tbuckley/cabot-search huggingface dataset:
Molecular comparison of primary colorectal cancer (pCRC) with peritoneal metastases (PM).
Authors: Matthew K Stein, Forrest W Williard, Miriam Tsao, Benjamin Deschner, Paxton Vandiver Dickson, Evan Scott Glazer, Michael Gary Martin, Jeremiah Lee Deneve
Journal: Journal of Clinical Oncology (2019)

498 Background: PM from CRC are associated with poor outcomes; however, molecular differences are not defined. Methods: We compared tumor profiles of pCRC and PM patients (pts) from Caris Life Sciences. Testing included next-generation sequencing (NGS) of 592 genes, immunohistochemistry (IHC), copy number variants (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were termed pathogenic (PATH) or variants of undetermined significance (VUS). TMB in mutations/Mb (MMB) was compared. Results: 617 pCRC and 348 PM pts had similar gender (55% male) and age (median 59). 232 pCRC were left-sided (LS), 189 right-sided (RS), 147 rectum (R) and 49 not otherwise specified (NOS); PM were 45 RS, 29 LS, 22 R and 252 NOS. For pts with IHC testing, expression was increased in PM in TOPO1 (62% v. 52%, p &lt; 0.01), ERCC1 (27% v. 18%, p &lt; 0.01) and MLH1 (96% v. 92%, p &lt; 0.05) and decreased in PD-1 (36% v. 65%, p &lt; 0.01), TOP2A (76% v. 100%, p &lt; 0.01) and PTEN (64% v. 72%, p &lt; 0.05). By sidedness, LS PM were more frequently TOP01 and PD-L1 and less commonly MGMT positive compared to pCRC. PTEN IHC was higher in R pCRC than PM. 7 CNVs were increased in PM ( ADGR2A2, CCND1, ELL, FGF3, FGF4, JAK3 and PDGFRB) and FLT3 CNVs were decreased. MYC CNVs were more common in RS PM compared to pCRC. No difference was seen in PM and pCRC PATHs in KRAS, BRAF, SMAD2, SMAD4, PTEN. PM had more PATHs in GNAS (8% v. 1%, p &lt; 0.01) while pCRC PATHs were increased in APC (76% v. 48%, p &lt; 0.01), TP53 (72% v. 53%, p &lt; 0.01), ARID1A (29% v. 12%, p &lt; 0.05), PIK3CA (22% v. 15%, p &lt; 0.05) and FBXW7 (13% v. 7%, p &lt; 0.01). LS PM had increased FLCN PATHs (12% v. 2%, p &lt; 0.01); R PM had more PATHs in KMT2D (20% v. 1%, p &lt; 0.01) and RNF43 (13% vs. 3%, p &lt; 0.05). VUS were increased in 39/592 (7%) genes for PM compared to pCRC. No MSI or fusion difference was seen. 53% pCRC (median = 8) pts had TMB ≥8 MMB compared to 43% PMs (median = 7; p = 0.03); no TMB difference was seen for LS, RS or R subgroups. Conclusions: Compared to pCRC, PM had more PATHs in GNAS and less in classic CRC markers APC and TP53. While TMB was generally lower in PM, differences in IHC expression, CNV and VUSs may serve as biomarkers for PM requiring further study.
Comparative Effects of Proximal and Distal Small Intestinal Glucose Exposure on Glycemia, Incretin Hormone Secretion, and the Incretin Effect in Health and Type 2 Diabetes
Authors: Xiang Zhang, Richard L. Young, Michelle Bound, Sanyuan Hu, Karen L. Jones, Michael Horowitz, Christopher K. Rayner, Tongzhi Wu
Journal: Diabetes Care (2019)

