tbuckley/cabot-search huggingface dataset:
Comment on “Exosome‐mediated activation of toll‐like receptor 3 in stellate cells stimulates interleukin‐17 production by γδ T cells in liver fibrosis”
Authors: Ming Ni, Jian Gu, Jianhua Rao, Yuchun Zhang, Zheng Ding, Xuehao Wang, Ling Lu
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read the article by Seo et al.,1 in which the investigators reported that exosomes secreted by hepatocytes increase Toll‐like receptor 3 (TLR3) expression in hepatic stellate cells (HSCs) and activate HSCs, with great interest. Interleukin (IL)‐17A released by the activated HSCs further promotes IL‐17A production by γδ T cells and exacerbates liver fibrosis. This study improved our understanding of the pathogenesis of liver fibrosis. Consistent with their findings, our center recently showed that IL‐17A increased liver injury in a different model of liver diseases.2 However, we have some questions about IL‐17A production by activated HSCs and the effects of TLR3 on liver fibrosis. The investigators noted that hepatocyte‐released exosomes activated HSCs and accelerated IL‐17A production by HSCs, which subsequently amplified IL‐17A production from γδ T cells.1 IL‐17 is primarily produced by CD4+IL‐17+ T (Th17) cells, as well as other immune cells, including γδ T cells, natural killer (NK) T cells, NK cells, receptor‐related orphan receptor gamma t (RORγt)+ neutrophils, and eosinophils.3 So far, there has been no evidence that quiescent or activated HSCs produce IL‐17A. Furthermore, our center previously reported that HSC activation may not up‐regulate IL‐17A expression in these cells.2 We believe that IL‐17A promotion may be derived from exosomes, rather than HSCs, as was described in Seo et al.'s study, during the CCl4‐induced liver fibrillation. Thus, the sources of IL‐17A promotion require further research. Moreover, data showed that TLR3 deficiency in HSCs markedly attenuates liver fibrosis. TLR3 is primarily expressed in macrophages and dendritic cells, rather than HSCs, in the liver.4 However, TLRs expressed on HSCs, including TLR4 and TLR9 among others, share similar downstream signaling pathways, such as myeloid differentiation primary response gene 88 and Toll/IL‐1 receptor‐domain‐containing adapter‐inducing interferon‐β.4 The function of TLR3 may be replaced by activation of the same downstream pathway by other TLRs, especially TLR4. Previous studies have even found that TLR3 can have a protective effect against liver fibrosis.5 Therefore, we question whether TLR3 expression by HSCs plays a strong promoting role in the development of liver fibrosis. We agree with the investigators' conclusion that exosomes and IL‐17 have substantial roles in development of liver fibrosis. However, further confirmation that IL‐17A production by activated HSCs subsequently amplifies IL‐17A production from γδ T cells, and that TLR3 expression by HSCs plays an independent promoting role in liver fibrosis, is needed.
A phase I, multicenter, open-label, first-in-human study to evaluate MEDI0680, an anti-programmed cell death-1 antibody, in patients with advanced malignancies.
Authors: Jeffrey R. Infante, Sanjay Goel, Fatemeh Tavakkoli, Shannon Marshall, Paul B. Robbins, Gina D'Angelo, Matthew Joseph Gribbin, Joyson Joseph Karakunnel, Aung Naing
Journal: Journal of Clinical Oncology (2015)

