tbuckley/cabot-search huggingface dataset:
Enhanced surveillance of Clostridium difficile infection occurring outside hospital, England, 2011 to 2013
Authors: Warren N Fawley, Kerrie A Davies, Trefor Morris, Peter Parnell, Robin Howe, Mark H Wilcox
Journal: Eurosurveillance (2016)

There are limited national epidemiological data for community-associated (CA)- Clostridium difficile infections (CDIs). Between March 2011 and March 2013, laboratories in England submitted to the Clostridium difficile Ribotyping Network (CDRN) up to 10 diarrhoeal faecal samples from successive patients with CA-CDI, defined here as C. difficile toxin-positive diarrhoea commencing outside hospital (or less than 48 hours after hospital admission), including those cases associated with community-based residential care, with no discharge from hospital within the previous 12 weeks. Patient demographics and C. difficile PCR ribotypes were compared for CA-CDIs in our study and presumed healthcare-associated (HA) CDIs via CDRN. Ribotype diversity indices, ranking and relative prevalences were very similar in CA- vs HA-CDIs, although ribotypes 002 (p ≤ 0.0001),020 (p = 0.009) and 056 (p &lt; 0.0001) predominated in CA-CDIs; ribotype 027 (p = 0.01) predominated in HA-CDIs. Epidemic ribotypes 027 and 078 predominated in institutional residents with CDI (including care/nursing homes) compared with people with CDI living at home. Ribotype diversity decreased with increasing age in HA-CDIs, but not in CA-CDIs. Ribotype 078 CA-CDIs were significantly more common in elderly people (3.4% (6/174) vs 8.7% (45/519) in those aged &lt; 65 and ≥ 65 years, respectively; p = 0.019). No antibiotics were prescribed in the previous four weeks in about twofold more CA-CDI vs HAs (38.6% (129/334) vs 20.3% (1,226/6,028); p &lt; 0.0001). We found very similar ribotype distributions in CA- and HA-CDIs, although a few ribotypes significantly predominated in one setting. These national data emphasise the close interplay between, and likely common reservoirs for, CDIs, particularly when epidemic strains are not dominant.
A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors.
Authors: Anthony B. El-Khoueiry, Yan Ning, Dongyun Yang, Sarah Cole, Michael Kahn, Marwan Zoghbi, Jennifer Berg, Masamoto Fujimori, Tetsuhi Inada, Hiroyuki Kouji, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

2501 Background: PRI-724 is a first-in-class modulator of Wnt signaling that inhibits the CREB binding protein and β-catenin interaction. In pre-clinical models, PRI-724 (active metabolite C82) increases p300/β-catenin binding and promotes stem cell differentiation thereby eliminating tumor initiating cells and increasing sensitivity to cytotoxic or targeted drugs. Methods: PRI-724 was given as a continuous infusion X 7 days q 2 wks. There was an initial accelerated dose escalation with one pt per dose level and a plan to revert to a 3+3 escalation after 640 mg/m2 unless a dose limiting toxicity (DLT) or 2 moderate toxicities occurred earlier. Eligibility criteria: adequate bone marrow function, AST/ALT &lt;5XULN, total bilirubin&lt;1.5 mg/dL. Survivin/BIRC5 expression was measured by immunomagnetic RT-PCR on circulating tumor cells (CTC). Results: 18 pts treated; median age: 53 years (38-71); 12 (67%) males; median number of prior therapies: 3 (1-5). There was one DLT of grade 3 hyperbilirubinemia. Grade 3 AEs were limited to hyperbilirubinemia in 2 pts, one of which did not meet DLT criteria. Grade 2 AEs were: diarrhea (2pts; 11%), bilirubin elevation (2 pts; 11%), hypophosphatemia (2pts; 11%), nausea (1pt; 6%), fatigue (1pt; 6%), anorexia (1pt; 6%), thrombocytopenia (1 pt; 6%) and alkaline phosphatase elevation (1pt; 6%). There was no MTD at the doses tested. The recommended phase 2 dose was 905 mg/m2 based on the incidence of AEs at 1280 mg/m2 and the plateau in pK parameters. The median Cmax and AUC 0-t for C-82 at 905 mg/m2/day were 887 ng/mL and 262787 h*ng/mL. Median elimination T ½ was 7.35 h. 3 pts with colon cancer had stable disease for 8, 10 and 12 weeks. Survivin expression in CTCs decreased in 72% of pts on C1D8 and 61% on C2D8. There was an inverse relationship between C82 plasma concentration and survivin expression on C1D8 (Spearman correlation coefficient r = -0.72; p=0.001). Conclusions: PRI-724 had an acceptable toxicity profile. Downregulation of survivin expression in CTCs may serve as a pharmacodynamic marker of drug-on-target effect. Studies combining PRI-724 with chemotherapy are ongoing. Clinical trial information: NCT01302405. [Table: see text]
Dual Inhibition of the STAT3 and Src Pathways by NS-018, a JAK2 and Src-Family Kinase Inhibitor, Reduces Myeloma Cell Proliferation and Adhesion and Suppresses Osteoclast Formation
Authors: Kazuya Kuramoto, Ayumi Kodama, Junko Homan, Yohei Nakaya, Toshio Kitamura, Haruna Naito
Journal: Blood (2011)
Time Trends in the Prevalence of Celiac Disease and Gluten-Free Diet in the US Population
Authors: Hyun-seok Kim, Kalpesh G. Patel, Evan Orosz, Neil Kothari, Michael F. Demyen, Nikolaos Pyrsopoulos, Sushil K. Ahlawat
Journal: JAMA Internal Medicine (2016)