OBJECTIVE Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3-O-methylglucose (a marker of glucose absorption) was infused into either site and 0.9% saline into the alternate site over 60 min. Matching intravenous isoglycemic clamp studies were performed on the other two days. Blood glucose, serum 3-O-methylglucose, and plasma hormones were evaluated over 180 min. RESULTS In both groups, blood glucose and serum 3-O-methylglucose concentrations were higher after proximal than distal glucose infusion (all P &amp;lt; 0.001). Plasma GLP-1 increased minimally after proximal, but substantially after distal, glucose infusion, whereas GIP increased promptly after both infusions, with concentrations initially greater, but less sustained, with proximal versus distal infusion (all P &amp;lt; 0.001). Both the incretin effect and GIGD were less with proximal than distal glucose infusion (both P ≤ 0.009). CONCLUSIONS The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM.
Sputum and serum immunoglobulins in patients with asthma and recurrent neutrophilic bronchitis
Authors: Terence N. Ho, Eiman Al-Selahi, Chynna Huang, Manali Mukherjee, Katherine Radford, Melanie Kjarsgaard, Nicola Lavigne, Janice Halabecki, Susan Waserman, Parameswaran K. Nair
Journal: Journal of Allergy and Clinical Immunology (2019)
Reply
Authors: Gonzalo Sapisochin, Jordi Bruix
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Bruix consults for, advises for, is on the speakers' bureau for, and received grants from Bayer. He consults for, advises for, and is on the speakers' bureau for BTG. He consults for and advises for Novartis and Roche. He consults for and received grants from Daichi and Arqule. He consults for Abbott, Bristol‐Myers Squibb, GlaxoSmithKline, Lilly, and Kowa. He received grants from Sirtex. Dr. Sapisochin receives research support from Bayer. We appreciate the interest of Dr. Gu in our study. As mentioned in their letter, we agree that there are selected patients in which liver transplantation (LT) for intrahepatic cholangiocarcinoma (iCCA) may represent an excellent treatment option achieving good long‐term outcomes.1 In our cohort, ∼30% of the patients had hepatitis B virus infection and <20% were patients with primary sclerosing cholangitis, so we believe our study did not only represent Western countries. On the other hand, the numbers in our study did not allow performing accurate subgroup analysis according to underlying liver disease. We are therefore unable to comment on potential better outcomes of patients with HBV and if the results of LT in these patients are better to other indications is unknown. As mentioned in their letter, we agree that a major risk factor is viral hepatitis infection and cirrhosis and therefore these patients will benefit from surveillance programs.3 Even though these patients most likely will not have a high Model for End‐Stage Liver Disease score, they would need to be granted with exception points (as was done with hilar cholangiocarcinoma).4 The role of antiviral therapy for HBV and its outcomes post‐LT could not be evaluated in our cohort. Nevertheless, we believe that the impact of this therapy on post‐LT outcomes for iCCA should be similar to those in HBV patients transplanted for HCC. Finally, even though neoadjuvant chemoradiation has been shown to be safe and effective under a strict protocol for patients with hila cholangiocarcinoma pre‐LT5 and given that the results of LT for “very early” iCCA show a 5‐year survival ∼65% without neoadjuvant therapy, we are uncertain at this point if this will need to be implemented. It is possible though that this will be considered as a strategy for patients with larger iCCA under a research protocol.
Target Doses of Heart Failure Medical Therapy and Blood Pressure
Authors: Poghni A. Peri-Okonny, Xiaojuan Mi, Yevgeniy Khariton, Krishna K. Patel, Laine Thomas, Gregg C. Fonarow, Puza P. Sharma, Carol I. Duffy, Nancy M. Albert, Javed Butler, Adrian F. Hernandez, Kevin McCague, Fredonia B. Williams, Adam D. DeVore, J. Herbert Patterson, John A. Spertus
Journal: JACC Heart Failure (2019)
The role of entitativity in perpetuating cycles of violence
Authors: Virginia K. Choi, Joshua C. Jackson, Michele J. Gelfand
Journal: Behavioral and Brain Sciences (2018)

Abstract Whitehouse's theory on fusion can explain why suicide terrorists are willing to make the ultimate sacrifice for their groups, but the following questions on violent extremism remain: (a) Why are victims of suicide terrorism often innocent bystanders? (b) Why do terrorists seem motivated by ancient conflicts? We incorporate findings from the entitativity literature to provide insights into how perceptions of in-groups and out-groups are key processes influencing violent extremism.
E-Cigarettes to Assist with Smoking Cessation
Authors: Belinda Borrelli, George T. O’Connor
Journal: New England Journal of Medicine (2019)