TPS3088 Background: Programmed cell death-1 (PD-1) is an inhibitory regulator or checkpoint of T-cell activation. Recent data from several large phase I studies have shown that targeting the PD-1/programmed cell death ligand-1 (PD-L1) axis has an acceptable safety profile, can enhance antitumor responses, and provide clinical benefit. MEDI0680 is a humanized immunoglobulin gamma 4, kappa monoclonal antibody specific for human PD-1 that blocks PD-L1 and programmed cell death ligand-2 (PD-L2). Blocking both PD-L1 and PD-L2 may provide more efficient pathway inhibition and may be more specific for different tumor groups in comparison to blocking either one alone. As well as blocking interactions between PD-1 and its ligands, MEDI0680 also improves the intrinsic functionality of T cells by triggering internalization of PD-1, thereby reducing the surface levels of PD-1 and membrane-proximal tyrosine phosphatase SHP2. Methods: This is an ongoing, phase I, multicenter, open-label, first-in-human, dose-escalation study (NCT02013804) evaluating MEDI0680 in patients with advanced malignancies. Eligible patients ( ≥ 18 years) will have an Eastern Cooperative Oncology Group performance status of 0 or 1, histologically- or cytologically-confirmed melanoma or clear-cell renal cell carcinoma that is refractory to standard treatment or for which no standard treatment exists, ≥ 1 measurable lesion per RECIST v1.1, with prior treatment toxicities of ≤ grade 1. The primary objectives of the study are to assess the safety and tolerability and define the maximum tolerated dose of MEDI0680. Secondary objectives include an evaluation of the pharmacokinetic and antitumor effects of MEDI0680. Recruitment is ongoing, with a target enrollment of approximately 48 patients across 5 centers in the United States. Clinical trial information: NCT02013804.
Expression of 5-a reductase type 1 (SRD5A1) in breast cancer: Association with tumor molecular subtypes and patient characteristics
Authors: R. H. Morant, S. Eppenberger-Castori, P. Urban, R. Zanetti, U. Eppenberger, V. Vuaroqueaux
Journal: Journal of Clinical Oncology (2008)

22170 Background: Preliminary reports indicate that dutasteride can suppress progesterone transformation into 5-alpha pregnane by SRD5A1 in breast cancer, resulting in suppression of cell proliferation and detachment. The aim of this study was to investigate SRD5A1 expression according to the breast cancer subtypes and patient characteristics. Methods: SRD5A1 mRNA expression levels were investigated in three breast cancer data sets consisting of a 64 genes Qrt-PCR data set (STB, 168 patients) and two micro-arrays data sets (295 and 286 patients). Results: SRD5A1 mRNA expression was found to be significantly higher in estrogen receptor (ER) negative tumors including the Basal like and HER2-positive subtypes. Moreover, elevated SRD5A1 were found to be associated with pre-menopausal status of the patients, high tumor grade and poor clinical outcome. Conclusions: SRD5A1 mRNA expression was found to be associated with ER-negative breast cancer phenotypes mainly found in tumors obtained from pre-menopausal women. Possible effects of dutasteride as well as a better characterization of 5-alpha pregnane receptors should be further investigated in these subtypes of breast cancer. No significant financial relationships to disclose.
Comparison between circulating tumor DNA and tumor tissue multiple gene detection in non-small cell lung cancer patients by targeted sequencing with the Ion PGM and AmpliSeq Cancer Panel.
Authors: Fan Yang, Kezhong Chen, Feng Lou, Jingbo Zhang, Hua Ye, Wei Chen, Tian Guan, Mingyu Zhao, Xuexia Su, Rong Shi, Si-Yi Chen, Jun Wang
Journal: Journal of Clinical Oncology (2016)

