tbuckley/cabot-search huggingface dataset:
A phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer
Authors: D. Grecea, R. Tanasescu, C. Vasiliniuc, L. Neamtiu, N. Ghilezan
Journal: Journal of Clinical Oncology (2005)

736 Background: A phase II study was conducted to evaluate the efficacy and tolerability of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. Methods: 60 patients with metastatic breast cancer received either docetaxel 35mg/m2 weekly for a median 10 (8–12) consecutive weeks (n=25), or docetaxel 100mg/m2 on day 1 every 3 weeks, 6 cycles (n=35). The median age of patients was 46 years(31–66) with 22(36,6%) premenopausal and 38 (63,4%) postmenopausal. 50 patients (83,3%) received docetaxel as first line treatment for metastatic breast cancer, and the other 10 patients (16,6%) received it as second line treatment. Results: The incidence of all grade 3–4 adverse events was higher in the 3-weekly group than in the weekly group (64 versus 30) and the number of patients with grade 3–4 adverse events was also grater in the 3-weekly group (23 versus 12). Intent to treat overall response rate was 42% and 36% in the 3 weekly and weekly group, respectively. Median time to progression was 5.8 and 5.2 months after 3-weekly and weekly docetaxel, respectively. Conclusions: Weekly docetaxel is an active regimen in metastatic breast cancer with comparable efficacy to 3-weekly docetaxel. Both schedules were well tolerated, weekly docetaxel appears to have a more favourable toxicity profile, providing an attractive strategy for palliative treatment of metastatic breast cancer. No significant financial relationships to disclose.
Abstract 1394: CD44 isoform expression illuminates multiple CSC subpopulations in PC3
Authors: James R. Hernandez, Steven M. Mooney, Gonzalo Torga, James E. Verdone, Kenneth J. Pienta
Journal: Cancer Research (2015)

Abstract The concept of the cancer stem cell (CSC) is neither new nor without controversy. It is important to study these cells since they are often hypothesized to be androgen insensitive and resistant to chemotherapeutics. Therefore, finding reliable markers for identifying and targeting these cells has become increasingly attractive. The hyaluronic acid receptor, CD44, is associated with a wide variety of cell types, including CSCs. CD44 has many different isoforms which can be categorized as belonging to one of two groups; one expressing different combinations of 10 variant extracellular exons (CD44v), and the other only expressing standard exons found in all isoforms, but none of the 10 variant exons (CD44s). CD44s is typically associated with the mesenchymal stem cell niche, while the various CD44v forms are related to hematopoietic stem cells and increased cell adhesion. However, both CD44s and CD44v have been linked to the CSC niche and cancer progression. Similar to CD44, the aldehyde dehydrogenases (ALDH) superfamily expression is also associated with CSCs and cancer progression. Previously, our laboratory demonstrated that epithelial cancer cells undergo an EMT upon exposure to M2 macrophages. In order to obtain a purely epithelial PCa population, our laboratory isolated a single cell clone of PC3 that had high E-cadherin expression, denoted PC3-Epi. PC3-Epi cells were then incubated with M2 macrophages, which caused a stable EMT to occur after only a few days in culture, denoted PC3-EMT. Our finding demonstrate that these PC3 clones exhibit numerous CSC characteristics, such as high ALDH activity, CD44 expression and cell plasticity. FACS analysis of CD44 isoform expression show distinct CSC subpopulations within these PC3-Epi and PC3-EMT cell types. These subpopulations showed the ability to recapitulate the presorted parental population after being returned to culture. This data suggests not only that the PC3 cell line displays numerous CSC characteristics, but also that distinct CSC subpopulations may exist. Note: This abstract was not presented at the meeting. Citation Format: James R. Hernandez, Steven M. Mooney, Gonzalo Torga, James E. Verdone, Kenneth J. Pienta. CD44 isoform expression illuminates multiple CSC subpopulations in PC3. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1394. doi:10.1158/1538-7445.AM2015-1394
Clathrin Assembly Protein CALM Plays a Key Role In Erythroid Differentiation Via Regulating Transferrin Receptor Endocytosis
Authors: Yuichi Ishikawa, Manami Maeda, Min Li, Sung-Uk Lee, Julie Teruya Feldstein, Yumiko Mori, Hitoshi Kiyoi, Tomoki Naoe, John E Heuser, Takahiro Maeda
Journal: Blood (2010)
Abstract 3024: Lack of CK1δ increases DNA damage and genomic instability due to defects in DNA repair and mitotic checkpoints
Authors: Yoshimi E. Greer, Bo Gao, Yingzi Yang, Stanley Lipkowitz, Jeff S. Rubin
Journal: Cancer Research (2015)

