tbuckley/cabot-search huggingface dataset:
Gut symbiotic microbes imprint intestinal immune cells with the innate receptor SLAMF4 which contributes to gut immune protection against enteric pathogens
Authors: Allison Cabinian, Daniel Sinsimer, May Tang, Youngsoon Jang, Bongkum Choi, Yasmina Laouar, Amale Laouar
Journal: Gut (2017)

Background Interactions between host immune cells and gut microbiota are crucial for the integrity and function of the intestine. How these interactions regulate immune cell responses in the intestine remains a major gap in the field. Aim We have identified the signalling lymphocyte activation molecule family member 4 (SLAMF4) as an immunomodulator of the intestinal immunity. The aim is to determine how SLAMF4 is acquired in the gut and what its contribution to intestinal immunity is. Methods Expression of SLAMF4 was assessed in mice and humans. The mechanism of induction was studied using GFP tg bone marrow chimaera mice, lymphotoxin α and TNLG8A-deficient mice, as well as gnotobiotic mice. Role in immune protection was revealed using oral infection with Listeria monocytogenes and Cytobacter rodentium . Results SLAMF4 is a selective marker of intestinal immune cells of mice and humans. SLAMF4 induction occurs directly in the intestinal mucosa without the involvement of the gut-associated lymphoid tissue. Gut bacterial products, particularly those of gut anaerobes, and gut-resident antigen-presenting cell (APC) TNLG8A are key contributors of SLAMF4 induction in the intestine. Importantly, lack of SLAMF4 expression leads the increased susceptibility of mice to infection by oral pathogens culminating in their premature death. Conclusions SLAMF4 is a marker of intestinal immune cells which contributes to the protection against enteric pathogens and whose expression is dependent on the presence of the gut microbiota. This discovery provides a possible mechanism for answering the long-standing question of how the intertwining of the host and gut microbial biology regulates immune cell responses in the gut.
Molecular predictors of response to sorafenib in patients with radioactive iodine-resistant advanced thyroid cancer.
Authors: Mark Yarchoan, Aaron Benjamin Cohen, Stephen J Stopenski, Chia A. Haddad, Nathan L Scott, Cathy Ma, Evan R. Ransom, Andrea B. Troxel, Michael D Feldman, Marcia S. Brose
Journal: Journal of Clinical Oncology (2014)

6088 Background: Sorafenib has demonstrated significant antitumor activity in patients with advanced iodine-refractory thyroid carcinoma. In order to identify molecular predictors of response to sorafenib, we studied tumor molecular markers and clinical responses obtained from a subset of patients entered in a phase 2 study of sorafenib in advanced thyroid cancer. Methods: Paraffin embedded tissues sections of the most recent tumor sample from patients were immunostained (IHC) with DAB-labeled antibodies to pERK, pAKT and pS6. Protein expression was quantified using a multispectral imaging system which allows for automated tumor segmentation, and cellular and subcellular stain localization and quantitation. Using this system, the optical density of the DAB for each immunostain on a cell by cell basis is achieved along with subcellular location. Protein expression levels were correlated with objective tumor response and progression free survival for all patients. BRAFV600E genetic mutation analysis was performed on all samples. Results: IHC was performed for 40 patients, of whom 17 (42.5%) achieved a partial response (PR), 21 (52.5%) achieved stable disease (SD), and 2 (5%) had disease progression as a best response. There was an inverse association between nuclear pAKT expression level and achieving a partial response to sorafenib (p=0.003). Only 2/10 patients in the highest quartile of pAKT expression achieved a partial response, as compared to 7/10 patients in the lowest quartile of pAKT expression. However, nuclear pAKT expression was not predictive of time to progression. Furthermore, there was no correlation of pERK or pS6 nuclear expression and response to sorafenib. In tumor endothelial cells, expression of pERK, pAKT and pS6 was not predictive of response to sorafenib. There was no correlation between BRAFV600E mutation status and response to sorafenib across the entire cohort or within the subset of patients with papillary thyroid cancer (n=22). Conclusions: These results suggest that lower nuclear pAKT expression may be a positive predictive biomarker for response to sorafenib in advanced thyroid cancer, and merits further evaluation in additional clinical trials. Clinical trial information: NCT00654238.
Clinical utility of quasimonomorphic variation range (QMVR) on the determination of microsatellite instability (MSI) status in Japanese patients (pts) with colorectal cancer (CRC): GI-SCREEN-CRC-MSI sub-study 01.
Authors: Hideaki Bando, Wataru Okamoto, Takafumi Fukui, Takeharu Yamanaka, Kiwamu Akagi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2017)