Benjamin Lebwohl, MD, MS; Peter H. R. Green, MD; Jonas Söderling, PhD; Bjorn Roelstraete, PhD; Jonas F. Ludvigsson, MD, PhD
Survival analysis of young patients with advanced-stage ovarian and primary peritoneal cancer.
Authors: L. T. Chuang, S. Romano, P. R. Dottino, J. Rahaman, D. Lerner
Journal: Journal of Clinical Oncology (2010)

e15534 Background: To compare survival outcome and identify differences in treatment between young (≤ 50 years) and older women (> 50 years) with advanced-stage epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC). Methods: A retrospective chart review of consecutive patients with stage III/IV EOC and PPC treated at Mount Sinai Medical Center from 2001 to 2008. Pathology, treatment data, and outcomes were abstracted from the patient charts. Kaplan-Meier, Cox proportional hazard analysis and chi-square tests were used for statistical analysis. Results: 147 patients with advanced-stage ovarian cancer were identified, 28 (19.2%) pts were 50 year old or younger and 119 (80.8%) pts were over 50 years old. The mean follow up was 26 months (range 2-133). The median survival in younger patients was 98 months compared to 41 months for older patients (p = 0.01). Younger patients were more likely to undergo more than two surgical cytoreductive procedures (p = 0.04). The mean number of chemotherapy cycles administered to patients in the younger group was 17.2 compared to 8.7 cycles for the older group (p = 0.03). In the univariate analysis of the 147 patients, residual disease (p = 0.03), age under 50 years (p = 0.01), number of chemotherapy cycles (< 12 vs. > 13, p = 0.04) were found to be significant predictors of survival. Multivariate analysis demonstrated that only younger age and residual disease remained as independent prognostic factors for survival. Conclusions: Younger women with advanced-stage EOC and PPC received more cycles of chemotherapy and underwent more surgical procedures. Younger age and residual disease status after primary cytoreductive procedure are independent prognostic factors for survival. No significant financial relationships to disclose.
Fibrinolytic crosstalk with endothelial cells expands murine mesenchymal stromal cells
Authors: Douaa Dhahri, Kaori Sato-Kusubata, Makiko Ohki-Koizumi, Chiemi Nishida, Yoshihiko Tashiro, Shinya Munakata, Hiroshi Shimazu, Yousef Salama, Salita Eiamboonsert, Hiromitsu Nakauchi, Koichi Hattori, Beate Heissig
Journal: Blood (2016)
The DLEU2/Mir-15a/Mir-16-1 Locus, Commonly Deleted in B-Cell Chronic Lymphocytic Leukemia (CLL), Controls B-Cell Compartment Expansion and Its Deletion Leads to CLL in Mice
Authors: Ulf Klein, Marie Lia, Qiong Shen, Paula M Smith, Hongyan Tang, Tongwei Mo, Marta Crespo, Rachael Siegel, Govind Bhagat, Riccardo Dalla-Favera
Journal: Blood (2008)
A prospective multicenter phase II trial of capecitabine plus oxaliplatin (CapOx) in advanced biliary system adenocarcinomas: The final results
Authors: O. Nehls, H. Oettle, J. Hartmann, R. Hofheinz, H. Hass, A. Hochhaus, J. Stieler, U. Koppenhöfer, M. Gregor, B. Klump
Journal: Journal of Clinical Oncology (2006)

