tbuckley/cabot-search huggingface dataset:
Abstract 190: A Mechanotransduction Study In Embryonic Zebrafish Heart
Authors: Jingchun Yang, Xiaolei Xu
Journal: Circulation Research (2013)

Background: While proper heart contraction requires an intact sarcomere structure, contraction reciprocally regulates sarcomere assembly and cardiomyocyte shape during heart morphogenesis and heart remodeling. However, how contraction modulates heart morphogenesis and the underlying molecular mechanism remains unclear. Here we address this question by manipulating cardiac contractility in a developing zebrafish embryo. Results: Cessation of heart contraction was achieved by treating zebrafish embryos with blebbistatin, a myosin II specific inhibitor, or Niferdipine, a Ca 2+ channel inhibitor. Loss of cardiac contractility reduces ventricular chamber size in 1 dpf embryo, but significantly increases ventricular chamber size in 2 dpf and 3 dpf embryos. In both circumstances, cessation of contraction consistently prevents or disrupts the lateral fusion of myofibril. Cessation of contraction-induced heart enlargement is reversible and also dependent on the time of drug treatment. This heart-remodeling event in 2dpf embryo, which manifests as increased cardiomyocyte surface area accompanied by reduced thickness, can be attenuated by reducing the transmural pressure towards the ventricle wall. This mechanotransductive process occurs in the myocardium without need of endocardium. At the molecular level, by screening several compounds, we found that PI3K signaling confers this contraction-regulated cardiomyocyte shape remodeling process without affecting the lateral fusion of sarcomere. Conclusion: Our data in an in vivo animal model distinguish two different and relatively independent functions of contraction in regulating lateral fusion of sarcomere and cardiomyocytes shape remodeling. The contraction-regulated heart shape remodeling is conveyed by PI3k signaling mediated mechanotransduction independent of endocardium.
A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis
Authors: Josef S Smolen, Stanley B Cohen, Hans-Peter Tony, Morton Scheinberg, Alan Kivitz, Andra Balanescu, Juan Gomez-Reino, Liyi Cen, Peijuan Zhu, Tamas Shisha
Journal: Annals of the Rheumatic Diseases (2017)

Objectives The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment. Methods In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid. The primary endpoint was the area under the serum concentration–time curve from study drug infusion to infinity (AUC 0-inf ). Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24. Results The 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208). Three-way PD equivalence of B cell depletion was also demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX. Conclusions Three-way PK/PD equivalence of GP2013, RTX-EU and RTX-US was demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX. Trial registration number NCT01274182; Results.
The Promise of Precision Oncology
Authors: Abigail Sindzinski
Journal: JNCI Journal of the National Cancer Institute (2017)

How effective has precision oncology been, and where does it need to go?President Barack Obama dedicated $215 million to the field with his Precision Medicine Initiative, and the Cancer Moonshot Initiative is set to put billions into the area.Many institutions have introduced precision programs.Precision oncology uses genetic information from DNA and other sequencing to identify driver mutations that lead to cancers.Researchers then produce targeted therapies and treatments, which they hope will yield better results for patients.Large-scale trials such as NCI-MATCH, which seeks to sequence the tumors of 6,000 patients and group by molecular profile, have arisen to assess and advance treatments.
Phase IB study of pembrolizumab in combination with chemoradiotherapy (CRT) for locally-advanced squamous cell carcinoma of the head and neck (LA-SCCHN).
Authors: Steven Francis Powell, Mark Mutuota Gitau, William Charles Spanos, Ashley Wayne Jensen, Ryan Kenneth Nowak, Michele Lohr, Susan E Puumala, Christie Ellison, Lora Jane Black, Jonathan D. Cheng, Assuntina Gesualda Sacco, Ezra E.W. Cohen, John H. Lee
Journal: Journal of Clinical Oncology (2016)