TPS808 Background: The current analysis for the determination of Microsatellite Instability (MSI) status in tumor requires matched normal DNA as a reference. The Promega MSI panel included five monomorphic markers (NR-21, BAT-26, BAT-25, NR-24, and MONO-27) which were known to have few variant alleles in Caucasian as well as Japanese. Therefore, these markers might be able to determine the MSI status without matched normal DNA, although it is conceivable that Quasi-Monomorphic Variation Range (QMVR) in each ethnic group could be different. In our pilot study, the QMVR in 149 Japanese healthy individuals were 98.4-104.4 base pair (bp) in NR-21, 111.4-117.4 bp in BAT-26, 121.0-127.0 bp in BAT-25, 129.5-135.5 bp in NR-24, and 149.9-155.9 bp in MONO-27, respectively. Methods: This clinical evaluation study is to establish the QMVR in Japanese colorectal cancer (CRC) patients (pts) and to evaluate the clinical utility of the QMVR on the determination of MSI status without matched normal DNA. The primary endpoint is the concordance of MSI status between the standard method using DNA from tumor plus matched normal samples and testing method using DNA from only tumor samples. The new MSI kits including the Promega MSI panel were manufactured under the Quality Management System (QMS) for in vitro diagnostics (IVDs). As the decision algorithm, tumors exhibiting 2 or more markers outside the QMVR were classified as MSI-High, cases with 1 marker outside the QMVR were classified as MSI-Low, and those without any marker outside the QMVRs were classified as microsatellite stable (MSS). Planned enrollment will be 400 pts. Clinical trial information: UMIN000024144.
Deviations from guideline-based therapy for febrile neutropenia in cancer patients.
Authors: Jason D. Wright, Alfred I. Neugut, Sharyn Nan Lewin, William M. Burke, Yu-Shiang Lu, Thomas J. Herzog, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2012)

6078 Background: Febrile neutropenia (FN) is a common cause of morbidity in cancer patients. We examined guideline and non-guideline based care for cancer patients hospitalized with FN and examined how treatment influenced outcomes. Methods: The Perspective database was used to examine the treatment of solid tumor patients with FN from 2000-2010. To capture initial decision-making, we examined treatment within 48 hrs of admission. Based on evidence-based guidelines we determined the appropriate use of guideline-based antibiotics as well as use of treatments not routinely recommended, vancomycin and granulocyte-colony stimulating factors (GCSF). Hierarchical mixed effects models were developed to examine the influence of patient, physician, and hospital characteristics on the quality of treatment. Patients were stratified into low and high-risk groups and the effect of initial treatment on outcome (nursing home discharge and death) examined. Results: Among 25,231 patients with FN, within 48 hours of admission blood cultures were obtained in 90%, guideline-based antibiotic administered to 79%, vancomycin to 37%, and GCSF to 63%. Patients treated at high-volume hospitals, by high-volume physicians and patients managed by hospitalists were more likely to receive guideline-based antibiotics (p&lt;0.05). Vancomycin use increased with time from 17% in 2000 to 55% in 2010 while GCSF use only decreased from 73% to 55%. Patients treated by internists and hospitalists were more likely to receive vancomycin; high-volume physicians were less likely to treat with both vancomycin and GCSF (p&lt;0.05). Among patients who received GCSF, 15% received only one dose and 22% received 2 doses of filgrastim. Among low-risk patients prompt initiation of guideline-based antibiotics decreased the risk of discharge to a nursing facility (OR=0.78; 95% CI, 0.66-0.91) and death (OR=0.65; 95% CI, 0.50-0.85). Conclusions: There is substantial variability in the initial treatment for FN in cancer patients. While use of appropriate empiric antibiotics is high, use of non guideline-based treatments such as vancomycin and GCSF are common. Physician and hospital factors are the most important predictors of both guideline and non guideline-based treatment.
Safety and efficacy results of a phase IV, open-label, multicenter, safety-monitoring study of icotinib in treating advanced non-small cell lung cancer (NSCLC): ISAFE study.
Authors: Fenlai Tan, Aiqin Gu, Yiping Zhang, Shun Chang Jiao, Chang-li Wang, Jintao He, Xueke Jia, Li Zhang, Jiewen Peng, Meina Wu, Kejing Ying, Junye Wang, Kewei Ma, Shucai Zhang, Changxuan You, Lieming Ding, Yinxiang Wang, Haijiao Shen, Jiang Wan, Yan Sun
Journal: Journal of Clinical Oncology (2013)

