tbuckley/cabot-search huggingface dataset:
The secret realm of phase I trials in healthy volunteers
Authors: J. Kimmelman
Journal: BMJ (2015)

Regulators should demand greater transparency

Phase I clinical trials in healthy volunteers aim at establishing safety, pharmacokinetics, and dosage for subsequent testing of new drugs. They are a necessary step in building the evidence for new treatments. But many view them with suspicion. Phase I trials expose humans to unproved drugs—often at plasma concentrations needed for detecting toxicity. Because volunteers are healthy, the ratio of medical risk to benefit for them is almost infinite. Another reason for suspicion is that healthy volunteers are paid—a fact that makes it likely that primary motivations for participation are misaligned with those of researchers,1 and that study participants will be drawn from underemployed people.

A few catastrophic events in phase I testing, including the death of a relatively healthy volunteer in 1999, and the occurrence of life threatening toxicities in six participants in 2006, have also fuelled concerns.2 3 Finally, there is the problem of opacity. What happens in phase I studies in healthy volunteers is largely hidden from public view.4 5 Some policies, such as the US Food and Drug Administration Amendments Act of 2007,6 exempt …
Amplification of the MET receptor to drive resistance to anti-EGFR therapies in colorectal cancer.
Authors: Alberto Bardelli, Simona Corso, Andrea Bertotti, Sebastijan Hobor, Giulia Siravegna, Andrea Sartore-Bianchi, Giorgia Migliardi, Francesco Galimi, Calogero Lauricella, Carlo Zanon, Alessio Amatu, Marcello Gambacorta, Luis A. Diaz, Victor E. Velculescu, Mark Sausen, Paolo M. Comoglio, Livio Trusolino, Federica Di Nicolantonio, Silvia Giordano, Salvatore Siena
Journal: Journal of Clinical Oncology (2013)

11005 Background: The anti EGFR monoclonal antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancer patients but their clinical efficacy is limited by the development of acquired resistance. We recently reported that secondary KRAS mutations are responsible for acquired resistance in approximately 50% of the patients who initially respond to cetuximab or panitumumab (Misale et al., Nature 2012; Diaz et al., Nature 2012). Here we studied the molecular bases of relapse in CRC patients who do not develop KRAS mutations during the course of anti-EGFR therapy. Methods: Next generation sequencing was applied to tumor biopsies to identify genetic alterations associated with relapse to cetuximab and panitumumab in mCRC patients. Detection and quantitation of genetic alterations in circulating tumor DNA was used to monitor the occurrence of KRAS mutations and MET amplification in blood samples. Results: Molecular analyses of tumor biopsies from patients who did not develop KRAS mutations during anti-EGFR therapy revealed high level of amplification of the MET proto-oncogene in 3/5 cases. Quantitative PCR, FISH and IHC analysis confirmed high level of MET amplification in the post-therapy samples but not in the matched pre-treatment tissues. We developed a PCR based assay to detect the presence of the MET amplicon in circulating, cell-free, DNA. We found that MET amplification could be detected in the blood as early as 3 months after initiation of anti EGFR therapy. To functionally evaluate the role of MET amplification on resistance to anti EGFR antibody therapies we exploited patient-derived CRC xenografts (‘xenopatients). We found that (2/2) xenopatients established from MET amplified tumors were completely refractory to cetuximab but showed sensitivity to the Met inhibitor crizotinib. Conclusions: Amplification of the MET proto-oncogene is responsible for acquired acquired resistance to anti-EGFR antibody therapy in a subset of CRCs. The emergence of MET amplification in circulating, cell-free, DNA may be used to select patients most likely to benefit from anti MET therapies.
Genome-Wide Polyadenylation Maps Reveal Dynamic mRNA 3′-End Formation in the Failing Human Heart
Authors: Esther E. Creemers, Amira Bawazeer, Alejandro P. Ugalde, Hanneke W.M. van Deutekom, Ingeborg van der Made, Nina E. de Groot, Michiel E. Adriaens, Stuart A. Cook, Connie R. Bezzina, Norbert Hubner, Jolanda van der Velden, Ran Elkon, Reuven Agami, Yigal M. Pinto
Journal: Circulation Research (2015)