TPS6107 Background: The host immune response is critical for the clearance of SCCHN during CRT. Recent translational research has demonstrated that the programmed death receptor 1 (PD-1) and its ligand (PD-L1, PD-L2) interaction may play a role in immune escape of SCCHN during CRT. Pembrolizumab is a humanized IgG4 monoclonal antibody that blocks this interaction and may restore T-cell activity in this setting. PD-1 inhibition in combination with cisplatin-based CRT suggests synergy in a pre-clinical SCCHN mouse model. Clinical data on the safety and efficacy of this approach is needed to determine the potential of this therapy for the definitive management of LA-SCCHN. Methods: This is a single-arm, multi-site, open-label trial of pembrolizumab used in combination with cisplatin-based, definitive CRT in patients with stage III-IVB SCCHN. 39 patients will be enrolled with safety and efficacy as the co-primary endpoints. Treatment consists of a loading dose of pembrolizumab 200 mg IV given 7 days prior to initiation of CRT and continued every 3 weeks during CRT and following completion of CRT for a total of 8 doses. CRT will consist of cisplatin 40 mg/m2 IV weekly x 6 doses given concurrently with radiation fractionated at 2 Gy once daily for 35 fractions (total 70 Gy). Efficacy will be measured by the complete response (CR) rate on treatment end imaging (100 days post-completion of CRT) or pathologic CR for those who undergo salvage surgery. Safety will be assessed by NCI-CTCAE v4.0 criteria. Secondary endpoints include best overall response rate (ORR), progression-free survival (PFS), overall survival (OS), locoregional control (LRC), and distant metastasis (DM) rate at 1- and 2- years. Patient reported outcomes (PRO) will be measured using the FACT H&N v4.0 survey. Correlative research will include analysis of circulating immunocyte populations during therapy and evaluation of tumor PD-L1 expression at baseline and in participants who have salvage surgery. The study is currently open with 6 of 39 participants enrolled. Clinical trial information: NCT02586207.
Anti-Tumor Activities of XBP1 Antigen-Specific Cytotoxic T Lymphocytes Are Enhanced By HDAC6 Inhibitor ACY241
Authors: Jooeun Bae, Matthew Ho, Brandon Nguyen, Arghya Ray, Dharminder Chauhan, Teru Hideshima, Nikhil Munshi, Kenneth C Anderson
Journal: Blood (2016)
Randomized phase II/III trial of active immunotherapy with OPT-822/OPT-821 in patients with metastatic breast cancer.
Authors: Chiun-Sheng Huang, Alice L Yu, Ling-Ming Tseng, Louis W. C. Chow, Ming-Feng Hou, Sara A. Hurvitz, Richard B. Schwab, Chi-Huey Wong, James L. Murray, Hsien-Kun Chang, Hong-Tai Chang, Shin-Cheh Chen, Sung-Bae Kim, Youe-Kong Shue, Hope S. Rugo
Journal: Journal of Clinical Oncology (2016)

1003 Background: Globo H is a glycolipid that is highly expressed in breast cancer (BC). Active immunotherapy with OPT-822, a Globo H–KLH conjugate, and the adjuvant OPT-821 in 2 phase (Ph) I trials, induced Globo H specific antibodies which could mediate in vitro binding and cytotoxicity to Globo H expressing BC cells. Methods: In this international, randomized, double-blind, placebo-controlled Ph II/III trial (NCT01516307), patients (pts) with metastatic BC who had ≤ 2 events of progressive disease (PD) and who achieved at least stable disease (SD) after ≥ 1 anticancer regimen were randomized 2:1 to receive subcutaneous OPT-822 (30 μg Globo H)/OPT-821 (100 μg) or control (PBS) on weeks 1, 2, 3, 5, 9, 13, 17, 25, and 37 or until PD, in combination with low-dose cyclophosphamide (300 mg/m2). Hormone therapy was allowed. The primary and secondary efficacy end points were progression-free survival (PFS) and overall survival (OS), correlated with humoral antibody response. Results: 349 pts were randomized, 348 received study drug (ITT), 168 (48%) received all 9 injections. 70% had hormone receptor positive BC, 13% were triple negative, and 62% received hormone therapy. No difference was observed in PFS (HR, 0.96 [95% CI, 0.74-1.25] P = .77) or in interim OS (HR, 0.79 [95% CI, 0.51-1.22] P = .29). However, PFS and OS were significantly improved in the 50% of pts who developed a Globo H specific IgG response to OPT-822/OPT-821 with a titer ≥ 1:160 at any time during treatment vs control (HR, 0.71 [95% CI, 0.52-0.97] P = .029 for PFS; HR, 0.57 [95% CI, 0.33-0.97] P = .04 for OS) and vs nonresponders (HR, 0.52 [95% CI, 0.37-0.71] P < .0001 for PFS; HR, 0.52 [95% CI, 0.29-0.92] P = .025 for OS), adjusted for baseline disease status/hormone use. In a time-dependent Cox model, PFS was improved in pts who received all 9 injections of OPT vs control (HR, 0.66 [95% CI, 0.42-1.01] P= .057). OPT-822/OPT-821 was well tolerated; the most common drug-related adverse event was grade 1/2 injection reaction. Conclusion: Vaccination with OPT-822/OPT-821 did not improve PFS in the ITT; however, PFS and interim OS were significantly improved in pts who developed an immune response to the vaccine. These subgroup data will be used to design a definitive Ph III trial. Clinical trial information: NCT01516307.
The plasticity region locus JHP947 is a pathogenicity marker found in Helicobacter pylori-associated gastric intestinal metaplasia
Authors: A Nami, P Dowling, M O'Sullivan, H O'Connor, C O'Morain
Journal: Endoscopy (2005)