8544 Background: Circulating tumor DNA (ctDNA) is a noninvasive assessment that can be used as an alternative method to detect gene mutations in lung cancer patients. However, previous studies have analyzed only a small subset of genes like EGFR and KRAS using a variety of detection methods. Feasibility to evaluate concordance between tumor tissue DNA(tDNA) and plasma ctDNA mutations in a large number of genes need to be assessed. We used a relatively inexpensive targeted sequencing method to analyze and compare mutations between tumor tissue and plasma. Methods: Fresh tumor tissue, peripheral blood lymphocytes and plasma samples were collected prospectively from 167 non-small-cell lung cancer(NSCLC) patients before treatment. We utilized the Ion PGM and AmpliSeq Cancer Panel which covers 739 mutational hotspot loci in 50 oncogenes and tumor suppressor genes in matched tDNA and plasma ctDNA samples with matched white blood cell DNA as a control. Results: Of the 167 NSCLC sample pairs analyzed, 118 contained mutations in one or more of the 50 genes screened in our cancer panel in tDNA. The majority of all mutations identified in both tDNA and plasma ctDNA were single nucleotide polymorphisms (SNPs) (112 and 162, respectively), insertions and deletions (Indels) accounted for 31 of tDNA mutations and 28 plasma ctDNA mutations, and 1 of tDNA and 2 of plasma ctDNA mutations were multi-nucleotide polymorphisms (MNPs). EGFR was most common mutation found in 60 of tDNA samples and 54 of plasma ctDNA samples. Overall study concordance is 70.66%, with a sensitivity and specificity of blood test were 77.53% and 62.82%, respectively. The concordance, sensitivity and specificity was (62.32%,68.42%,54.84%) in stage Ⅰ,(68.00%,81.82%,57.14%) in stage Ⅱ,(80.36%,85.19%,75.86%)in stage Ⅲ, and (76.47%,84.62%,50%) in stage Ⅳ patients, respectively. Conclusions: Target sequencing with the Ion PGM and AmpliSeq cancer panel can detect ctDNA mutations in plasma from NSCLC patients with high concordance to mutations found in the primary tumor, even in early stage patients. This approach could easily be implemented and standardized for clinical use.
メサンギウム細胞の細胞内Cl‐濃度([Cl-])の調節:アンギオテンシンII(AII)、ウシ胎仔血清(FCS)とクロライドチャネル遮断剤の効果
Authors: Okuda T, Naruse M, Ogata E, Kurokawa K
Journal: Kidney International (1990)
R-HCVAD/R-MTX-ARAC Is an Effective Regimen for Untreated Diffuse Large B-Cell Lymphoma (DLBCL) with Aggressive Features in Patients Younger Than 60 Years
Authors: Luis Fayad, Barbara Pro, Fredrick Hagemeister, Fernando Cabanillas, Felipe Samaniego, Peter McLaughlin, Michael Wang, Sattva Neelapu, Larry Kwak, Jorge Romaguera, Maria A. Rodriguez
Journal: Blood (2007)
Single Center Experience of Allogenic Hematopoietic Stem Cell Transplantation in 100 Patients with Myelodysplasia: The Impact of Graft-Versus-Host Disease
Authors: Colombe Saillard, Raynier Devillier, Sabine Furst, Jérome Rey, Angela Granata, Aude Charbonnier, Samia Harbi, Jean El Cheikh, Bilal Mohty, Catherine Faucher, Evelyne D'Incan, Luca Castagna, Christian Chabannon, Norbert Vey, Didier Blaise
Journal: Blood (2015)
Chronotherapy: Intuitive, Sound, Founded…But Not Broadly Applied
Authors: Julia M. Selfridge, Tetsuya Gotoh, Samuel Schiffhauer, JingJing Liu, Philip E. Stauffer, Andrew Li, Daniel G. S. Capelluto, Carla V. Finkielstein
Journal: Drugs (2016)