e19161 Background: The phase III ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS), based on which icotinib was approved by State Food and Drug Administration of China. We conducted a safety-monitoring study to assess the safety and efficacy of icotinib in a broad range of patients with advanced non-small-cell lung cancer (NSCLC) across China. Methods: This study was a single-arm, open-label, multi-center trial in advanced NSCLC patients who were suitable for treatment with oral icotinib 125 mg three times daily. Endpoints included safety, objective response rate (ORR) and disease control rate (DCR), were investigated overall and in subgroups. EGFR mutation analysis was performed retrospectively. Results: Between August, 2011 and August, 2012, 6,087 advanced NSCLC patients were registered with a median age of 63 years (range: 21-95 years), and 5,549 patients were evaluable for safety and tumor response. Baseline characteristics (%) were: male/female 50.8/49.2; non-smoker/ex- or current-smoker/no data 67.2/32.7/0.1; adenocarcinoma/non-adenocarcinoma/other 78.6/15.4/6.0; stage IIIB/IV/other 7.4/90.2/2.4; and 1,571(28.3%) patients were ≥ 70 years of age. The overall incidence of drug-related adverse events (AEs) of any grade was 31.5%, in which the most common drug-related AEs including rash (17.4%) and diarrhea (8.5%), and 3 patients experienced with interstitial lung disease (ILD) associated with icotinib. ORR and DCR were 30.0% and 80.6%, respectively. The safety in the elder patients (age ≥70, n=1,571) were similar to that in the overall population, the incidence of drug-related AEs of any grade was 30.6%, most of which were grade I or II. Among 989 patients who undertook EGFR mutation detection, 738 (74.6%) patients were mutation-positive with an ORR of 49.2% and a DCR of 92.3%. Moreover, in 251 (25.4%) wild type patients, the ORR and DCR were 17.8% and 75.7%, respectively. Conclusions: The data from over 6,000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated efficacy and a favorable toxicity profile in the routine clinical setting.
Neovascular deterioration, impaired NADPH oxidase and inflammatory cytokine expression in adipose-derived multipotent cells from subjects with metabolic syndrome
Authors: Wilfredo Oliva-Olivera, Said Lhamyani, Leticia Coín-Aragüez, Daniel Castellano-Castillo, Juan Alcaide-Torres, Elena María Yubero-Serrano, Rajaa El Bekay, Francisco José Tinahones
Journal: Metabolism (2017)
An automated smartphone-based diagnostic assay for point-of-care semen analysis
Authors: Manoj Kumar Kanakasabapathy, Magesh Sadasivam, Anupriya Singh, Collin Preston, Prudhvi Thirumalaraju, Maanasa Venkataraman, Charles L. Bormann, Mohamed Shehata Draz, John C. Petrozza, Hadi Shafiee
Journal: Science Translational Medicine (2017)

This work demonstrates that a low-cost smartphone accessory can be used for home-based male infertility screening.
Trivalent ganglioside vaccine and immunologic adjuvant versus adjuvant alone in metastatic sarcoma patients rendered disease-free by surgery: A randomized phase 2 trial.
Authors: Richard D. Carvajal, Mark Agulnik, Christopher W. Ryan, Mohammed M. Milhem, Suzanne George, Robin Lewis Jones, Bartosz Chmielowski, Brian Andrew Van Tine, Hussein Abdul-Hassan Tawbi, Anthony D. Elias, William L. Read, G. Thomas Budd, Joe Hirman, Paul Weiden, Cathryn M. Bennett, Philip O. Livingston, David Hansen, Robert G. Maki, Gary K. Schwartz, Rashmi Chugh
Journal: Journal of Clinical Oncology (2014)