4136 Background: To investigate the safety and efficacy of capecitabine and oxaliplatin combination therapy (CapOx) in unresectable or metastatic adenocarcinomas of the biliary system. Methods: 65 patients (pts) (27 male, and 38 female) were enrolled (median age, 61 yrs). Major eligibility criteria: histologically proven, measurable disease, age ≤ 75 yrs, ECOG PS 0–2. A total number of 364 cycles (median, 5; range, 1–16) of oxaliplatin (130 mg/m 2 , d1) plus capecitabine (2 g/m 2 , d 1–14) were administered 3 weekly for gallbladder carcinoma (GBC) (27 pts), extrahepatic (20 pts), and intrahepatic (18 pts) cholangiocarcinoma (CCC). Response rates were assessed according to WHO criteria. Clinical outcome was determined separately for pts with either GBC/extrahepatic CCC or intrahepatic CCC (mass-forming type). Results: Grade 4 toxicities (WHO): diarrhea in 1 pt (1% of cycles), thrombocytopenia in 1 pt (1%), leukocytopenia in 1 pt (1%), and fever in 2 pts (1%); grade 3 toxicities: nausea/vomiting in 1 pt (1%), diarrhea in 2 pts (1%), thrombocytopenia in 3 pts (2%), and fever in 1 pt (1%). Grade 3/4 peripheral sensory neuropathy (Lévis scale) was found in 13 pts (14% of cycles). Two pts were excluded from study because of oxaliplatin-related allergic reactions. One patient died due to sepsis and another due to cerebral insult during the first treatment cycle. The overall disease control rate in 47 pts with GBC or extrahepatic CCC was 72% (complete response (CR), n = 2 (4%); partial response (PR), n = 11 (23%); stable disease (NC), n = 21 (45%)), whereas progressive disease (PD) was found in 13 pts (28%). In 18 pts with intrahepatic mass-forming CCC, no CR or PR was observed, 5 pts (28%) had SD, and 13 pts (72%) experienced PD. Conclusions: The CapOx protocol is well tolerated and remarkably active for advanced GBC as well as extrahepatic CCC with a disease-control rate of 72%. However, activity appears to be limited in the subset of pts with intrahepatic mass-forming type tumors. Survival data will be presented at the meeting. No significant financial relationships to disclose.
AB0691 Six-Minute Walk Test in Systemic Sclerosis: A Systematic Review and Meta-Analysis: Table 1.
Authors: E. Vandecasteele, S. Decuman, M. De Pauw, E. Deschepper, G. Brusselle, F. De Keyser, V. Smith
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are nowadays the leading causes of death in patients with Systemic Sclerosis (SSc). Six-Minute Walk Test (6MWT) is a submaximal exercise test generally used for evaluating severity of disease, prognosis and response to treatment in patients with PAH and ILD. Data on 6MWT in SSc are scarce. <h3>Objectives</h3> This study evaluates what is known about 6MWT in SSc by systematic review and meta-analysis. <h3>Methods</h3> A systematic literature search on PubMed was performed using all combinations of keywords "SSc" and "6MWT". Two investigators evaluated the eligibility for the articles. Reference lists were searched for additional studies. <h3>Results</h3> A total of 45 articles were included in the systematic review (36 of the 210 articles from literature search on PubMed and additional 9 articles from screening of the reference lists). Data of 38 of the 45 included articles were retained for the meta-analysis on Six-Minute Walk Distance (6MWD). The 6MWD of 1031 SSc-pulmonary hypertension (PH) patients was significantly lower than the 6MWD of 1401 SSc patients (283m [95% Confidence Interval [CI]: 255-311m] vs. 426m [95% CI: 401-451m] table 1). Within the SSc-PH group, consisting of a SSc-PAH, a SSc-ILD-PH and a SSc not specified PH subgroup, the estimated pooled mean 6MWD was clinically comparable between the SSc-PAH and SSc-ILD-PH subgroup with a strong overlap between the associated CIs. For 235 SSc-ILD patients, the pooled mean 6MWD was 381m (95% CI: 344-417m), which was clinically considerable lower as compared to the pooled mean of 1401 SSc patients, without reaching the level of statistical significance. <h3>Conclusions</h3> This study is the first meta-analysis of the 6MWT in SSc, demonstrating that the 6MWD in SSc-PH patients (both SSc-PAH and SSc-ILD-PH) is significantly decreased compared to SSc patients. <h3>Disclosure of Interest</h3> None declared
Neuroendocrine differentiation in breast carcinoma: clinicopathological features and outcome
Authors: G. Bogina, E. Munari, M. Marconi, L. Bortesi, M. Turazza, P. Cassandrini, M. Cirillo, S. Duranti, A. Inno, R. Magarotto, M. Nicodemo, V. Picece, G. Lunardi, S. Gori
Journal: Annals of Oncology (2015)
Immunoglobulin (Ig) Repertoire in Multiple Myeloma: High Frequency of Recurrent Aminoacid Substitutions in the FR2 and CDR2.
Authors: Marco Ladetto, Daniela Drandi, Loredana Santo, Barbara Mantoan, Michela Boi, Maria Dell’Aquila, Luigia Monitillo, Chiara Lobetti Bodoni, Antonio Palumbo, Monica Astolfi, Mario Boccadoro
Journal: Blood (2006)
MiR-124-3p/B4GALT1 axis plays an important role in SOCS3-regulated growth and chemo-sensitivity of CML
Authors: Yu-xiao Liu, Li Wang, Wen-jia Liu, Hai-tao Zhang, Jing-hui Xue, Zhi-wen Zhang, Chun-ji Gao
Journal: Journal of Hematology & Oncology (2016)