Circadian rhythms are a collection of endogenously driven biochemical, physiological, and behavioral processes that oscillate in a 24-h cycle and can be entrained by external cues. Circadian clock molecules are responsible for the expression of regulatory components that modulate, among others, the cell's metabolism and energy consumption. In clinical practice, the regulation of clock mechanisms is relevant to biotransformation of therapeutics. Accordingly, xenobiotic metabolism and detoxification, the two processes that directly influence drug effectiveness and toxicity, are direct manifestations of the daily oscillations of the cellular and biochemical processes taking place within the gastrointestinal, hepatic/biliary, and renal/urologic systems. Consequently, the impact of circadian timing should be factored in when developing therapeutic regimens aimed at achieving maximum efficacy, minimum toxicity, and decreased adverse effects in a patient. However, and despite a strong mechanistic foundation, only 0.16 % of ongoing clinical trials worldwide exploit the concept of 'time-of-day' administration to develop safer and more effective therapies. In this article, we (1) emphasize points of control at which circadian biology intersects critical processes governing treatment interventions; (2) explore the extent to which chronotherapeutics are incorporated into clinical trials; (3) recognize roadblocks; and (4) recommend approaches to precipitate the integration of chronobiological concepts into clinical practice.
Efficacy of Imatinib Mesylate Dose-Escalation in CML Patients Showing Suboptimal Response to Standard Dose.
Authors: D.Y. Kim, H.J. Kim, J.S. Jeong, S.J. Kim, Y.D. Joo, S.K. Sohn, I. Kim, J.S. Kim, H.S. Song, S.S. Yoon, C.S. Kim, C.W. Jung, K.H. Yi, Y.H. Min, M.S. Hyun, N.R. Lee, D.Y. Chang, D.Y. Jo, J.A. Kim, J.W. Park, B.K. Kim, S. Park
Journal: Blood (2007)
Autologus Hematopoietic Stem Cell Transplant in Type 1 Diabetes Mellitus in a Nonmyeloablative and Outpatient Setting
Authors: Olga Graciela Cantú-Rodríguez, Fernando Lavalle-Gonzalez, Miguel Angel Herrera-Rojas, Cesar H Gutiérrez-Aguirre, Consuelo Mancías-Guerra, Jose Carlos Jaime-Pérez, Oscar Gonzalez-Llano, Alfonso Zapata-Garrido, Jesus Zacarias Villarreal-Perez, David Gomez-Almaguer
Journal: Blood (2014)
Conventional Oral Prednisone Versus High-Dose Dexamethasone for Management of Adult Immune Thrombocytopenia: A Prospective Randomized Multicenter Clinical Trial
Authors: Yu Wei, Xuebin Ji, Jingxia Wang, Enqin Yang, Zhengcheng Wang, Yuqi Sang, Zuomu Bi, Cuiai Ren, Fang Zhou, Guoqiang Liu, Xin Wang, Jun Peng, Ming Hou
Journal: Blood (2014)
Hunt aims for fully home grown doctor workforce
Authors: Ingrid Torjesen
Journal: BMJ (2016)

Expanding the number of medical student places by 25%, announced by England’s health secretary at the Conservative Party conference in Birmingham on Tuesday 4 October, will take at least a decade to have an effect in the NHS, doctors’ leaders have warned.

In his speech Jeremy Hunt announced that “from September 2018 we will train up to 1500 more doctors every year” in England in a bid to expand the number of home grown doctors and to replace doctors recruited from overseas, who currently make up 25% of the medical workforce. “Of course, it will take a number of years before those doctors qualify, but by the end of the next parliament we will make the NHS self sufficient in doctors,” he said.

The number of medical school places fell by 2% in 2013 and currently stands at 6000 a year. Doctors’ leaders have welcomed the planned rise in …
Ultra-rare disruptive and damaging mutations influence educational attainment in the general population
Authors: Andrea Ganna, Giulio Genovese, Daniel P Howrigan, Andrea Byrnes, Mitja I Kurki, Seyedeh M Zekavat, Christopher W Whelan, Mart Kals, Michel G Nivard, Alex Bloemendal, Jonathan M Bloom, Jacqueline I Goldstein, Timothy Poterba, Cotton Seed, Robert E Handsaker, Pradeep Natarajan, Reedik Mägi, Diane Gage, Elise B Robinson, Andres Metspalu, Veikko Salomaa, Jaana Suvisaari, Shaun M Purcell, Pamela Sklar, Sekar Kathiresan, Mark J Daly, Steven A McCarroll, Patrick F Sullivan, Aarno Palotie, Tõnu Esko, Christina M Hultman, Benjamin M Neale
Journal: Nature Neuroscience (2016)
Volume-outcome relationship of gastrectomy for cancer in Texas
Authors: D. L. Smith, C. P. Raut, L. S. Elting, P. F. Mansfield
Journal: Journal of Clinical Oncology (2004)

