tbuckley/cabot-search huggingface dataset:
Proton pump inhibitors alter the composition of the gut microbiota
Authors: Matthew A Jackson, Julia K Goodrich, Maria-Emanuela Maxan, Daniel E Freedberg, Julian A Abrams, Angela C Poole, Jessica L Sutter, Daphne Welter, Ruth E Ley, Jordana T Bell, Tim D Spector, Claire J Steves
Journal: Gut (2015)

<h3>Objective</h3> Proton pump inhibitors (PPIs) are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted, and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. Small studies have identified possible associations between PPI use and GI microbiota, but this has yet to be carried out on a large population-based cohort. <h3>Design</h3> We investigated the association between PPI usage and the gut microbiome using 16S ribosomal RNA amplification from faecal samples of 1827 healthy twins, replicating results within unpublished data from an interventional study. <h3>Results</h3> We identified a significantly lower abundance in gut commensals and lower microbial diversity in PPI users, with an associated significant increase in the abundance of oral and upper GI tract commensals. In particular, significant increases were observed in Streptococcaceae. These associations were replicated in an independent interventional study and in a paired analysis between 70 monozygotic twin pairs who were discordant for PPI use. We propose that the observed changes result from the removal of the low pH barrier between upper GI tract bacteria and the lower gut. <h3>Conclusions</h3> Our findings describe a significant impact of PPIs on the gut microbiome and should caution over-use of PPIs, and warrant further investigation into the mechanisms and their clinical consequences.
Continued high activity of figitumumab (CP-751,871) combination therapy in squamous lung cancer
Authors: D. D. Karp, S. Novello, F. Cardenal, P. Haluska, L. J. Blakely, L. Garland, L. G. Paz-Ares, M. P. Dolled-Filhart, E. D. Johnson, A. Gualberto
Journal: Journal of Clinical Oncology (2009)

8072 Background: Figitumumab (CP-751,871) is a fully human, IgG 2 monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR). We reported in a randomized phase II study (ASCO 2008), preliminary evidence of high activity of the combination of paclitaxel (T), carboplatin (C) and figitumumab (F) in advanced treatment-naïve NSCLC of squamous cell histology (n=11 pts). A single arm trial extension cohort was conducted to confirm those findings. Methods: Fifty-six pts with non-adenocarcinoma NSCLC were enrolled. Pts received T (200 mg/m2), C (AUC of 6) and F (20 mg/kg) q3weeks for up to 6 cycles; pts with response (PR) or stable disease were eligible to continue F as single agent until disease progression. Statistical hypotheses were 30% (null) versus 50% (response of interest). Protein expression of the IGF-IR in core tumor biopsies was quantified using automated quantitative analysis (AQUA) technology. Results: Pts were 72% male, 28% &gt;70 years old and 91% stage IV. Median number of treatment cycles was 4, with 46% of pts receiving single agent F beyond cycle 4. TCF was well tolerated. The most common all-causality grade 3, 4 CTCAE adverse events were neutropenia (21%), hyperglycemia (14%) and fatigue (14%). Hyperglycemia adverse events almost always occurred within the first treatment cycle and were manageable with standard measures. Responses in squamous pts are currently 25 out of 40 pts according to RECIST, with final response assessment still pending for 7 additional pts (≥53%, p&lt;0.001). One complete response and 7 striking PRs (50–80% tumor size reduction at cycle 2) were observed. Tumor size reductions with F maintenance treatment were also seen in 2 pts. Median progression free survival has not been yet reached at 4 months follow up. A trend (p=0.1) for higher IGF-IR expression in patients responding to TCF was observed in a small data set (n=12). Median tumor IGF-IR expression in pts responding to TCF therapy and non-responders were respectively 6287 and 4131 AQUA scores. Analysis of IGF-IR and other members of the IGF-IR pathway continues. Conclusions: These data further support the activity of figitumumab combination therapy in pts with squamous NSCLC. [Table: see text]
Intensive versus standard platinum therapy for the treatment of children with hepatoblastoma (HB): A report of the Intergroup Hepatoblastoma Study P9645
Authors: M. H. Malogolowkin, H. Katzenstein, M. Krailo, L. Bowman, M. Reynolds, M. Finegold, B. Greffe, J. Rowland, K. Newman, R. Castleberry
Journal: Journal of Clinical Oncology (2004)