Abstract Casein kinase 1 delta (CK1δ) is a conserved serine/threonine protein kinase that regulates diverse cellular processes including vesicle trafficking and circadian rhythm. We previously reported that CK1δ is a mediator of Wnt-3a-dependent neurite outgrowth (Greer and Rubin, JCB, 2011) and ciliogenesis (Greer et al. MBoC, 2014). Mice that lack Csnk1d exhibit a perinatal lethal phenotype and typically weigh 30-50% less than their wild type littermates, however, the exact causes of death and small size are unknown. We hypothesized that the absence of CK1δ contributes to cellular stresses that adversely affect cell survival. Mouse embryonic fibroblasts (MEFs) were collected from mice homozygous for a Csnk1d floxed allele, and MEFCsnk1d null cells were generated by infection with adenovirus (Ad) expressing Cre. As control, MEFCtl. cells were produced by infection with Ad-GFP. In addition, MEFCtl cells were treated with CK1δ siRNA reagents to transiently suppress endogenous expression. Cells were analyzed by confocal microscopy, western blotting and flow cytometry. At early passage (P2), many MEFCsnk1d null cells had detached from the culture dish, raising the possibility of cell death. Subsequent MTS assay confirmed a significantly lower cell viability of MEFCsnk1d null cells compared to MEFCtl cells. MEFCsnk1d null cells (P3) exhibited a larger sub-Go fraction (64%) than MEFCtl cells (34%) in flow cytometric analysis. γ-H2AX staining and comet assay confirmed significant DNA damage in MEFCsnk1d null cells. MEFCsnk1d null cells exhibited micronuclei, a characteristic of genomic instability. Similarly, abrogation of CK1δ expression in MEFCtl cells induced micronuclei formation in response to DNA damage triggered by doxorubicin, suggesting that the absence of CK1δ increases susceptibility to genotoxic exposure. Chk1, a kinase with a major role in DNA damage response, and its downstream substrate, Cdc2/CDK1 kinase, were inhibited in MEFCsnk1d null cells as well as in MEFCtl cells transfected with CK1δ siRNA, suggesting that CK1δ is required for the G2/M mitotic checkpoint. Hydroxyurea-induced Chk1 activation was also impaired in cells lacking CK1δ, and re-expression of CK1δ rescued the phenotype. Together, the data indicate that CK1δ is required for efficient repair of DNA damage and the proper functioning of mitotic checkpoints. The mechanism(s) responsible for these activities are currently under investigation. Citation Format: Yoshimi E. Greer, Bo Gao, Yingzi Yang, Stanley Lipkowitz, Jeff S. Rubin. Lack of CK1δ increases DNA damage and genomic instability due to defects in DNA repair and mitotic checkpoints. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3024. doi:10.1158/1538-7445.AM2015-3024
NPM1 Mutations Are Responsible for Better Response to Induction Therapy in AML Patients through the Inactivation of NF-kB.
Authors: Daniela Cilloni, Francesca Messa, Valentina Rosso, Sonia Carturan, Francesca Arruga, Ilaria Defilippi, Renata Catalano, Annalisa Chiarenza, Alessandro Morotti, Emanuela Messa, Enrico Bracco, Giuseppe Saglio
Journal: Blood (2005)
Curbing Firearm Violence
Authors: Steven Weinberger
Journal: Annals of Internal Medicine (2016)