10520 Background: Recurrence after resection of metastatic sarcoma is common. The gangliosides GM2, GD2 and GD3 are strongly expressed on many sarcomas. The generation of anti-ganglioside antibodies might control micrometastases and improve outcomes. Methods: We conducted a randomized phase 2 study of the immunological adjuvant OPT821 with a KLH conjugated ganglioside vaccine targeting GM2, GD2 and GD3 (vaccine) or placebo (control) in patients (pts) with metastatic sarcoma following complete metastastectomy. Randomization was stratified by disease state (relapsed disease vs metastasis at diagnosis) and for those with relapse by disease-free interval (<12 vs ≥12 months) and number of relapses (1 vs >1). Pts received 10 injections at weeks (wks) 1, 2, 3, 8, 16, 28, 40, 52, 68 and 84. Imaging was performed at wk 16 and every 12 wks subsequently. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and serologic response. Results: We randomized 136 pts: median age 51 (range 17-84); 52% male; 77% ECOG PS 0 (range 0-1); 90% with relapsed disease; 14% had ≥4 metastases resected. Histology included leiomyosarcoma (n=48), spindle cell (n=19), undifferentiated/pleomorphic (n=18), osteosarcoma (n=14), synovial (n=12), liposarcoma (n=12) and others (n=13). Toxicities included grade 1/2 injection site reactions (79%), fatigue (32%), fever (15%) and flu-like symptoms (10%) and were more frequent with complete vaccine. With 89 PFS events observed, median PFS and 1-year PFS rate were 6.4 months (mos) and 35%, respectively, with no difference between arms. With a median follow-up of 18 mos and 22 pts deceased, the 1-year OS rate was >90%. Serologic responses (IgM and/or IgG) to GM2 and GD2 were observed in 98% and 21% of pts treated with complete vaccine and control, respectively. At wks 40-68, induction of high (>160) IgM and IgG titers was observed in 52% and 24% of pts receiving vaccine and 0% and 2% of pts receiving control. Conclusions: A sustained serologic response to vaccination was induced with the complete vaccine. No difference in PFS was observed between arms. Follow-up for OS is ongoing. Clinical trial information: NCT01141491.
Breaking the Stigma — A Physician’s Perspective on Self-Care and Recovery
Authors: Adam B. Hill
Journal: New England Journal of Medicine (2017)

Interview with Dr. Stuart Slavin on depression and suicide among physicians and trainees and how to address stigma associated with mental illness. (06:24)Download Through his own recovery, a physician with a history of depression, suicidal ideation, and alcoholism has learned important lessons for the medical community — about self-care, stereotyping, stigma, vulnerability, professionalism, patient safety, and support.
A combination chemotherapy, temozolomide (TMZ) with etoposide (VP), in relapsed or refractory pediatric solid cancer: Preliminary report of randomized phase II study of two different outpatient setting regimens (rPII).
Authors: Atsushi Ogawa, Hiroshi Kawamoto, Mari Saito Oba, Ako Hosono, Yoshiyuki Kosaka, Junichi Hara, Yuji Ishida, Kenji Yamada, Katsuyoshi Koh, Yasuhiro Okamoto, Hideo Mugishima, Atsushi Kikuta, Takashi Taga
Journal: Journal of Clinical Oncology (2014)

10055 Background: Each of TMZ and VP has been shown its own anti-cancer activity and they have oral formulation. Although there are established active combinations comprising alkylating agent and topoisomerase inhibitor, TMZ and VP combination (TE), has never been evaluated in pediatric solid cancer. We report efficacy, safety, feasibility of outpatient setting of TE in advance of final analysis of rPII. Methods: This multicenter rpII included children and young adults with recurrent or refractory pediatric solid cancer, who received disease-specific standard chemotherapies. The study design has been reported in ASCO2010 (TPS328). TMZ (150 mg/m2) and VP (50 mg/m2) were administered orally on d1-5 and d1-12 respectively every 28 days, repetitively. The main efficacy endpoint, DSMC approved to be published, was response rate. Response was evaluated according to RECIST 1.1 and toxicity was assessed by CTCAE v4.0. Results: Thirty-four patients(pts) from 13 centers, median age 14 years (range 3-30), received TE: 8 neuroblastoma (NB), 5 rhabdomyosarcoma, 6 Ewing sarcoma family tumor, 8 osteosarcoma (OS), 3 CNS tumors and 4 others. Overall 114 cycles were administered (median 3 per patient; range 1-20). Seventeen pts experienced grade 3-4 neutropenia, but none developed febrile neutropenia. Eight pts had grade 3-4 thrombocytopenia and twelve pts developed grade 3-4 anemia. No grade 4 non-hematological toxicity occurred. Hospitalization was required only in two pts due to VZV infection and grade 2 fever episode, respectively. Response rate (RR) was 14.7% with CR 1 and PR4. Disease control rate (CR+PR+ more than two courses stable disease (SD)) was 38.2% with eight SD. Clinical benefit ratio (CBR, CR+PR+long SD) was 29.4% with five long SD (stable disease during more than 4 course). In NB, CBR was 62.5% with 1 CR, 1 PR and 3 long SD. In OS, RR was 40.7% with 3 PR/7 (one who terminated therapy first 2-3 days due to tumor hemorrhage was excluded). Conclusions: TE is a promising regimen for heavily pretreated recurrent pediatric solid cancer, especially in NB and OS, with acceptable toxicities in outpatient setting. Clinical trial information: 000003002.
Measuring Iran's success in achieving Millennium Development Goal 4: a systematic analysis of under-5 mortality at national and subnational levels from 1990 to 2015
Authors: Younes Mohammadi, Mahboubeh Parsaeian, Parinaz Mehdipour, Ardeshir Khosravi, Bagher Larijani, Ali Sheidaei, Anita Mansouri, Amir Kasaeian, Kamran Yazdani, Maziar Moradi-Lakeh, Elaheh Kazemi, Saeide Aghamohamadi, Nazila Rezaei, Maryam Chegini, Rosa Haghshenas, Hamidreza Jamshidi, Farnaz Delavari, Mohsen Asadi-Lari, Farshad Farzadfar
Journal: The Lancet Global Health (2017)