8516 Background: The use of systemic chemotherapy has improved the survival of patients with HB by increasing tumor resectability, decreasing the development of metastasis, and reducing the incidence of local recurrence. The INT-0098 Intergroup Liver Tumor Study demonstrated no statistically significant differences in event-free or overall survival between patients randomized to treatment with either cisplatin+5-FU+vincristine (C5V) or cisplatin+doxorubicin. Results from this and other therapeutic trials suggested that cisplatin is the most active agent against HB. In order to increase the platinum dose intensity, a novel regimen was developed alternating carboplatin and cisplatin (CC) every 2 weeks. The P9645 study was designed to compare the event free survival rate for patients with Stage III/IV HB randomized to either C5V or CC. Methods: C5V was given as previously described and CC consisted of Carbo 700 mg/m2 on day 0 (560 mg/m2 after 2 cycles) followed by CDDP 100 mg/m2 on day 14. G-CSF was used after each CC cycle. All patients received 4–6 cycles of chemotherapy. Results: A total of 56 eligible patients were randomized to receive CC and 56 were randomized to receive C5V at the time the randomization was halted. To date, 109 eligible patients have been assigned to receive C5V. Results: The 1-year event-free survival was 37% for CC patients and 57% for C5V, p=0.013. There were no differences in the toxicities noted with each regimen. This randomization was discontinued early because of the increased risk of event associated with CC therapy. Conclusions: Intensification of platinum agents as used in this study resulted in a worsening of the survival for children with unresectable or metastatic HB. No significant financial relationships to disclose.
Marrow Matters: A computer program designed to compute the percentage of bone marrow irradiated with external beam radiation therapy
Authors: K. E. Hertzfeld, N. Kumar, W. Barrett
Journal: Journal of Clinical Oncology (2008)

22137 Background: Therapeutic external beam radiation therapy affects normal bone marrow and can have implications regarding the safety of administering chemotherapy or radionuclide therapy. The amount of bone marrow irradiated can correlate with a decrease in the patient's blood counts and risk of infection, bleeding, and/or anemia. We set forward to develop a computer program to estimate the percentage of bone marrow irradiated. Methods: Whole body digitally reconstructed radiographs from the AP, PA, and lateral viewpoints have been integrated into the software. Individual matrices were then created which are based off of the standard, adopted, active marrow distribution data for a forty-year old adult. The matrices were then laid over the DRRs to create three scale models of the human skeleton containing the appropriate distribution of active bone marrow throughout the bony skeleton. Results: The program allows the user to outline a radiation treatment field on the AP, PA, or lateral DRR. The percentage of bone marrow irradiated will then be expressed numerically. This also allows the user to summate the bone marrow volume irradiated from multiple treatment fields. Conclusions: Marrow Matters is an effective and simple computer program that allows the user to adequately and quickly estimate the percentage of bone marrow irradiated thus enabling the clinician to evaluate the safety of administering additional therapy. This program does not take into account the variability in active bone marrow distribution in children, or the impact of previous myeloablative chemotherapy. No significant financial relationships to disclose.
PET/CT and Occult Primary Tumors
Authors: Donald A. Podoloff
Journal: Journal of the National Comprehensive Cancer Network (2009)

Within the past 5 years, F-18 fluorodeoxyglucose (FDG) PET/CT has become one of the more frequent imaging modalities in the management of patients with cancer of unknown primary origin. FDG PET/CT detects more sites of metastasis than other modalities, and in 20% to 40% of cases it discloses the site of the primary tumor. Its exact role is yet to be defined because of a lack of prospective clinical trials comparing the performance of PET/CT with conventional anatomic imaging modalities. This article reviews the available literature, attempts to place PET/CT using F-18–labeled FDG in clinical perspective and compares the combined modality with conventional anatomic imaging technologies.
Abstract 15197: Renal Resistive Index Predicts Cardiovascular and Renal Outcomes in Essential Hypertension
Authors: Yoshio Iwashima, Yohei Doi, Fumiki Yoshihara, Kei Kamide, Shin-ichirou Hayashi, Satoko Nakamura, Takeshi Horio, Yuhei Kawano
Journal: Circulation (2012)

Background-Increased renal restive index (RI) measured using Doppler ultrasonography has been shown to correlate with the degree of renal impairment in hypertensive patients; however, the prognosti...
Abstract 15404: Relation Between EPC and Atherosclerosis in Severe Obesity: the Detrimental Modulating Effect of Diabetes
Authors: Francesca Graziani, Pio Cialdella, Eloisa Basile, Antonio M Leone, Roberta Della Bona, Giovanna Liuzzo, Geltrude Mingrone, Giuseppe Nanni, Luigi M biasucci, Filippo Crea
Journal: Circulation (2011)