Helicobacter pylori (H. pylori) and Intestinal Metaplasia (IM) are each associated with an increased risk of gastric cancer. The H. pylori genome contains genes that are located in a zone called the “plasticity region “ (45 kb in strain J99 and 68 kb in strain 26695). This region is highly variable. We evaluated the status of certain loci (JHP940, JHP947 and HP986) as well as H. pylori virulence genes (cagA, and vacA) by polymerase chain reaction (PCR). A total of 40 gastric biopsies (antrum & corpus) were obtained. Eighteen samples from 12 patients were classified according to disease group as gastritis (G) and 22 samples from 19 patients as intestinal metaplasia based on histopathology findings. The results demonstrated that the jhp947 locus was completely linked with the presence of the cag pathogenicity island and was also significantly associated with the percancerous lesion IM when compared with gastritis. There is no association between jhp940 or HP986 and IM. Therefore, the jhp947 locus may be considered as a new H. pylori marker for disease outcome independent of the virulence genes.
Association of circulating inflammatory biomarkers and dietary inflammation potential with postmenopausal breast cancer prognosis.
Authors: Isabell Ge, Anja Rudolph, Theron Johnson, Stefanie Jaskulski, Nitin Shivappa, James R. Hébert, Rudolf Kaaks, Dieter Flesch-Janys, Kathrin Thoene, Jenny Chang-Claude
Journal: Journal of Clinical Oncology (2016)

1566 Background: Accumulating evidence implicates inflammation and diet in cancer. Our aim was to investigate the associations between levels of 16 circulating biomarkers,dietary inflammation index (DII) scores and breast cancer prognosis. Methods: The study was conducted in 2193 postmenopausal breast cancer patients of the MARIEplus, a prospective case-cohort. C-reactive protein (CRP), interleukin(IL-)1β, -2, -4, -5, -6, -8, -10, tumor necrosis factor-alpha (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF), serum amyloid A (SAA), intercellular and vascular adhesion molecule 1 (ICAM-1, VCAM-1), vascular endothelial growth factor (VEGF), resistin and adiponectin were measured in blood samples collected shortly after diagnosis (baseline). Developed to measure the inflammatory potential of individuals’ diets, the DII scores were derived from food frequency questionnaire data at baseline. Hazard ratios (HR) were estimated using Cox regression for overall (OS) and recurrence-free survival (RFS). Chi-square tests were used to assess the relationship between biomarkers and the DII. Results: Patients were followed for a median of 6.1 years. In multivariable analyses adjusted for established prognostic factors, significant associations with poor OS were observed for CRP ( ≥ 5 vs < 5 mg/l, HR: 1.56 (1.13-2.14); continuous: p-cont = 0.01), IL-4 ( ≥ 5 vs. < 5 pg/dl: HR: 1.79 (1.21-2.65); p-cont = 0.001), IL-6 ( ≥ 10 vs. < 10 pg/ml, HR: 1.77 (1.16-2.69); p-cont = 0.03), IL-1β (p-cont = 0.0002) and TNF-α (p-cont = 0.035). Poor RFS was associated with CRP ( ≥ 5 vs. < 5mg/l, HR: 2.57 (1.48-4.45), p-cont = 0.046), SAA ( ≥ 5 vs. < 5µg/ml: HR: 2.02 (1.21-3.39); p-cont = 0.038), IL-2 (p-cont = 0.04) and adiponectin (highest tertile vs. lowest, HR: 1.88 (1.03-3.43); p-cont = 0.08). The DII was not significantly associated with OS or RFS in multivariable analyses, but showed associations with tumor size, IL-4, -6, -8, -10, TNF-a, GM-CSF, and resistin (p < 0.0001 to 0.04). Conclusions: Although the DII may reflect dietary inflammation potential, our results suggest that circulating inflammatory biomarkers are independent and more promising predictors of breast cancer prognosis.
MRX34, a liposomal miR-34 mimic, in patients with advanced solid tumors: Final dose-escalation results from a first-in-human phase I trial of microRNA therapy.
Authors: David S. Hong, Yoon-Koo Kang, Andrew Jacob Brenner, Jasgit C. Sachdev, Samuel Ejadi, Mitesh J. Borad, Tae-You Kim, Ho Yeong Lim, Keunchil Park, Carlos Becerra, Andreas G. Bader, Jay Stoudemire, Susan Smith, Sinil Kim, Muhammad Shaalan Beg
Journal: Journal of Clinical Oncology (2016)