BackgroundChild mortality as one of the key Millennium Development Goals (MDG 4—to reduce child mortality by two-thirds from 1990 to 2015), is included in the Sustainable Development Goals (SDG 3, target 2—to reduce child mortality to fewer than 25 deaths per 1000 livebirths for all countries by 2030), and is a key indicator of the health system in every country. In this study, we aimed to estimate the level and trend of child mortality from 1990 to 2015 in Iran, to assess the progress of the country and its provinces toward these goals.MethodsWe used three different data sources: three censuses, a Demographic and Health Survey (DHS), and 5-year data from the death registration system. We used the summary birth history data from four data sources (the three censuses and DHS) and used maternal age cohort and maternal age period methods to estimate the trends in child mortality rates, combining the estimates of these two indirect methods using Loess regression. We also used the complete birth history method to estimate child mortality rate directly from DHS data. Finally, to synthesise different trends into a single trend and calculate uncertainty intervals (UI), we used Gaussian process regression.FindingsUnder-5 mortality rates (deaths per 1000 livebirths) at the national level in Iran in 1990, 2000, 2010, and 2015 were 63·6 (95% UI 63·1–64·0), 38·8 (38·5–39·2), 24·9 (24·3–25·4), and 19·4 (18·6–20·2), respectively. Between 1990 and 2015, the median annual reduction and total overall reduction in these rates were 4·9% and 70%, respectively. At the provincial level, the difference between the highest and lowest child mortality rates in 1990, 2000, and 2015 were 65·6, 40·4, and 38·1 per 1000 livebirths, respectively. Based on the MDG 4 goal, five provinces had not decreased child mortality by two-thirds by 2015. Furthermore, six provinces had not reached SDG 3 (target 2).InterpretationIran and most of its provinces achieved MDG 4 and SDG 3 (target 2) goals by 2015. However, at the subnational level in some provinces, there is substantial inequity. Local policy makers should use effective strategies to accelerate the reduction of child mortality for these provinces by 2030. Possible recommendations for such strategies include enhancing the level of education and health literacy among women, tackling sex discrimination, and improving incomes for families.FundingIran Ministry of Health and Education.
An evaluation of mobile mammography outreach in urban and rural communities.
Authors: Lauren T Steward, Susan Kraenzle, Bettina F. Drake, Sarah Lyons, Melody S. Goodman
Journal: Journal of Clinical Oncology (2014)

e17524 Background: Mobile mammography has been used to reach underserved women in a diverse number of settings. In this work, we demonstrate similarities and differences between rural and urban communities served by a single mobile mammography unit (MMU) affiliated with a comprehensive cancer center in the Missouri. Methods: An outreach registry of patients serviced by the MMU was created and includes data from medical records and responses to a brief questionnaire completed at each visit. Data was examined by point of care (urban/rural) to assess the efficacy of mobile mammography as an outreach strategy in each of these environments. Bivariate analyses were used to examine the relationships between demographic characteristics such as age, income, race/ethnicity, education, employment status, marital status, insurance status, and living environment proxy. Results: Between 2006 and 2011, 8,289 women received their care on the mobile mammography van. The sample was stratified by point of care (urban vs. rural) served, with majority of the women (84%) residing in urban/suburban St. Louis City/County, and 16% in rural regions. Urban zip codes had a lower percentage of women with income greater than $20,000 (11% v. 21%) and higher percentage of women with income less than $10,000 (49% v. 37%) in comparison to rural communities(p=0.007). There were higher proportions of black women in urban communities (63%) compared to rural communities (10%; p<0.001). Almost half (47%) the women that received mobile mammography in rural zip code were married compared to less than a quarter of women from urban zip codes (24%; p<0.001). Rural communities (83%) had a higher percentage of uninsured women compared to urban communities (67%; p<0.001). Women in urban and rural communities were similar in respect to age, employment status, and education. Conclusions: Mobile mammography has the potential to reach a large population of women with limited educational, financial, and healthcare resources. Future studies will be needed to determine if increasing the range and extent of mobile units, such as this one, would be effective in increasing the screening rates of not only women in Missouri, but also in other portions of this country.