Purpose: Endothelial Progenitor Cells (EPCs) contribute to angiogenesis and tissue repair and their circulating levels are inversely correlated with vascular function. Adipose tissue represents a s...
Treatment of Localized Primary Non-Hodgkin's Lymphoma of Bone in Children: A Pediatric Oncology Group Study
Authors: Kaveri Suryanarayan, Jonathan J. Shuster, Sarah S. Donaldson, Robert E. Hutchison, Sharon B. Murphy, Michael P. Link
Journal: Journal of Clinical Oncology (1999)

PURPOSE: The treatment of primary lymphoma of bone (PLB) in children has traditionally included radiotherapy to the primary site; more recently, it has included systemic chemotherapy. Because of concern about the untoward effects of treatment in a disease that is curable, we attempted to determine whether radiotherapy can be safely excluded from treatment. PATIENTS AND METHODS: The results of three consecutive Pediatric Oncology Group (POG) studies were examined to determine the impact on outcome of radiotherapy as adjunctive treatment in children and adolescents receiving chemotherapy for early-stage primary lymphoma of bone. RESULTS: From 1983 to 1997, 31 patients with localized PLB were entered onto POG studies of early-stage non-Hodgkin's lymphoma (NHL). Between 1983 and 1986, seven patients were treated with 8 months of chemotherapy with irradiation (XRT) of the primary site. After 1986, patients were treated without XRT; four received 8 months of chemotherapy, and 20 received 9 weeks of chemotherapy. Primary sites were the femur (nine), tibia (eight), mandible (five), mastoid (one), maxilla (one), zygomatic arch (one), rib (one), clavicle (one), scapula (one), ulna (one), talus (one), and calcaneous (one). Histologic classification revealed 21 cases of large-cell lymphoma, five cases of lymphoblastic lymphoma, two cases of small, noncleaved-cell lymphoma, and three cases of NHL that could not be classified further. One patient relapsed at a distant site 22 months after completion of therapy. There have been no deaths. CONCLUSION: Localized PLB is curable in most children and adolescents with a 9-week chemotherapy regimen of modest intensity, and radiotherapy is an unnecessary adjunct.
Impact of the mode of estrogen receptor determination on breast cancer prognosis
Authors: P. Martin, C. Mazouni, F. André, P. Bonnier
Journal: Journal of Clinical Oncology (2009)

e11609 Background: Impact of the mode of estrogen receptor determination on breast cancer prognosis Abstract Background: We examined if the mode of estrogen receptor (ER) determination and expression in primary breast cancer impact on patient's prognosis. Methods: We conducted an analysis on a prospective cohort of 1012 patients treated for stage I-III Breast Cancer at Conception Hospital, Marseille, France between 1984 to 2003. ER was determined according to enzyme immuno-assay (EIA) and immunohistochemistry (IHC). Disease-free and overall survivals were evaluated according to the mode of ER quantification and in function of qualitative or quantitative ER expression. Results: ER was a strong predictor of overall survival in the whole population whatever method used for the status determination (p&lt;0.001); however when stratifying the analysis on ER quantitative expression, ER was still a prognostic indicator in the EIA group for OS (p= 0.004) and DFS (p&lt;0.001), group but not in the IHC group for OS (p=0.58) and DFS (p= 0.195). Conclusions: ER determination in breast cancer is strongly associated with a better prognosis, but the level of influence of ER varies with the assay and ER expression. No significant financial relationships to disclose.
Abstract P3-11-07: Changes in PgR and Ki-67 in residual tumour and outcome of breast cancer patients treated with neoadjuvant chemotherapy
Authors: Emilia Montagna, Vincenzo Bagnardi, Giuseppe Viale, Nicole Rotmensz, Andrea Sporchia, Giuseppe Cancello, Alessandra Balduzzi, Viviana Galimberti, Paolo Veronesi, Alberto Luini, Mauro G Mastropasqua, Chiara Casadio, Claudia Sangalli, Aron Goldhirsch, Marco Colleoni
Journal: Cancer Research (2015)