Abnormal expression of SOCS3 has been implicated in myeloproliferative neoplasms, but the role of SOCS3 in the pathogenesis of leukemia remains largely unknown. Here, we examined the function of SOCS3 in the growth and chemo-sensitivity of chronic myeloid leukemia (CML) and explored the involved mechanisms.Expression levels of SOCS3 in several leukemia cell lines and bone marrow mononuclear cells (BMNCs) from CML patients were determined using quantitative real-time PCR (qPCR) and Western blotting (WB). The roles of SOCS3 in the proliferation, apoptosis, and drug resistance of CML cells were examined by clonogenic progenitor cell assay, flow cytometry, and CCK-8 assay. A detailed analysis of the underlying mechanism of SOCS3 in K562 cells was performed using the Human HT-12 v4 Expression BeadChip, which has more than 48000 gene probes including 600 microRNAs (miRNA) probes. The correlation between the mRNA expression of SOCS3 and miR-124-3p in BMNCs from 30 CML patients was tested by qPCR and analyzed by Pearson correlation and linear regression analysis. The potential target of miR-124-3p in CML cells was explored using the luciferase reporter assay, qPCR, and WB. The effect of SOCS3 on the miR-124-3p/B4GALT1 axis was investigated by qPCR, WB, CCK-8 assay, and tumorigenicity assays in nude mice.SOCS3 was down-regulated in CML cell lines and most of BMNCs from CML patients, and the expression level of SOCS3 was associated with the inhibition of cell proliferation and drug resistance of CML cells. Over-expression of SOCS3 in K562 cells inhibited the expression of leukemia-specific genes and promoted the expression of some miRNAs, among which miR-124-3p was the highest. SOCS3 over-expression enhanced the expression of miR-124-3p and vice versa. The mRNA expression of miR-124-3p and SOCS3 in BMNCs from 30 CML patients was positively correlated. Consistently, the tumor suppressing effects of SOCS3 were partially neutralized by the miR-124-3p inhibitor. B4GALT1 was downstream of miR-124-3p and regulated by SOCS3/miR-124-3p in vitro. Furthermore, SOCS3 over-expression could inhibit the growth and B4GALT expression of K562 cells in vivo.SOCS3/miR-124-3p/B4GALT1 axis plays an important role in the pathogenesis of CML.
Radiotherapy combination opportunities leveraging immunity for the next oncology practice
Authors: Fernanda G. Herrera, Jean Bourhis, George Coukos
Journal: CA A Cancer Journal for Clinicians (2016)