The prevalence of tobacco smoking in the United States has declined to 14.0% but still exceeds 25% among high-risk subgroups.1,2 Electronic cigarettes (e-cigarettes) are not approved by the Food and Drug Administration (FDA) for smoking cessation, but Americans trying to quit smoking use these products more frequently than FDA-approved cessation aids.3 Comparative-effectiveness trials are needed to learn whether smokers have a better chance of quitting with e-cigarettes. Previous trials have had methodologic shortcomings, used first-generation e-cigarettes, or did not assess long-term outcomes. Hajek et al.4 now report in the Journal the results of a multicenter, pragmatic, randomized trial of e-cigarettes, . . .
Home Use of Day-and-Night Hybrid Closed-Loop Insulin Delivery in Very Young Children: A Multicenter, 3-Week, Randomized Trial
Authors: Martin Tauschmann, Janet M. Allen, Katrin Nagl, Maria Fritsch, James Yong, Emily Metcalfe, Dominique Schaeffer, Muriel Fichelle, Ulrike Schierloh, Alena G. Thiele, Daniela Abt, Harald Kojzar, Julia K. Mader, Sonja Slegtenhorst, Nicole Barber, Malgorzata E. Wilinska, Charlotte Boughton, Gianluca Musolino, Judy Sibayan, Nathan Cohen, Craig Kollman, Sabine E. Hofer, Elke Fröhlich-Reiterer, Thomas M. Kapellen, Carlo L. Acerini, Carine de Beaufort, Fiona Campbell, Birgit Rami-Merhar, Roman Hovorka
Journal: Diabetes Care (2019)

OBJECTIVE We aimed to assess the feasibility and safety of hybrid closed-loop insulin delivery in children with type 1 diabetes aged 1–7 years as well as evaluate the role of diluted insulin on glucose control. RESEARCH DESIGN AND METHODS In an open-label, multicenter, multinational, randomized crossover study, 24 children with type 1 diabetes on insulin pump therapy (median age 5 years [interquartile range 3–6] and mean ± SD HbA1c 7.4 ± 0.7% [57 ± 8 mmol/mol] and total insulin 13.2 ± 4.8 units/day) underwent two 21-day periods of unrestricted living and we compared hybrid closed-loop with diluted insulin (U20) and hybrid closed-loop with standard strength insulin (U100) in random order. During both interventions, the Cambridge model predictive control algorithm was used. RESULTS The proportion of time that sensor glucose was in the target range between 3.9 and 10 mmol/L (primary end point) was not different between interventions (mean ± SD 72 ± 8% vs. 70 ± 7% for closed-loop with diluted insulin vs. closed-loop with standard insulin, respectively; P = 0.16). There was no difference in mean glucose levels (8.0 ± 0.8 vs. 8.2 ± 0.6 mmol/L; P = 0.14), glucose variability (SD of sensor glucose 3.1 ± 0.5 vs. 3.2 ± 0.4 mmol/L; P = 0.16), or the proportion of time spent with sensor glucose &amp;lt;3.9 mmol/L (4.5 ± 1.7% vs. 4.7 ± 1.4%; P = 0.47) or &amp;lt;2.8 mmol/L (0.6 ± 0.5% vs. 0.6 ± 0.4%; P &amp;gt; 0.99). Total daily insulin delivery did not differ (17.3 ± 5.6 vs. 18.9 ± 6.9 units/day; P = 0.07). No closed-loop–related severe hypoglycemia or ketoacidosis occurred. CONCLUSIONS Unrestricted home use of day-and-night closed-loop in very young children with type 1 diabetes is feasible and safe. The use of diluted insulin during closed-loop does not provide additional benefits compared with standard strength insulin.
Studies Made by Simulating Systole at Necropsy
Authors: ISAAC STARR, S. I. ASKOVITZ, W. FEDER, A. SCHILD
Journal: Circulation (1955)