Abstract PURPOSE We assessed the frequency of the change in biological features between the diagnostic biopsy and final surgery in breast cancer patients with residual disease after neoadjuvant chemotherapy. We also valued the impact of change on outcome in terms of disease free survival (DFS) and overall survival (OS) PATIENTS AND METHODS We collected information through the institutional clinical database on all consecutive breast cancer patients treated with neoadjuvant chemotherapy at the European Institute of Oncology (EIO), Milan, Italy, between 1999 and 2011. We selected patients who did not achieved pathological complete response (pCR) at final surgery. All patients had pathological evaluation, including ER, PgR, HER2 protein and ki-67 expression performed at EIO both at diagnostic core biopsy and final surgery. RESULTS We identified a total of 904 patients. The 5% of patients with ER positive at diagnostic biopsy had ER negative residual tumor at final surgery. For PgR expression, 67% of patients, whose tumors had a PgR&amp;gt; 20% at diagnostic biopsy had a PgR&amp;lt;20% at final surgery. The ki-67 expression changes from &amp;gt;20% to &amp;lt;20% in 40% of patients. At the multivariate analysis the decrease of PgR -immunoreactive cells correlated with improved outcome in terms of DFS (HR 0.73; CI 0.54-1.00 p 0.046). In addition, the decrease of ki-67 expression to &amp;lt; 20% of the cells at final surgery was found to be associated with better outcome both in terms of DFS (HR 0.52; CI 0.40-0.68 p &amp;lt;0.0001) and OS (0.45 CI 0.32-0.64 p&amp;lt;0.0001) CONCLUSION The decrease of PgR and Ki-67 expression after preoperative chemotherapy have a prognostic role in breast cancer patients with residual disease and should be considered in the adjuvant therapeutic algorithm. Citation Format: Emilia Montagna, Vincenzo Bagnardi, Giuseppe Viale, Nicole Rotmensz, Andrea Sporchia, Giuseppe Cancello, Alessandra Balduzzi, Viviana Galimberti, Paolo Veronesi, Alberto Luini, Mauro G Mastropasqua, Chiara Casadio, Claudia Sangalli, Aron Goldhirsch, Marco Colleoni. Changes in PgR and Ki-67 in residual tumour and outcome of breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-07.
Cilengitide in newly diagnosed glioblastoma with <i>MGMT</i> promoter methylation: Protocol of a multicenter, randomized, open-label, controlled phase III trial (CENTRIC).
Authors: R. Stupp, M. J. Van Den Bent, S. C. Erridge, D. A. Reardon, Y. Hong, H. Wheeler, M. Hegi, J. R. Perry, M. Picard, M. Weller
Journal: Journal of Clinical Oncology (2010)

TPS152 Background: Infiltration and migration is characteristic of glioblastoma. Cilengitide, a novel selective αvβ3/5 integrin inhibitor, interferes with tumor cell attachment, tumor-stroma crosstalk and angiogenesis. Activity appears most pronounced when cilengitide is combined with an active cytotoxic agent or radiotherapy (RT), and particular sensitivity to temozolomide (TMZ) has been shown in tumors with a methylated MGMT promoter. Methods: CENTRIC is an international, randomized, controlled phase III study of cilengitide 2000 mg twice weekly i.v. in addition to standard TMZ/RT→MZ compared to standard TMZ/RT→TMZ (Stupp et al. NEJM 2005). For nonprogressive patients, maintenance cilengitide is continued for up to 18 months. This trial is organized in a collaborative effort by Merck KGaA (Germany), the European Organization for Research and Treatment (EORTC) and the Canadian Brain Tumor Consortium (CBTC). Overall survival time is the primary endpoint. Secondary objectives include progression-free survival time, safety, and quality of life. Eligibility criteria include histologically confirmed, newly diagnosed glioblastoma with a methylated MGMT promoter, age ≥ 18 year, performance status of 0-1, and prior tumor resection or open biopsy. Recruitment and randomization is a 2-step process: after informed consent, MGMT is centrally determined and only patients with a methylated MGMT promoter will be randomized. Aiming for a hazard ratio of 0.71 with 80% power and a 2-sided p-value of 0.05, randomization of 504 patients is estimated. Accrual is ongoing in more than 150 medical centers worldwide. Start of therapy within 5 weeks from surgery requires rapid turnaround with registration, central pathology review and MGMT testing, and has been shown to be feasible even in a complex multicenter setting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA Merck KGaA, Merck Serono, OncoMethylome Sciences, Roche, Schering-Plough Pfizer Merck KGaA, Merck Serono, Schering Plough Merck KGaA, Merck Serono, Schering-Plough
Abstract P212: Reduced High-Density Lipoprotein Efflux in Psoriasis Relates to Increased Coronary Plaque Burden by Quantitative CT Angiography
Authors: Taufiq Salahuddin, Balaji Natarajan, Mariana Selwaness, Ahmed Sadek, Martin Playford, Julia Doveikis, David Bluemke, Nehal N Mehta
Journal: Circulation (2015)

INTRODUCTION: Psoriasis is known to increase cardiovascular risk, possibly due to the presence of inflammatory, lipid-rich, non-calcified plaques in the coronary arteries. Psoriasis is also known to decrease HDL activity. However, whether having abnormal or low-functioning HDL increases arterial disease is currently unknown.