6091 Background: The association between hospital volume and outcomes has been well described in a variety of surgical resections in cancer patients, but not for gastrectomy. Our goal was to assess the mortality differences for gastrectomies between low and high volume hospitals. Methods: We conducted a population-based study of mortality following gastrectomy in Texas. A database was constructed of every cancer patient that underwent a gastrectomy for adenocarcinoma between 1/1/99 and 12/31/01 from the Texas Hospital Inpatient Discharge Public Use Data File. We evaluated mortality rates for high volume (HV, >15 gastrectomies/yr) versus low volume (LV, ≤15 gastrectomies/yr) hospitals and developed a multivariate model of risk of mortality using a random effects model to account for clustering of patients with hospitals. All data obtained were based on individual hospital reporting of mortality and all diagnoses were obtained from hospital billing codes. Results: There were 1864 gastrectomies performed for gastric adenocarcinoma in 214 hospitals. In univariate analysis, the overall complication rate following gastrectomy at LV vs HV centers was not significantly different (22% vs 18%), however the complication related mortality rates were (22.9% vs 4.9%, p=0.007). The in-hospital all-cause mortality rates were also significantly different (6% vs 1%, p=0.01). Using multivariate analysis, age greater than 75 years, type of gastrectomy, and development of complications were all associated with a higher mortality (Table). Additionally, gastrectomy at HV hospitals is associated with an 80% decreased risk of mortality. Conclusions: Gastrectomy performed at HV hospitals is associated with a lower mortality than at LV hospitals, particularly following a post-operative complication. A further understanding of this relationship is required to develop effective regionalization and referral policies for gastric cancer patients. No significant financial relationships to disclose.
A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons
Authors: D. Gowanlock R. Tervo, Bum-Yeol Hwang, Sarada Viswanathan, Thomas Gaj, Maria Lavzin, Kimberly D. Ritola, Sarah Lindo, Susan Michael, Elena Kuleshova, David Ojala, Cheng-Chiu Huang, Charles R. Gerfen, Jackie Schiller, Joshua T. Dudman, Adam W. Hantman, Loren L. Looger, David V. Schaffer, Alla Y. Karpova
Journal: Neuron (2016)
Activity of front-line FOLFIRINOX (FFX) in stage III/IV pancreatic adenocarcinoma (PC) at Memorial Sloan-Kettering Cancer Center (MSKCC).
Authors: Maeve A Lowery, Kenneth H. Yu, Nelly G. Adel, Arlyn J. Apollo, Michelle S. Boyar, Philip Caron, David Ilson, Neil Howard Segal, Yelena Yuriy Janjigian, Diane Lauren Reidy, Ghassan K. Abou-Alfa, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2012)

4057 Background: The PRODIGE/ACCORD trial recently established FFX as a treatment option for good performance status (PS) pts with stage IV PC (Conroy et al, NEJM 2011). We evaluated the activity and toxicity associated with FFX therapy in pts with advanced PC treated at MSKCC outside of a clinical trial. Methods: 80patients (pts) treated withFFX as 1st-line therapyat MSKCC between 07/1/10 and 12/30/11, were identified from an institutional database (prior IRB approval). Records were reviewed for demographic, treatment, toxcity, and response data. Results: 61 and 19 pts received FFX for stage IV and III PAC respectively. Demographics and outcomes are summarized in the table. Median starting dose of FFX was 80% of that used in the PRODIGE/ACCORD trial. Median overall survival (OS) was 12.5 months (mo) (95% CI 9.5–15.5) in pts treated with 1st line FFX for stage IV PAC and 13.7 mo (95% CI 11.3–15.8) in pts with stage III PAC. 68% of pts with stage IV PAC who discontinued FFX for disease progression (PD) or toxicity received 2nd-line gemcitabine-based therapy. Conclusions: We observed activity and acceptable toxicity in carefully selected patients treated with FFX at 80% dose intensity and routine use of growth factor support. Treatment with FFX resulted in median OS of &gt; 1 year in pts with stage IV PAC and is an active front-line regimen. [Table: see text]
Shared decision-making and surgical treatment for breast cancer
Authors: S. J. Katz, P. M. Lantz, N. K. Janz, A. Fagerlin, B. Salem, I. Lakhani, M. Morrow
Journal: Journal of Clinical Oncology (2004)