"Left ventricular" work can be estimated with great accuracy in cadaver experiments in which both pressure curves and curves of cardiac output at each instant of systole were recorded. Using these accurate estimates as a target, methods have been sought which would permit the estimation of cardiac work from measurements which could be made in the clinic and the accuracy of such methods has been assessed. A method of approximating the left ventricular work has been devised which is so simple that it could be used by any doctor practising medicine.
Abstract A074: Aberrant activation of a gastrointestinal transcriptional circuit in prostate cancer mediates castration resistance
Authors: Shipra Shukla, Joanna Cyrta, Devan Murphy, Edward Walczak, Leili Ran, Praveen Agrawal, Yuanyuan Xie, Yuedan Chen, Shangqian Wang, Yu Zhan, Wai Pung E. Wong, Andrea Sboner, Himisha Beltran, Juan-Miguel Mosquera, Jessica Sher, Zhen Cao, John Wongvipat, Richard P. Koche, Anuradha Gopalan, Deyou Zheng, Mark Rubin, Howard I. Scher, Ping Chi, Yu Chen
Journal: Cancer Research (2018)

Abstract Prostate cancer exhibits a remarkable lineage-specific dependence on androgen signaling. Lineage-directed therapy using androgen deprivation has been the mainstay of prostate cancer treatment for 70 years. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. Our studies found that an aberrant gastrointestinal lineage transcriptome is expressed in ~5% of primary prostate cancer that is characterized by abbreviated response to androgen deprivation therapy and in ~30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal lineage genes, independent of AR signaling. In HNF4G/1A-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the GI transcriptome, chromatin landscape and leads to relative castration resistance. Citation Format: Shipra Shukla, Joanna Cyrta, Devan Murphy, Edward Walczak, Leili Ran, Praveen Agrawal, Yuanyuan Xie, Yuedan Chen, Shangqian Wang, Yu Zhan, Wai Pung E. Wong, Andrea Sboner, Himisha Beltran, Juan-Miguel Mosquera, Jessica Sher, Zhen Cao, John Wongvipat, Richard P. Koche, Anuradha Gopalan, Deyou Zheng, Mark Rubin, Howard I. Scher, Ping Chi, Yu Chen. Aberrant activation of a gastrointestinal transcriptional circuit in prostate cancer mediates castration resistance [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A074.
A Closer Look at Sepsis-Associated Mortality
Authors: Laura Evans
Journal: JAMA Network Open (2019)

Chanu Rhee, MD, MPH; Travis M. Jones, PharmD; Yasir Hamad, MD; Anupam Pande, MD, MPH; Jack Varon, MD; Cara O’Brien, MD; Deverick J. Anderson, MD, MPH; David K. Warren, MD, MPH; Raymund B. Dantes, MD, MPH; Lauren Epstein, MD, MS; Michael Klompas, MD, MPH; for the Centers for Disease Control and Prevention (CDC) Prevention Epicenters Program
Preclinical Characterization of AMG 424, a Novel Humanized T Cell-Recruiting Bispecific Anti-CD3/CD38 Antibody
Authors: Christina de Zafra, Mercedesz Balazs, Flordeliza Fajardo, Lingming Liang, Wendy Zhong, Anja Henn, Matthew J. Bernett, Gregory Moore, Umesh Muchhal, Dwight Winters, Brendon Frank, Kevin Cook, Josh Pearson, Murad Melhem, Vladimir Petrovic, Robert J. Pelham, Matthias Friedrich, Hong Tan, Gordon Moody, Jenitte Stevens, John Desjarlais, Angela Coxon, Olivier Nolan-Stevaux
Journal: Blood (2017)
Safety, efficacy, and pharmacokinetics of intravenous C1 esterase inhibitor (human) prophylaxis in children with hereditary angioedema (HAE)
Authors: Daniel F. Soteres, Emel Aygoren-Pursun, Sandra A. Nieto-Martinez, Jim Christensen, Kraig W. Jacobson, Dumitru Moldovan, Shmuel Kivity, Moshe Vardi, Jovanna Baptista, Inmaculada Martinez-Saguer
Journal: Journal of Allergy and Clinical Immunology (2019)
Activation of central/effector memory T cells in advanced gastric cancer patients treated with antiprogrammed death-1 antibody.
Authors: Hirofumi Ohmura, Kyoko Yamaguchi, Fumiyasu Hanamura, Mamoru Ito, Akitaka Makiyama, Keita Uchino, Hozumi Shimokawa, Taito Esaki, Kenji Mitsugi, Yoshihiro Shibata, Hisanobu Oda, Kenji Tsuchihashi, Hiroshi Ariyama, Hitoshi Kusaba, Koichi Akashi, Eishi Baba
Journal: Journal of Clinical Oncology (2019)

