clinical outcomes. Results: A total of 100 patients were identified with 40 patients collected for the interim analysis. Of these patients 82.5% (N = 33) received FOLFIRINOX and 17.5% (N = 7) received GNP. Patients who received FOLFIRINOX, 78.8% went for surgical resection compared to 85.7% in the GNP group. The number of patients who had a reported College of American Pathology (CAP) grade ≤1, representing no or minimal residual disease, was 3 for the FOLFIRINOX group and no patients in the GNP group. The percent of patients in the FOLFIRINOX group who achieved R0 resections was 90% compared to 83% for the GNP group. Mean initial CA 19-9 was 38.5U/ml, 386.7U/ml, and 1799.8U/ml in CAP grade 1, 2, 3 respectively, while percent reduction in CA 19-9 level during neoadjuvant was 33.3%, 69.7%, and 72.4% respectively. Assessment of the impact of relative dose intensity for each neoadjuvant regimen on clinical outcomes is ongoing. Conclusions: FOLFIRINOX neoadjuvant treatment was associated with improved surgical outcomes including an increased rate of R0 and CAP grade ≤1 resections. Low initial CA 19-9 levels were associated with favorable surgical and pathologic outcomes whereas absolute or relative CA 19-9 reductions with neoadjuvant were not. Final analysis of all 100 patients will be reported.
Abstract 16741: Impact of Level of Post-procedural B-type Natriuretic Peptides on Mortality After Successful Transcatheter Edge-to-Edge Mitral Valve Repair Using MitraClip
Authors: Krissada Meemook, Mamoo Nakamura, Shunsuke Kubo, Yoshifumi Nakajima, Yukiko Mizutani, Guangyuan Song, Saibal Kar
Journal: Circulation (2016)

Introduction: High level B-type natriuretic peptide (BNP) is associated with poor outcomes in patient with valvular heart disease. However, prognostic impact of post-procedural BNP level in patient undergoing MitraClip was not thoroughly evaluated. Methods: A retrospective single center study was conducted in 147 consecutive patients who were successfully treated by MitraClip for severe mitral regurgitation. BNP level was measured in all patients at 30-day follow-up. The study population was grouped based on BNP level: low BNP (≤ 256 pg/mL), mid BNP (257-517 pg/mL), and high BNP (≥518 pg/mL) and post-procedural mortality was compared. Results: Low BNP group was at lower baseline surgical risk compared with mid, and high BNP group (STS score 7.3±5.9 vs 11.6±7.6 vs 13.9±7.7, respectively, p<0.001). All-cause death at 1-year follow-up was 6.1%, 10.2%, and 26.5%, respectively (p=0.009). Mortality rate at 2-year follow-up was significantly higher in high BNP group (8.2% vs 24.5% vs 38.8% for the low, mid, and ...
Abstract 18424: Ventricular Shape Correlates to Arrhythmic Events in ARVC Patients
Authors: Kristin McLeod, Samuel Wall, Ida S Leren, Jørg Saberniak, Kristina H Haugaa
Journal: Circulation (2016)

Introduction: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) patients undergo ventricular shape remodeling as the disease progresses. Since this remodeling may be indicative of arrhythmic r...
The NHS at 70: letting the excellent be the enemy of the good
Authors: Stephen Longworth
Journal: BMJ (2018)

Appleby and Abbasi question the future of the NHS.1 After working as a doctor for the NHS from age 23 to 57 (31 years as a general practitioner and 15 years as a hospital specialist), I have come to three major conclusions about the NHS.

Firstly, its greatest strength is that it is free at the point of delivery; its greatest weakness is that it is free at …
Enterotoxigenic Escherichia coli–blood group A interactions intensify diarrheal severity
Authors: Pardeep Kumar, F. Matthew Kuhlmann, Subhra Chakraborty, A. Louis Bourgeois, Jennifer Foulke-Abel, Brunda Tumala, Tim J. Vickers, David A. Sack, Barbara DeNearing, Clayton D. Harro, W. Shea Wright, Jeffrey C. Gildersleeve, Matthew A. Ciorba, Srikanth Santhanam, Chad K. Porter, Ramiro L. Gutierrez, Michael G. Prouty, Mark S. Riddle, Alexander Polino, Alaullah Sheikh, Mark Donowitz, James M. Fleckenstein
Journal: Journal of Clinical Investigation (2018)