Letters20 December 2016Curbing Firearm ViolenceSteven Weinberger, MDSteven Weinberger, MDFrom American College of Physicians, Philadelphia, Pennsylvania.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L16-0540 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Dr. Sklaroff politicizes the view expressed in my editorial, framing it as a “gun control” position rather than a recognition of the medical profession's responsibility to address issues that affect public health and the potential for injury or death to each clinician's patients and family members. There is absolutely no intent for physicians to be deputized to report gun ownership to local, state, or federal governments, and it is unfortunate that gun rights advocates, such as Dr. Sklaroff, take this unfounded position. There is also no proposal to impose “mandated questioning” on physicians but rather a recognition that ...Reference1. Weinberger SE, Hoyt DB, Lawrence HC, Levin S, Henley DE, Alden ER, et al. Firearm-related injury and death in the United States: a call to action from 8 health professional organizations and the American Bar Association. Ann Intern Med. 2015;162:513-6. [PMID: 25706470]. doi:10.7326/M15-0337 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From American College of Physicians, Philadelphia, Pennsylvania.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0968. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoCurbing Firearm Violence: Identifying a Specific Target for Physician Action Steven E. Weinberger Curbing Firearm Violence Robert B. Sklaroff Metrics 20 December 2016Volume 165, Issue 12Page: 894KeywordsDisclosureFirearm injuriesPrevention, policy, and public health ePublished: 20 December 2016 Issue Published: 20 December 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
P0118 : Phase 1–2 clinical trial in patients with decompensated liver cirrhosis treated with bone-marrow derived endothelial progenitor cells
Authors: D. D’Avola, V. Fernandez-Ruiz, F. Carmona de la Torre, M. Mendez, F. Prosper, E. Andreu, J.I. Herrero, M. Iñarrairaegui, C. Fuertes, B. Sangro, J. Prieto, J.I. Bilbao, J. Quiroga
Journal: Journal of Hepatology (2015)
PWE-016 The Endoscopic Retrograde Cholangiopancreatography Quality Network: a tool for improving standards: a preliminary comparison of UK and US practice: Abstract PWE-016
Authors: K W Oppong, H L Smart, R M Charnley, D Nylander, T Reilly, H Mitchison, S Campbell, M Nayar, D Garrow, P Cotton
Journal: Gut (2010)

<h3>Introduction</h3> There is increasing interest in documenting the performance of individual endoscopists for their own education and to safeguard quality standards.1 What has hitherto been lacking is an infrastructure to facilitate collection and analysis of data to allow practioners to easily compile a “report card” of their own practice or benchmark themselves against their peers. <h3>Methods</h3> The Endoscopic Retrograde Cholangiopancreatography Quality Network (ERCP N) is a web-based tool that started as a voluntary reporting system in the US.2 Anonymised key data points (indications, sedation/anaesthesia, therapies, successes and adverse events) on each case are uploaded through a web-based interface onto a central server. 73 American endoscopists have uploaded data on 11 015 ERCP procedures. Eight British endoscopists enrolled more recently and have reported so far on 1007 procedures. Individual report cards or benchmark reports against the average of all users can be user-generated online. <h3>Result</h3> The table shows some of the areas (mean values) where practice differed between countries. All numbers (except the total) are percentage, and all differences are statistically significant. These data do not purport to reflect average UK and US practice, as participants are self-selected and not necessarily representative. UK endoscopists in this study performed less complex procedures as judged by the accepted complexity grade3 with lower (but acceptable) technical success rates. There were no significant differences in average procedure and fluoroscopy times or the proportion of cases involving trainees (Abstract 016). <h3>Conclusion</h3> UK users have found it quick and easy to enter data and that it provides very useful information. Collection of this level of data about one9s own practice is likely to become mandatory in the near future. We hope that these very preliminary data will encourage other UK endoscopists to participate.
OC-070 Assessment of rectal compliance and sensory function following temporary sacral nerve stimulation
Authors: M R E Abdel-Halim, A C Windsor, C R G Cohen, A V Emmanuel
Journal: Gut (2010)

<h3>Introduction</h3> Sacral Nerve Stimulation (SNS) is an increasingly used minimally invasive treatment option in anorectal functional disorders. However, little is understood about its mechanism of action and studies report inconsistent anorectal physiological changes with stimulation. The study aim was to examine the effect of SNS on rectal compliance and rectal sensory function. <h3>Methods</h3> Nineteen consecutive patients (all female, median age 49 (30–74)) undergoing temporary SNS for faecal incontinence (FI) were studied prospectively. The clinical response was assessed using bowel diaries and Wexner scores. Anal manometry, rectal compliance and volume and pressure thresholds to rectal distension (barostat) were measured pre- and post- stimulation. <h3>Results</h3> Aetiology of FI was obstetric (9 patients, 47%), post-surgical (2, 10.5%), atrophic (2, 10.5%), scleroderma, subarachnoid haemorrhage and “idiopathic” (6, 32%). Endo-anal Ultrasound showed normal intact sphincters in 11 (58%), sphincter atrophy in 3 (16%) and sphincter defects in 5 (26%). Thirteen patients (68%) had favourable response to the stimulation, with Wexner scores reducing from 14.1±3.4 to 6.5±4.8 (p=0.0002). The presence of sonographic sphincter abnormalities did not influence the clinical response (p=0.806). Anal manometry: Anal pressures increased with stimulation: mean resting pressure increasing from 45±25 to 55±31 cm H<sub>2</sub>O (p=0.095) and mean squeeze pressure from 62±47 to 88±61 cm H<sub>2</sub>O (p=0.019). Compliance: Rectal compliance did not change with stimulation (pre: 12.9±3.9 ml/mm Hg, post: 12.5±3.9 ml/mm Hg, p=0.727). Sensory function: There was a trend towards reduction of the volume threshold for First Sensation (pre: 83±39 ml, post: 64±30 ml, p=0.062) and increase in the Maximum Tolerated Pressure (pre: 21.7±5.7 mm Hg, post: 25.0±8.0 mm Hg, p=0.036). <h3>Conclusion</h3> Short-term SNS is not associated with altered rectal compliance, but there are changes in thresholds to rectal distension. Taken together with the observation that outcome is not related to sphincter integrity, this supports the hypothesis of an afferent-mediated mechanism of action. The observed increase in anal pressures is most likely reflex-mediated and further assessment at more central levels of the brain-gut axis is indicated.
Retroviral Ectopic Expression of a Signaling-Defective Thrombopoietin Receptor (Mpl) Induces a Systemic Loss of Hematopoietic Stem Cells in Mice,
Authors: Sabine Wintterle, Dirk Heckl, Adrian Schwarzer, Guntram Buesche, Christopher Baum, Ute Modlich
Journal: Blood (2011)
741. Development of LNA Gapmer Oligonucleotide Based Therapy for FTD/ALS Caused by the C9orf72 Repeat Expansion
Authors: Yoshitsugu Aoki, Raquel Manzano, Shin'ichi Takeda, Kevin Talbot, Matthew Wood
Journal: Molecular Therapy (2016)