Rationale: Alternative cleavage and polyadenylation (APA) of mRNA represents a layer of gene regulation that to date has remained unexplored in the heart. This phenomenon may be relevant, as the positioning of the poly(A) tail in mRNAs influences the length of the 3′-untranslated region (UTR), a critical determinant of gene expression. Objective: To investigate whether the 3′UTR length is regulated by APA in the human heart and whether this changes in the failing heart. Methods and Results: We used 3′end RNA sequencing (e3′-Seq) to directly measure global patterns of APA in healthy and failing human heart specimens. By monitoring polyadenylation profiles in these hearts, we identified disease-specific APA signatures in numerous genes. Interestingly, many of the genes with shortened 3′UTRs in heart failure were enriched for functional groups such as RNA binding, whereas genes with longer 3′UTRs were enriched for cytoskeletal organization and actin binding. RNA sequencing in a larger series of human hearts revealed that these APA candidates are often differentially expressed in failing hearts, with an inverse correlation between 3′UTR length and the level of gene expression. Protein levels of the APA regulator, poly(A)-binding protein nuclear-1 were substantially downregulated in failing hearts. Conclusions: We provide genome-wide, high-resolution polyadenylation maps of the human heart and show that the 3′end formation of mRNA is dynamic in heart failure, suggesting that APA-mediated 3′UTR length modulation represents an additional layer of gene regulation in failing hearts.
Abstract #5489: Sorafenib inhibits IL-6 induced STAT3 signaling in cholangiocarcinoma cells and demonstrates in vivo efficacy
Authors: Boris Blechacz, Rory Smoot, Steven Bronk, Nathan Werneburg, Scott Wilhelm, Alphonse Sirica, Gregory Gores
Journal: Cancer Research (2009)

Introduction and aims: Cholangiocarcinoma (CCA) is a devastating neoplasm with no proven medical therapy. IL-6 signaling pathways play a pivotal role in the biology of this cancer. Sorafenib is a multikinase inhibitor approved by the FDA for the treatment of hepatocellular carcinoma. However, its effect on the IL-6 signaling cascade and its in vivo efficacy in CCA is unknown. Our aims were, therefore, to evaluate sorafenib as a therapeutic agent for CCA. Methods: Studies were performed using the human CCA cell lines HuCCT-1 and KMCH-1. Expression and activation of the IL-6 signaling axis were evaluated by immunoblot analysis and STAT3 nuclear translocation by immunofluorescence studies. Apoptosis was morphologically quantified by DAPI-staining and fluorescence microscopy; apoptosis was confirmed by caspase-3/7 analysis. In vivo efficacy analysis was performed in a recently described novel orthotopic, syngeneic CCA rat model (Sirica et al.: Hepatology 2008; 47: 1178-1190). Results: Sorafenib (10 \#956;M) does not interfere with IL-6 secretion by CCA cells as quantified by an ELISA assay. Likewise, it does not alter expression of gp130, gp80, JAK 1 and 2, key proteins of the IL-6 signaling complex. In contrast, sorafenib completely abrogates STAT3 phosphorylation, a key mediator of IL-6 signaling, without altering total cellular STAT3 levels. Sorafenib treatment also reduced nuclear localization of this transcription factor four-fold. The Sorafenib-mediated effect on the phosphorylated form of STAT3 was inhibited in the presence of the phosphatase inhibitor sodium pervanadate. Further analysis revealed that the effect of sorafenib on STAT3 dephosphorylation was mediated by Raf-kinase inhibition. Sorafenib treatment also reduced cellular levels of the anti-apoptotic protein Mcl-1, a transcriptional target of STAT3. As Mcl-1 downregulation is known to sensitize cells to TRAIL-mediated cytotoxicity, we examined TRAIL-mediated apoptosis. Treatment with sorafenib markedly sensitized HuCCT-1 and KMCH-1 CCA cells to TRAIL killing. Finally, our in vivo data demonstrate that sorafenib elicits a significant tumor suppressive effect in an orthotopic, syngeneic rat CCA model. Treatment with 10 mg/kg Sorafenib achieved significant tumor suppression. 21 days after tumor implantation, 60% of Sorafenib treated animals were alive versus 0% in the treatment group. Conclusions: In cholangiocarcinoma cells, Sorafenib-mediated Raf-kinase inhibition interferes with IL-6 activation of STAT3, reducing cellular expression of Mcl-1, and, thereby, sensitizing CCA cells to TRAIL-cytotoxicity. Significant therapeutic effects were observed with Sorafenib treatment in an orthotopic, syngeneic CCA rat model. Sorafenib merits evaluation for the treatment of human CCA.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5489.
Vertigo and the pill. (Letter)
Authors: Siegler J
Journal: BMJ (1977)