54 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.
Heterogeneous Uptake of 18F-FDG and 68Ga-PSMA-11 in Hepatocellular Carcinoma
Authors: Paola M. Perez, Robert R. Flavell, Robin K. Kelley, Sarah Umetsu, Spencer C. Behr
Journal: Clinical Nuclear Medicine (2019)

We present the case of an 87-year-old man with a history of melanoma metastatic to the lungs found to have an FDG-negative liver lesion that was initially thought to be benign. Follow-up CT revealed growth of the liver lesion despite excellent response to nivolumab therapy of the pulmonary melanoma metastases. Biopsy of the lesion confirmed primary hepatocellular carcinoma. Follow-up F-FDG PET/CT showed minimal FDG uptake, slightly above liver background, and subsequent Ga-PSMA-11 PET/MR showed focal, intense uptake of radiotracer in a different region of the tumor. These imaging findings support intratumor metabolic heterogeneity with radiotracer uptake in different tumor locations.
PD-1/PD-L1 immune check points blockade to attenuate growth of metastatic colon cancer in the CBP/β-catenin inhibited liver.
Authors: Kiminori Kimura, Yosuke Osawa, Koji Nishikawa, Masamichi Kimura, Yutaka Kawakami
Journal: Journal of Clinical Oncology (2019)

556 Background: Immune check points blockade with specific antibodies can accelerate anti-tumor immunity, resulting in a clinical response in patients with various types of cancer. Thus, a wide variety of treatment combinations based on PD-L1/ PD-1 pathway blockage are under development to enhance the therapeutic effect. Here, the effects of the combination treatment of PRI-724, a selective inhibitor of the CBP/β-catenin, with anti-PD-L1 antibody were examined in a mouse model of the liver metastasis of colon cancer. Methods: Mice were inoculated with SL4 colon cancer cells into the spleen to produce metastatic liver tumors. The animals were intraperitoneally injected with or without PRI-724 and/or anti-PD-L1 antibody (10F.9G2) 3 times a week. A part of mice treated with PRI-724 and anti-PD-L1 antibody was administrated with anti-mouse CD4 or CD8 antibody 3 times a week. First, to evaluate anti-tumor effect in those mice, we analyzed liver histology and survival rates after treatment. Next, to examine immune response in the liver, intrahepatic lymphocytes were analyzed by FACS for CD8 memory phenotype, Treg cells, macrophages, and dendritic cells, and the cytokine production from these cells (TNFa, IFNg etc.). Furthermore, inflammatory cytokines and chemokines mRNAs levels and PCR array concerned to Wnt signaling in the liver and serum cytokines levels were also analyzed. Results: The combination of the treatments resulted in regression of tumor growth, whereas monotherapy of each treatment did not show any anti-tumor activity. PRI-724 increased T lymphocytes recruitment, including CD8 + T cells, in the tumor, which may have been induced by inflammatory chemokines and a change of the macrophage property to the cytotoxic phenotype in the liver. Anti-PD-L1 antibody induced CD69 + -activated T lymphocytes in the PRI-724-treated livers of mice inoculated with SL4. Administration of anti-CD8 antibody canceled the anti-tumor effects of the combination treatments of PRI-724 and anti-PD-L1 antibody. Conclusions: Targeting CBP/β-catenin combined with PD-1/PD-L1 immune check points blockade shows potential as a new therapeutic strategy for treating the liver metastasis of colon cancer.
Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin (DA-EPOCH) Is Active and Well-Tolerated in Adults with Newly-Diagnosed Acute Lymphoblastic Leukemia/Lymphoma (ALL): Initial Results of a Phase II Trial
Authors: Ryan D. Cassaday, Lorinda A. Soma, Olga Sala-Torra, Philip A. Stevenson, Mary-Elizabeth M. Percival, Vivian G. Oehler, Andrei R. Shustov, Pamela S. Becker, Anna B. Halpern, Kelsey-Leigh Garcia, Christen N. Heye, Jerald P. Radich, Elihu H. Estey
Journal: Blood (2018)