Enterotoxigenic Escherichia coli (ETEC) infections are highly prevalent in developing countries, where clinical presentations range from asymptomatic colonization to severe cholera-like illness. The molecular basis for these varied presentations, which may involve strain-specific virulence features as well as host factors, has not been elucidated. We demonstrate that, when challenged with ETEC strain H10407, originally isolated from a case of cholera-like illness, blood group A human volunteers developed severe diarrhea more frequently than individuals from other blood groups. Interestingly, a diverse population of ETEC strains, including H10407, secrete the EtpA adhesin molecule. As many bacterial adhesins also agglutinate red blood cells, we combined the use of glycan arrays, biolayer inferometry, and noncanonical amino acid labeling with hemagglutination studies to demonstrate that EtpA is a dominant ETEC blood group A-specific lectin/hemagglutinin. Importantly, we have also shown that EtpA interacts specifically with glycans expressed on intestinal epithelial cells from blood group A individuals and that EtpA-mediated bacterial-host interactions accelerate bacterial adhesion and effective delivery of both the heat-labile and heat-stable toxins of ETEC. Collectively, these data provide additional insight into the complex molecular basis of severe ETEC diarrheal illness that may inform rational design of vaccines to protect those at highest risk.
New Biologics for Asthma
Authors: Jeffrey M. Drazen, David Harrington
Journal: New England Journal of Medicine (2018)

Two articles now published in the Journal indicate that dupilumab, a monoclonal antibody directed against the alpha subunit of the interleukin-4 receptor that inhibits interleukin-4 and interleukin-13 signaling, has a salutary treatment effect in severe asthma. In the first trial,1 patients with oral glucocorticoid–dependent severe asthma were able to reduce their oral glucocorticoid dose without losing control of their asthma when dupilumab was added to their regimens as compared with placebo. Even though the glucocorticoid dose was reduced, there were, on average, fewer exacerbations in the active-treatment group than in the placebo group, and lung function, as measured by the . . .
Factors Linked to Depression in Sexual Minority Youth
Authors: Rita Rubin
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract B33: CRISPR/Cas9 generation of Ret and Ntrk1 fusion oncogenes and novel in vitro sgRNA screening method
Authors: Laura Schubert, Anh T. Le, Stephen P. Malkoski, Raphael Nemenoff, Robert C. Doebele
Journal: Cancer Research (2018)

Abstract Chromosomal rearrangements of ALK, RET, ROS1, and NTRK1 collectively represent approximately 10% of oncogenic drivers in lung adenocarcinoma. These rearrangements result in the aberrant expression and constitutive activation of a chimeric fusion kinase, which promotes growth, proliferation and survival of the cancer cell. CRISPR/Cas9 technology can now be employed to generate these chromosomal rearrangements both in vitro and in vivo. sgRNAs can be designed to target the Cas9 endonuclease to introns within the 5′ and 3′ gene partners of the rearrangement. A unique advantage of this approach is that it is compatible with immunocompetent mouse models. We have developed a novel in vitro screening strategy to identify sgRNAs that successfully generated the intended rearrangements. Ba/F3 cells are a murine B-cell cell line whose proliferation is normally dependent on the exogenous addition of the cytokine interleukin 3 (IL3), but can be rendered IL3 independent if an oncogenic alteration is introduced. We hypothesized that IL3-independence in Ba/F3 cells could be used as a method to select for cells that had successfully created chromosomal rearrangements leading to oncogenic fusions. This strategy eliminates the need for single cell cloning to confirm that successful CRISPR genome editing has occurred. We transfected Ba/F3 cells with pairs of sgRNAs within the PX330 Cas9 containing plasmid and then withdrew IL3. Cells that became IL3 independent were tested for rearrangements. Using this screening system, we successfully generated Kif5b-Ret, Trim24-Ret, and Tpm3-Ntrk1 rearrangements in Ba/F3 cells. These rearrangements were confirmed using PCR or RT-PCR and sequencing using fusion-specific primers. Additionally, the Ret rearrangements and Ntrk1 rearrangements were far more sensitive to RET and TRK inhibitors, respectively, than parental Ba/F3 cells, further confirming that the Ba/F3 cells' growth was now dependent on signaling from the fusion kinase. RET protein expression was also detected with Western blotting in the two Ret rearranged Ba/F3 cell lines. Our future plans are to introduce adenovirus containing validated sgRNAs into immune-competent mice, and confirm that they generate tumors with the intended rearrangements. Citation Format: Laura Schubert, Anh T. Le, Stephen P. Malkoski, Raphael Nemenoff, Robert C. Doebele. CRISPR/Cas9 generation of Ret and Ntrk1 fusion oncogenes and novel in vitro sgRNA screening method [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B33.
Brain Nutrition: A Life Span Approach
Authors: Manu S. Goyal, Lora L. Iannotti, Marcus E. Raichle
Journal: Annual Review of Nutrition (2018)