HYPOTHESIS: We aimed to test our hypothesis that coronary plaque burden assessed by quantitative CT angiography is related to HDL efflux capacity and other cardiometabolic parameters in a well-phenotyped psoriasis cohort (NCT# 01778569).

METHODS: Psoriasis patients (N=67) underwent coronary CT angiography (Toshiba 320 slice). Coronary plaque was assessed using QAngio CT (Medis, The Netherlands). Total (TB), dense calcium (DCB), and non-calcified burden (NCB) plaque indices were calculated by dividing total vessel plaque volume by total vessel length. We also performed deep phenotyping for lipid markers including HDL efflux capacity and other cardiometabolic parameters.

RESULTS: The study population was middle aged (52.2 ± 12.4 yr), had relatively low Framingham Risk Score (median 4%, IQR 2-7%), and had normal Apo A1 (156 ± 26.3 mg/dL) and HDL levels (54 ± 17 mg/dL). However, HDL efflux capacity was similar to that in coronary artery disease (0.95 ± 0.17). In univariate regression, NCB increased as HDL efflux capacity decreased (β= -0.84, p=0.01) and was robust to adjustment for cardiometabolic risk factors (β= -0.67, p=0.03). Furthermore, when stratified by median HDL efflux (0.94), patients having lower HDL efflux capacity had higher TB and NCB (TB 3.80 ± 0.82, 4.17 ± 0.97 mm2, p=0.003; NCB 3.59 ± 0.68, 3.94 ± 0.75 mm2, p=0.001 in the low and high HDL efflux groups, respectively). Additional biologic relations in univariate regression are shown in Table 1.

CONCLUSIONS: We show that HDL efflux is negatively associated with coronary plaque burden measured by quantitative CT angiography. Low HDL efflux may therefore be a strong biomarker for subclinical coronary atherosclerosis.

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Does dopamine use several signal pathways to inhibit Na-Pi transport in OK cells?
Authors: A D Baines, R Drangova
Journal: Journal of the American Society of Nephrology (1998)

In opossum kidney (OK) cells, L-dihydroxyphenylalanine (10 microM) raised dopamine to 10 nM and inhibited Na-inorganic phosphate (Pi) uptake 20% (P = 0.001). Inhibition was completely blocked by carbidopa or SCH23390. Dopamine (1 microM) inhibited uptake 55% (half-maximal inhibition, 0.03 microM). Fenoldopam (0.1 microM, DA1 agonist) inhibited uptake 45 +/- 2%. DA1 antagonists (SKF83566 and SCH23390), but not DA2-antagonist (sulpiride), blocked dopamine inhibition. Quinpirole (DA2 agonist) did not modify Pi uptake. Bisindolylmaleimide (10 microM), a protein kinase C inhibitor, blocked inhibition of Pi uptake by phorbol ester but had no effect on the response to dopamine. Dopamine inhibited Pi uptake in cells that had been exposed to phorbol ester for 18 to 24 h. Dopamine inhibition was not reduced by 1 microM U73,122 but was reduced 20% by 10 microM, which is 10 times the concentration reported to completely inhibit phospholipase C in OK cells. Adenylate cyclase inhibitors SQ 22536 (100 microM) and 2,5-dideoxyadenosine (100 microM) reduced dopamine-stimulated cAMP production, but not dopamine inhibition of Pi uptake. Rp-cAMPS counteracted the inhibition of Pi uptake by Sp-cAMPS but had no effect on the dopamine response. H-89 inhibited dopamine-stimulated protein kinase A activity, but neither H-89 nor H-9 alone or with bisindolylmaleimide altered dopamine inhibition of Pi uptake. Genistein and herbimycin A (tyrosine kinase inhibitors) reduced Pi uptake. However, dopamine, a benzoquinone like several tyrosine kinase inhibitors, did not inhibit tyrosine kinase activity. Thus, dopamine inhibited Pi uptake in this OK cell clone by activating a G protein-linked pathway that operates independently from adenylyl cyclase, protein kinase A, protein kinase C, and protein tyrosine kinase.