A hexanucleotide repeat expansion mutation in the C9orf72 locus is the commonest genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Currently, the biological function of C9orf72 remains unknown. However, bioinformatic analysis has revealed that the C9orf72 gene product has a differentially expressed in normal and neoplasia (DENN)-like domain and might regulate membrane trafficking as a Rab-GTPase GDP/GTP exchange factor. Here, using comprehensive GST-Rab pulldown analysis, we show that C9orf72 physically interacts with the Rab29 GTPase (also known as Rab7L1), suggesting that C9orf72 is a Rab29 effector. Further, we show that loss of the C9orf72/Rab29 interaction leads to dramatically reduced trafficking of extracellular vesicles (EVs), impaired intracellular trans-Golgi trafficking, and a consequent deficiency of autophagy in fibroblasts and iPSC-derived neurons from patients with C9ALS/FTD. Both overexpression of C9orf72 and antisense oligonucleotides targeting repeat-containing C9orf72 transcripts to upregulate normal variant 1 transcript levels are able independently to rescue the defective EV, trans-Golgi vesicle trafficking and basal autophagy phenotype. Our findings identify C9orf72 haploinsufficiency as a major contributing factor in ALS/FTD neurodegenerative disorders and directly link ALS/FTD to EV biogenesis. Furthermore, we demonstrate that this novel ALS/FTD pathogenic mechanism can be rescued by an antisense-based intervention.
Abstract 422: The role of CCL2 in the breast cancer tumor microenvironment and metastasis
Authors: Nicole Lavender, Jiqing Sai, Jinming Yang, Sergey V. Novitskiy, Ann Richmond
Journal: Cancer Research (2015)

Abstract Background: Although many effective breast cancer treatments exist, metastasis remains a major problem. Increasing evidence suggests that leukocyte-associated chemokines may play an important role in tumor growth and metastasis. For instance, recent data shows that reduction of CCL2 diminishes the recruitment of inflammatory monocytes to the tumor microenvironment (TME) and inhibits metastatic seeding to lung and bone marrow. Therefore, our goal is to examine the impact of CCL2 on the TME and pre-metastatic niche (i.e., lung). Methods: We are investigating how delivery of this chemokine affects breast tumor growth and metastasis by treating mice possessing highly metastatic and poorly metastatic tumors with CCL2, a CCL2 receptor (CCR2) antagonist, or vehicle for two weeks. Treatment will start 7 days after tumor implantation. On days 7, 14 or 21, tumors, lungs, and regional lymph nodes will be harvested and tumor size, number of metastases, and leukocyte infiltrate in both the tumor and the metastatic niche will be analyzed by FACS. This will allow us to fully characterize how intranasal delivery of CCL2 will affect the presence of mesenchymal stem cells (CD44+, CD73+, CD90+, CD146+/NOTCH3+, CD19-, CD45-), subsets of T cells, and myeloid cells in the TME or pre-metastatic niches. We will evaluate the intracellular cytokine and enzymatic profile (IL-4, IL-13, IL-17, ARG1 or IFNγ, IL-12, iNOS2) of Brefeldin-treated leukocytes to reveal whether they are pro- or anti-tumorigenic, respectively. Results: Our preliminary studies demonstrate that CCL2 enhances the release of hydrogen peroxide from neutrophils, a mechanism utilized by these cells to kill tumors cells. Furthermore, the addition of CCL2 to co-cultures of neutrophils and tumor cells increases the ability of neutrophils to kill tumor cells. Conclusions &amp; Future Directions: Our data shows that delivery of CCL2 in vitro enhances the activity of neutrophils and their ability to kill tumor cells. Ongoing studies are examining the effects of in vivo and ex-vivo delivery of CCL2 or a CCR2 antagonist on primary tumor growth and metastasis. We will also investigate how administration of CCL2 or a receptor antagonist will affect the presence or absence of leukocytes in the TME. These findings will determine whether the addition of CCL2 during treatment of the primary tumor will provide a mechanism for reducing the potential of future breast cancer metastases. Citation Format: Nicole Lavender, Jiqing Sai, Jinming Yang, Sergey V. Novitskiy, Ann Richmond. The role of CCL2 in the breast cancer tumor microenvironment and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 422. doi:10.1158/1538-7445.AM2015-422
660. Bowel/Bladder Sensation and Control in Patients with Spinal Cord Injury Treated with Human Embryonic Stem Cell Therapy
Authors: Geeta Shroff
Journal: Molecular Therapy (2015)