Appraising success in meeting the world's nutritional needs has largely focused on infant mortality and anthropometric measurements with an emphasis on the first 1,000 days (conception to approximately age 2 years). This ignores the unique nutritional needs of the human brain. Although the intrauterine environment and the early postnatal years are important, equally critical periods follow during which the brain's intricate wiring is established for a lifetime of experience-driven remodeling. At the peak of this process during childhood, the human brain may account for 50% of the body's basal nutritional requirement. Thus, the consequences of proper nutritional management of the brain play out over a lifetime. Our motivation in preparing this review was to move the human brain into a more central position in the planning of nutritional programs. Here we review the macro- and micronutrient requirements of the human brain and how they are delivered, from conception to adulthood.
Biological effects of cabozantinib on bone microenvironment.
Authors: Francesco Pantano, Marco Fioramonti, Michele Iuliani, Giulia Ribelli, Bruno Vincenzi, Giuseppe Tonini, Daniele Santini
Journal: Journal of Clinical Oncology (2016)

e23004 Background: Cabozantinib (CBZ) is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, FLT3, c-KIT, and RET. Pre-clinical studies in models of prostate cancer bone metastasis demonstrated that CBZ treatment induced both a suppression of tumour growth and an alteration in bone remodelling, suggesting that both tumour and bone microenvironment represented potential CBZ targets. This is the first study exploring the potential direct activity of CBZ in bone using a totally human model of primary osteoclasts (OCLs) and osteoblasts (OBLs). Methods: Primary OCLs were differentiated from CD14+ monocytes; primary OBLs were obtained from mesenchymal stem cells. OCL differentiation and activity were evaluated by TRAP and Bone Resorption assays; OBL differentiation was analysed by ALP and Alizarin Red assays. Gene expression analyses was performed by Real Time PCR and OPG and RANKL protein secretion measured by ELISA. Results: Our results showed that non-cytotoxic doses of CBZ had a statistically significant inhibitory effect on OCL differentiation (P = 0.0145) and bone resorption activity (P = 0.0252). Moreover, we found that CBZ down-modulated the expression of OCL marker genes: TRAP (P = 0.006) and CATHEPSIN K (P = 0.004). On the other hand CBZ treatment had no a significant impact on OBLs vitality, differentiation and activity. Intriguingly we found that CBZ induced in OBLs an alteration of RANKL/OPG balance increasing OPG mRNA levels (P = 0.015) and down-modulating RANKL expression (P < 0.001). A significant drop in RANKL secretion (P = 0.043) and an increase of OPG production (P = 0.004) was confirmed by ELISA. Conclusions: Overall, this is the first evidence in human of the “direct” effect of CBZ on OCLs and “indirect” osteoblast-mediated through a modulation of RANKL/OPG balance. These multiple effects of CBZ on the cells of bone microenvironment are consistent with its effectiveness in reducing lesions from prostate cancer metastases.
Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis
Authors: Masaru Noda, Hirokazu Okayama, Kazunoshin Tachibana, Wataru Sakamoto, Katsuharu Saito, Aung Kyi Thar Min, Mai Ashizawa, Takahiro Nakajima, Keita Aoto, Tomoyuki Momma, Kyoko Katakura, Shinji Ohki, Koji Kono
Journal: Clinical Cancer Research (2018)

Purpose: We aimed to discover glycosyltransferase gene (glycogene)-derived molecular subtypes of colorectal cancer associated with patient outcomes.Experimental Design: Transcriptomic and epigenomic datasets of nontumor, precancerous, cancerous tissues, and cell lines with somatic mutations, mismatch repair status, clinicopathologic and survival information were assembled (n = 4,223) and glycogene profiles were analyzed. IHC for a glycogene, GALNT6, was conducted in adenoma and carcinoma specimens (n = 403). The functional role and cell surface glycan profiles were further investigated by in vitro loss-of-function assays and lectin microarray analysis.Results: We initially developed and validated a 15-glycogene signature that can identify a poor-prognostic subtype, which closely related to deficient mismatch repair (dMMR) and GALNT6 downregulation. The association of decreased GALNT6 with dMMR was confirmed in multiple datasets of tumors and cell lines, and was further recapitulated by IHC, where approximately 15% tumors exhibited loss of GALNT6 protein. GALNT6 mRNA and protein was expressed in premalignant/preinvasive lesions but was subsequently downregulated in a subset of carcinomas, possibly through epigenetic silencing. Decreased GALNT6 was independently associated with poor prognosis in the IHC cohort and an additional microarray meta-cohort, by multivariate analyses, and its discriminative power of survival was particularly remarkable in stage III patients. GALNT6 silencing in SW480 cells promoted invasion, migration, chemoresistance, and increased cell surface expression of a cancer-associated truncated O-glycan, Tn-antigen.Conclusions: The 15-glycogene signature and the expression levels of GALNT6 mRNA and protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis. Clin Cancer Res; 24(18); 4468-81. ©2018 AACR.
Expanded benefits of curing the extrahepatic manifestations of HCV infection
Authors: Francesco Negro
Journal: Gut (2018)