2508 Background: Each miRNA modulates expression of hundreds of genes across distinct cellular pathways, giving miRNA-based therapy potential to simultaneously repress multiple oncogenic processes in the tumor microenvironment, including growth and proliferation, resistance, cancer stem cells, metastasis, and immune evasion. The tumor suppressor miR-34a down-regulates expression of >30 oncogenes (eg, MET, MEK1, PDGFR-α, CDK4/6, BCL2, WNT 1/3, NOTCH1, CD44), as well as genes involved in tumor immune evasion (eg, PD-L1, DGKζ). MRX34, a liposomal miR-34a mimic, is a potential first-in-class miRNA therapy for cancer. Methods: Pts with advanced solid tumors (N=99) were enrolled in a standard 3+3 dose escalation trial of MRX34 infused IV on a biweekly (BIW) or daily x 5 (QDx5) schedule. The primary objective was MTD and recommended phase II dose (RP2D); secondary objectives were safety, PK, and biological and clinical activity. Results: Pts with HCC (42), RCC (2), acral melanoma (2), and other tumor types (53) were enrolled. Most were Caucasian (58%) and male (65%), with median age 60 y and 4 median prior therapies (range, 1–12). Most common AEs (% all/grade 3/4) were fever (64/2/0), chills (54/0/0), fatigue (49/4/0), back pain (44/8/0), nausea (40/2/0), vomiting (25/2/0), anorexia (25/2/0), and headache (25/0/0). Lab abnormalities (% grade 3/4) included lymphocytopenia (37/18), thrombocytopenia (22/2), elevated AST (21/3), neutropenia (19/9), and hyponatremia (18/3). Required steroid premedication reduced infusion-related AEs, and the QDx5 schedule improved safety and PK, with AUC increased ~10-fold on day 5 vs 1. The QDx5 MTD/RP2D was 70 mg/m2 for HCC and 93 mg/m2for non-HCC solid tumors. Analysis of RNA from WBCs showed dose-dependent repression of miR-34a target oncogenes, including FOXP1, BCL2, HDAC1, and CTNNB1. Three pts (HCC, RCC, acral melanoma) achieved prolonged confirmed PR per RECIST and 14 pts had SD (median duration, 136 days; range, 79–386). Conclusions: MRX34 has a manageable toxicity profile and evidence of activity in HCC, RCC and melanoma. Enrollment into phase Ia expansion cohorts continues, and phase II studies are being planned. Clinical trial information: NCT01829971.
Multimedia: Blood and Bone
Authors: Sandra Goldbeck-Wood
Journal: BMJ (1999)

Eds Angela Belli, Jack Coulehan


University of Iowa Press, £16.95, pp 224 




ISBN 0 87745 638 0

———————

Rating: ★★

Why do some doctors write poems? In Poems Before and After Miroslav Holub wrote that a poem arises when there’s nothing else to be done, as a last attempt at order when one can’t stand disorder any longer: “Although poets are most needed when freedom, vitamin C, communications, laws and hypertension therapy are also most needed, a poem is not one of the last but one of the first things of man.” As a world class poet, immunologist, and citizen of the Czech Republic, Holub is uniquely qualified to comment.