Introduction: Spinal cord injury (SCI) involves a complex series of pathological events resulting in long-lasting locomotor and sensory neuron degeneration. The present study evaluated the bowel/bladder sensation and control in patients with SCI after human embryonic stem cell (hESC) therapy.
Vitamin D repletion and prevention of bone loss in nonosteoporotic women with breast cancer.
Authors: S. Servitja, D. Prieto-Alhambra, M. Martinez-Garcia, L. Garrigos, M. J. Pena, A. Diez-Perez, J. Albanell, X. Nogues, I. Tusquets
Journal: Journal of Clinical Oncology (2011)

9026 Background: Aromatase inhibitor (AI)-associated bone loss increases fracture rates. Vitamin D might play a role in minimizing this fracture risk. We sought to assess the association between 25-hydroxy-Vitamin D concentrations ([25(OH)D]) at baseline, after 3-months of supplementation, and bone loss after 1 year on AI therapy. Additionally, we investigated the relationship between [25(OH)D] increments ([25(OH)D] at 3 months minus baseline) and AI-associated bone loss. Methods: Prospective cohort study including a consecutive women initiating AIs for early breast cancer from January/2006 to June/2009 (N=230). Serum [25(OH)D] was measured at baseline and at 3 months, and bone loss was defined as: lumbar spine (LS) absolute loss (baseline minus 1-year BMD) and bone loss rate (absolute loss over baseline BMD). Participants were supplemented with daily oral calcium (1g) and vitamin D3 (800 IU) and, in those with baseline [25(OH)D] was <30 ng/ml,with additional oral 16,000 IU every 2 weeks if. Linear regression models were fitted to adjust for potential confounders. For the current analyses, we included those whithout basal osteoporosis and, hence, not eligible for bisphosphonate therapy. Results: In the overall population (N=156), increasing levels of [25(OH)D] at 3 months were inversely correlated to LS bone loss rates (adjusted beta for each 10ng/ml -0.41 [95%CI - 0.68 to -0.13], p=0.005) and to absolute bone loss (-0.004 g/cm2, [-0.007 to -0.004], p=0.003) at 1 year. [25(OH)D] increments at 3 months were also protective (adjusted beta for each 10 ng/ml for bone loss rates: -0.46 [-0.71 to -0.21], p<0.001; for absolute bone loss: -0.004 [-0.007 to -0.002], p<0.001). Of note, in the subset with baseline deficiency, baseline [25(OH)D] appeared directly related with BMD loss, although this was of borderline significance (adjusted beta for each 10 ng/ml 1.1, 95%CI -0.008 to 2.25, p-val 0.07). Conclusions: [25(OH)D] increments due to supplementation prevents AI-associated bone loss, independently of baseline [25(OH)D]. Hence, vitamin D supplements, with higher dosage than the standard 400 to 800 IU/day, might be useful to minimize bone loss in low risk women starting on AIs.
Intensity of FDG Uptake on PET Scan Varies by Histologic Subtype of Hodgkin Lymphoma.
Authors: Nagaraj Holalkere, Ephraim P. Hochberg, Ronald Takvorian, Michael Blake, Christiana Toomey, James Michaelson, Aliyah Rahemtullah, Jeremy S. Abramson
Journal: Blood (2007)