ABSTRACT Approximately one‐half of patients with newly diagnosed cancer and many patients with persistent or recurrent tumors receive radiotherapy (RT), with the explicit goal of eliminating tumors through direct killing. The current RT dose and schedule regimens have been empirically developed. Although early clinical studies revealed that RT could provoke important responses not only at the site of treatment but also on remote, nonirradiated tumor deposits—the so‐called “abscopal effect”— the underlying mechanisms were poorly understood and were not therapeutically exploited. Recent work has elucidated the immune mechanisms underlying these effects and has paved the way for developing combinations of RT with immune therapy. In the wake of recent therapeutic breakthroughs in the field of immunotherapy, rational combinations of immunotherapy with RT could profoundly change the standard of care for many tumor types in the next decade. Thus, a deep understanding of the immunologic effects of RT is urgently needed to design the next generation of therapeutic combinations. Here, the authors review the immune mechanisms of tumor radiation and summarize the preclinical and clinical evidence on immunotherapy‐RT combinations. Furthermore, a framework is provided for the practicing clinician and the clinician investigator to guide the development of novel combinations to more rapidly advance this important field. CA Cancer J Clin 2017;67:65–85. © 2016 American Cancer Society .
Kahlbaum, Hecker, and Kraepelin and the Transition From Psychiatric Symptom Complexes to Empirical Disease Forms
Authors: Kenneth S. Kendler, Eric J. Engstrom
Journal: American Journal of Psychiatry (2016)

The nosology for major psychiatric disorders developed by Emil Kraepelin in the 1890s has substantially shaped psychiatry. His theories, however, did not arise de novo, being strongly influenced by Karl Kahlbaum and Ewald Hecker. From the 1860-1880s, they articulated a paradigm shift in the conceptualization of psychiatric diagnosis, from symptom-based syndromes, popular since the late 18th century, to proto-disease entities. This effort was influenced by parallel developments in general medicine, especially the rise of bacterial theories of disease where different syndromes had distinctive symptoms, courses, and etiologies. Their thinking was particularly shaped by the increasing understanding of general paresis of the insane. Indeed, this disorder, with its distinct course and characteristic symptoms, was paradigmatic for them. Their hope was that a similar progression of medical understanding would evolve for the other major psychiatric syndromes. Their thinking and its connection with Kraepelin's nosology are illustrated through a close reading of their essays on hebephrenia, catatonia, and cyclic insanity. Kahlbaum, Hecker, and Kraepelin shared both a commitment to a clinical research agenda for psychiatry (to utilize methods of clinical assessment and follow-up to help define disease forms) and a skepticism for the brain-based neuropathological paradigm of psychiatric research then dominant in most European centers. Understanding the historical origins of our key diagnostic concepts can help us to evaluate their strengths and limitations. It remains to be determined whether this "Kahlbaum-Hecker-Kraepelin paradigm"-defining disorders based on distinctive symptoms and course-will produce psychiatric syndromes of sufficient homogeneity to yield their etiologic secrets.
Refined strategies for the treatment of pancreatic carcinoma: targeting myeloid cells in order to overcome T cell exhaustion
Authors: Christian Bauer
Journal: Gut (2016)