At worst, doctors’ poetry is a benign form of self medication, a valve for those who feel creatively underchallenged by the humdrum routine of clinical practice or an alternative to sex, spirits, shrinks, or suicide when the pressure of containing other people’s unmet needs as well as one’s own becomes too much. At best, it is much more.

It is this sense of doctors meeting their own need for resolution that most marks the anthology Blood and Bone. A collection of poems written by predominantly American physicians and culled from medical journals and literary magazines, the book is above all about what doctoring means to doctors.

Some of the poems shine, like those of Dannie Abse and Rafael Campo. Clear, tight, and crafted, they encapsulate without pathos, melodrama, or self importance moments that speak to people beyond the narrow medical world they inhabit. They use the restricted code we speak not to show off, but playfully and inclusively. These are “human to human” poems, and medicine features only as another sieve through which human consciousness can be filtered.

Others are doctor to doctor poems, self referential, exclusive, and cosy, using words like spinal tap and trochar in a way that is neither explanatory nor metaphorical. Some seem simply to “let it all hang out,” a far cry from the rigour of Carlos Williams and Holub, in whose hands words are a surgical instrument—sparing, assiduous, neat, incisive, and to be used only when all other options have been explored.

But as a collection of imaginative reflections on doctoring, this book will interest doctors in a way it may not move those interested only in the quality of each individual poem. Clinical situations will resonate, and the more exclusive language will not so readily alienate. Some of the therapeutic effects might even rub off on us. Provided, as Holub says, “a poem, which is the poet’s modest attempt to put off disintegration for a while, is not regarded as the philosopher’s stone, bringing salvation and deliverance to stupefied mankind.”
Acute effects of lipase inhibition onthe glycaemic and cardiovascular responses to a high fat meal in type 2 diabetes
Authors: D O'Donovan, D Zou, D Gentilcore, C Feinle, M Horowitz, KL Jones
Journal: Endoscopy (2005)

Aims: To examine the effects of lipase inhibition with orlistat, on gastric emptying of, and the glycaemic and cardiovascular responses to, a high fat/carbohydrate meal in patients with type 2 diabetes.
Use of peripheral blood genomic markers whose expression levels reflect that of breast tumor genomic markers to predict drug treatment and sensitivity
Authors: S. Lee, X. Xu, P. Tan, J. Lee, P. Iau, N. Sukri, S. Tan, S. Lim, B. Chuah, B. Goh
Journal: Journal of Clinical Oncology (2009)

3588 Background: Tumor gene expression signatures have been used to predict drug response, and we have previously reported drug-induced signatures to be more informative than the untreated baseline signatures. However, repeated tumor sampling during treatment is not feasible for most patients. We studied peripheral mononuclear cell (PBMC) gene expression levels in association with tumor gene expression levels in an attempt to identify peripheral blood markers that may serve as more accessible surrogates to predict drug treatment and response. Methods: Chemonaive breast cancer patients were treated with an alternating sequential regimen of doxorubicin and docetaxel and randomized to start with either drug. RNA from primary tumor before and 3 weeks, and from PBMC before and 24 hours after the first cycle of each drug was hybridized on the Affymetrix HG-U133+2 array containing 54,675 probe sets. Results: Pre- and post-treatment tumors from 47 patients were studied, including 35 with paired PBMC samples. 230 pre- and 85 posttreatment PBMC probe sets showed strong correlation in expression level (Pearson correlation coefficient &gt;0.9) with the corresponding pre- and posttreatment tumor probe set, and included genes involved in transcription regulation and binding. Of the 975 tumor probe sets whose changes distinguished doxorubicin from docetaxel treatment, 12 corresponding PBMC probe sets were identified (p &lt; 0.001) whose changes at 24 hours distinguished the two treatments with 77% accuracy. Of the 1,081 and 1,526 tumor probe sets whose changes predicted treatment response to doxorubicin and docetaxel, 19 and 15 informative PBMC probe sets predicted response to each drug with 100% and 80% accuracy, and included TNF receptor associated protein 1 and trefoil factor 1 for doxorubicin-, and folliculin and dynein for docetaxel-response. When the PBMC probe sets were validated in an independent test set treated with docetaxel (n = 23), 87% was correctly classified as docetaxel-treated, while 89% of non-responders clustered together. Conclusions: Peripheral blood contains genomic markers whose expression levels closely reflect that of breast tumor markers, and may be promising as surrogates to predict drug treatment and sensitivity. No significant financial relationships to disclose.