HCV infection is a major global health threat. HCV is estimated to infect ~71.1 million persons worldwide and to cause approximately 400 000 deaths annually.1 Although HCV-related mortality is reportedly due to the end-stage complications of chronic hepatitis C (decompensated cirrhosis and hepatocellular carcinoma), the above official figures do not take into consideration the mortality attributable to the multifaceted extrahepatic disorders caused by this pathogen.2 3 The list of such extrahepatic manifestations (EHM) is long and includes—but is not limited to—the cryoglobulinaemia-associated syndrome (characterised by fatigue, arthralgia, skin vasculitis, glomerulonephritis and cerebritis, among others), some subtypes of non-Hodgkin’s B cell lymphoma, insulin resistance (which may progress to type 2 diabetes and its cardiovascular sequelae) and various neurological conditions, such as cognitive dysfunction. The causal link between most of these EHM and HCV infection has been established, thanks to a wealth of epidemiological and clinical data, and especially based on the repeated observation that treatment-induced viral clearance is associated with clinical improvement.2 Their pathogenesis encompasses direct and indirect mechanisms, and may involve autoimmune reactions. Incidentally, for the latter reason, some EHMs have been for long time considered a contraindication to interferon (IFN)-α therapy. The recent advent …
Chronic myelomonocytic leukemia: 2018 update on diagnosis, risk stratification and management
Authors: Mrinal M. Patnaik, Ayalew Tefferi
Journal: American Journal of Hematology (2018)

Disease overview Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (∼15%‐20% over 3‐5 years). Diagnosis Diagnosis is based on the presence of sustained (&gt;3 months) peripheral blood monocytosis (≥1 × 10 9 /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼ 30% of patients, while &gt;90% have gene mutations. Mutations involving TET2 (∼60%), SRSF2 (∼50%), ASXL1 (∼40%) and the oncogenic RAS pathway (∼30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over‐all survival. Risk stratification Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM), and the CMML specific prognostic model (CPSS‐Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count &gt; 10 × 10 9 /L, hemoglobin &lt;10 gm/dL, platelet count &lt;100 × 10 9 /L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into 4 groups; high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively. Risk‐adapted therapy Hypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ∼30%‐40% and complete remission rates of ∼7%‐17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.
Systematic Identification of Druggable Epithelial–Stromal Crosstalk Signaling Networks in Ovarian Cancer
Authors: Tsz-Lun Yeung, Jianting Sheng, Cecilia S Leung, Fuhai Li, Jaeyeon Kim, Samuel Y Ho, Martin M Matzuk, Karen H Lu, Stephen T C Wong, Samuel C Mok
Journal: JNCI Journal of the National Cancer Institute (2018)

Bulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma–cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer–stroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer. Transcriptome profiles from microdissected ovarian cancer–associated fibroblasts (CAFs) and ovarian cancer cells from patients with high-grade serous ovarian cancer (n = 70) were used as input data for the computational systems biology program CCCExplorer to uncover crosstalk networks between various cell types within the tumor microenvironment. The crosstalk analysis results were subsequently used for discovery of new indications for old drugs in ovarian cancer by computational ranking of candidate agents. Survival analysis was performed on ovarian tumor–bearing Dicer/Pten double-knockout mice treated with calcitriol, a US Food and Drug Administration–approved agent that suppresses the Smad signaling cascade, or vehicle control (9–11 mice per group). All statistical tests were two-sided. Activation of TGF-β-dependent and TGF-β-independent Smad signaling was identified in a particular subtype of CAFs and was associated with poor patient survival (patients with higher levels of Smad-regulated gene expression by CAFs: median overall survival = 15 months, 95% confidence interval [CI] = 12.7 to 17.3 months; vs patients with lower levels of Smad-regulated gene expression: median overall survival = 26 months, 95% CI = 15.9 to 36.1 months, P = .02). In addition, the activated Smad signaling identified in CAFs was found to be targeted by repositioning calcitriol. Calcitriol suppressed Smad signaling in CAFs, inhibited tumor progression in mice, and prolonged the median survival duration of ovarian cancer–bearing mice from 36 to 48 weeks (P = .04). Our findings suggest the feasibility of using novel multicellular systems biology modeling to identify and repurpose known drugs targeting cancer–stroma crosstalk networks, potentially leading to faster and more effective cures for cancers.