Cancer creates an environment of constant antigen exposure and inflammation. In this setting, T cells transform into a differentiation state that has been termed T cell exhaustion, which is characterised by upregulation of inhibitory receptors, like TIM-3 and PD-1, resulting in loss of effector function. The discovery of receptor-mediated immune checkpoints, which prevent uncontrolled T cell reactions, led to the development of a new class of antibodies termed checkpoint inhibitors, bringing exhaustion phenomena to the forefront of tumour research. Data on the efficacy of checkpoint inhibitors in pancreatic cancer are still sparse; however, preliminary results indicate limited efficacy as single agents. In order to increase therapeutic efficacy, knowledge on T cell exhaustion mechanisms in pancreatic cancer is mandatory.

Recently, sophisticated models have confirmed the notion that components of …
Disengaging from the ultrasocial economy: The challenge of directing evolutionary change
Authors: John Gowdy, Lisi Krall
Journal: Behavioral and Brain Sciences (2016)

We appreciate the depth and breadth of comments we received. They reflect the interdisciplinary challenge of our inquiry and reassured us of its broad interest. We believe that our target article and the criticisms, elaborations, and extensions of the commentators can be an important contribution to establishing human ultrasociality as a new field of social science inquiry. A few of the commentators questioned our definition of ultrasociality, and we begin our response with an elaboration of that definition and a defense of our argument that human ultrasociality began with agriculture. We then respond to the second major area of controversy, namely, our use of group selection to explain the economic drivers behind the agricultural transition. We then focus on the issue of human intentionality raised by the phenomenon of collective intelligence. The intriguing question is to what extent can an entire culture change its own destiny? We then address the issue of the division of labor raised by a number of commentators. The complex division of labor was both a driver and a defining characteristic of ultrasociality, even though it was present in simpler forms in earlier societies. The remaining issues addressed include energy and complexity, expansion and sustainability, and the accelerating evolution of human ultrasociality. These were raised by only a few commentators, but their importance warrants further elaboration.
Long-term Consequences of Finasteride vs Placebo in the Prostate Cancer Prevention Trial
Authors: Joseph M. Unger, Cathee Till, Ian M. Thompson, Catherine M. Tangen, Phyllis J. Goodman, Jason D. Wright, William E. Barlow, Scott D. Ramsey, Lori M. Minasian, Dawn L. Hershman
Journal: JNCI Journal of the National Cancer Institute (2016)

Background: Finasteride has been found to reduce the risk of low-grade prostate cancer but to have no impact on overall survival. The long-term adverse and beneficial consequences of finasteride have not been examined. Methods: We used a linkage between data from the Prostate Cancer Prevention Trial (PCPT) and Medicare claims. Patients were examined by randomized study arm (finasteride vs placebo for 7 years) for long-term consequences of the intervention, including cardiac, endocrine, and sexual dysfunction, depression, diabetes, and benign prostatic hyperplasia (BPH)–related events. To examine time to events, we used cumulative incidence and Cox regression, adjusting for covariates. All statistical tests were two-sided. Results: A total of 13 935 of 18 880 participants (73.8%) in the PCPT were linked to Medicare claims, with median Medicare follow-up assessment time of 16 years from trial registration. There were no differences between finasteride and placebo participants with respect to important baseline factors or amount of Medicare follow-up assessment time. Finasteride patients had a 10% higher risk of new claims for depression (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.01 to 1.19, P = .04) and a 6% lower risk of procedures for BPH-related events (primarily lower urinary tract symptoms; HR = 0.94, 95% CI = 0.89 to 1.00, P = .03). No other differences were found in rates of long-term consequences of intervention in the two study arms. Conclusions: Finasteride use is associated with reduced need for procedures for relief of BPH-related events and a modest increase in depression. Overall, there is little need to worry about long-term noncancer consequences of finasteride use in those who use it for treatment of symptomatic BPH, hair growth, or prevention of cancer.