556 Background: Persistent high rates of mastectomy (mast) use for breast cancer have motivated lingering concerns about over-treatment. Policy makers have suggested that large regional variation in patterns of treatment is evidence of failure to involve women about the treatment they prefer. To address these issues, we examined the relationship between patient involvement in decision-making and receipt of surgical treatment for women with breast cancer. Methods: All women with DCIS and a 20% random sample of women with invasive breast cancer aged 79 and younger diagnosed in 2002 and reported to the Detroit and Los Angeles metropolitan SEER registries were identified and surveyed shortly after receipt of surgical treatment. Response rate was 74.3% (N=1489). Results: The mean age was 59.9 years; 68.7% were Caucasian, 17.0% were African American and 14.3% were of other ethnic groups. Overall, 26.4% of women received mast as initial treatment (23.6% of Caucasians, 30.2% of African Americans and 34.6% of other ethnic groups). One fifth of patients reported that their surgeon made the decision; 37.9% that the decision was shared; and 41.0% said they made the decision. The table below shows percent of patients (stages 0–2) who received mast by perceived levels of involvement and race, controlling for stage, tumor size, histologic grade, contra-indication to lumpectomy, age, and education. Patient involvement was positively associated with receipt of mast as initial surgical treatment. However, this was observed largely for Caucasian women (p=.01). Conclusions: Most women reported that they made or shared the decision about surgical treatment. Results suggest that patient preferences may partly explain persistently high rates of mastectomy and regional variation in surgical treatment. Racial differences in the association of involvement with receipt of treatment suggest that the decision-making process varies by racial groups. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NCI RO1 CA8837-A1
Gene expression in serial biopsies in locally advanced breast cancer patients who failed to respond to neoadjuvant chemotherapy.
Authors: M. M. Magbanua, S. E. Davis, J. Crothers, E. Sosa, C. M. Haqq, L. van't Veer, L. Esserman
Journal: Journal of Clinical Oncology (2010)

10515 Background: To elucidate candidate genes and pathways associated with poor response, we retrospectively analyzed gene expression profiles in serial biopsies from women with locally advanced breast cancer who failed to respond to anthracycline-based chemo followed by taxane in the I-SPY TRIAL (CALGB150007/150012/ACRIN 6657). Methods: Of the 221 patients who completed neoadjuvant chemotherapy, 215 patients had surgery with 73% not achieving a pathologic complete response (pathCR). In these patients, cDNA microarray expression profiles from pretreatment biopsy (T1) were compared to those biopsy specimens obtained 24-72 hours after initiation of treatment (T2) or in tumors surgically removed after chemotherapy (TS). Paired expression data for T1vsT2 and T1vsTS were available for 29 and 39 patients with no pathCR, respectively. Paired differential expression analyses were performed via significance analysis of microarrays (SAM) and differentially expressed genes were subjected to ingenuity pathway analysis. Results: Comparison of paired T1vsT2 and T1vsTS profiles detected altered expression of 245 and 272 transcripts, respectively. Compared to baseline levels, MMP9 and FRZB were among the genes that were down regulated after the first dose of chemotherapy in non-responding tumors while CYR61, JUN, and JUNB were up regulated in remaining tumors after chemotherapy. Further analysis revealed numerous signaling and metabolic pathways that were significantly modulated at T2, including CD40 (p = 0.0002) and Toll-like receptor signaling (p = 0.0006) and at TS, including SAPK/JNK (p = 0.005) and IGF1 (p = 0.03) signaling. Conclusions: Serial gene expression analysis in non-responders revealed genes and pathways that may serve as biomarkers for poor response. Candidate pathways identified will be further explored in the I-SPY 2 TRIAL where targeted therapies will be tested in combination with standard neoadjuvant chemotherapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Agendia, Cougar Biotechnology Agendia