I have read with interest your leading article on the incidence of vertigo in children (November 5 p. 1173).  My experience as an otolaryngologist has led me to believe that there are many causes of vertigo especially in young people which have not been recognized so far.  The common causes of labyrinthine vertigo such as Menieres disease or labyrinthitis usually occur in the older age groups but in my personal practice I have met with an increasing number of young women who have suffered from true vertigo.  Examination of their respiratory tract has not shown evidence of disease in the ears nor has there been very much in the way of deafness or disorder of labyrinthine function as shown on an electronystagmograph.  There has been 1 common thread in all these patients and that is that most of them are young women in their 20s and 30s taking a contraceptive pill.  They have often related the onset of the symptoms to the time when they began taking the pill.  In many cases I have persuaded the patient to discontinue the pill and perhaps adopt an alternative method of contraception and the incidence of vertigo has subsided.  An attempt was made to gain the cooperation of a family planning clinic to send patients along who are on the pill with a view to testing their hearing as well as their labyrinthine function but unfortunately most of them were unwilling to  submit to such an investigation and it had to be abandoned.(Full text)
Weight loss results in significant improvements in quality of life for patients with nonalcoholic fatty liver disease: A prospective cohort study
Authors: Elliot B. Tapper, Michelle Lai
Journal: Hepatology (2015)

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and associated with decreased quality of life (QOL). The currently available treatment is weight loss through lifestyle modification. However, longitudinal QOL data are lacking on whether weight loss improves QOL. We prospectively enrolled 151 patients with NAFLD from 2009 to 2014. All patients received a liver biopsy, lifestyle assessment, blood tests, and QOL tools, including the Chronic Liver Disease Questionnaire (CLDQ), a validated health‐related quality of life measurement. All patients were followed with a repeat CLDQ at 6 months. The cohort included 91 (60%) men, ages 51.5 ± 12.6 years, 46 (30%) of whom were diabetic. Thirty (21%) had advanced fibrosis or cirrhosis and 67 (47%) had a NAFLD Activity Score &gt;4. Overall, 47 (31%) patients achieved at least a 5% reduction in weight. The cohort's median baseline total CLDQ value was 5.6 (interquartile range: 4.8‐6.2). Those who achieved at least a 5% reduction in weight had a 0.45 (95% confidence interval [CI]: 0.24‐0.66; P &lt; 0.0001) point improvement in the total CLDQ, compared to 0.003 (95% CI: ‐0.12‐0.12; P = 0.95) in those who did not. Nondiabetic patients with nonalcoholic steatohepatitis and without advanced fibrosis are most likely to achieve QOL benefits from weight loss. For every decrement in body mass index (BMI), there was a corresponding increase of 0.09 (95% CI: 0.03‐0.16) points in the CLDQ scale ( P = 0.005), adjusting for histology, diabetes, sex, age, and change in alanine aminotransferase level and change in FIB‐4 index. A decrease by 5 points in BMI leads to a 10% adjusted improvement in QOL. Conclusion: Patients with NAFLD can experience significant improvements in QOL that appear specific to weight loss and not biochemical improvements. (H epatology 2016;63:1184–1189)
Older people are afraid to complain, says ombudsman
Authors: Adrian O’Dowd
Journal: BMJ (2015)

Many people in England aged over 65 are either too scared to complain about their care, because of negative consequences, or don’t know how to raise concerns, claims the parliamentary and health service ombudsman.

Julie Mellor, who makes final decisions on complaints that have not been resolved by the NHS in England, published a report on 30 December in which she highlighted …
Novel strategy increases capacity of tumor vaccine to provide cross-protection against unique MCA-induced sarcomas.
Authors: Chris Twitty, Shawn Jensen, Hong-Ming Hu, Bernard Fox
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2847 

Vaccination with irradiated 3-Methylcholanthrene (MCA)-induced tumor cells provides protection from a subsequent viable challenge with the same MCA tumor, but not other MCA-induced tumors. This observation of unique tumor-specific protection, first reported in 1957 by Prehn and Main, has been well documented by numerous laboratories, including ours and is a well-established paradigm in tumor immunology. We postulated that all MCA-induced sarcomas overexpress some genes in common, but only the unique tumor-rejection antigens are stable enough to be cross-presented and induce antitumor immunity. We further postulated that the overexpressed genes common to most/all sarcomas are proteins with a very short half-life, such as Defective Ribosomal Proteins (DRiPs) and Short-Lived Proteins (SLiPS), which are not cross-presented due to their transient nature. Recently we (H. Hu, manuscript submitted) developed a strategy where DRiPs and SLiPs could be stabilized and isolated in autophagic-like vesicles (DRibbles) for use as a vaccine and documented that this approach allowed efficient cross-presentation of antigens that were normally too labile to stimulate an immune response. This strategy was employed to ask whether vaccination with DRibbles isolated from one antigenically distinct MCA sarcoma would cross-protect from another antigenically distinct MCA sarcoma. Individual MCA sarcomas were treated with a proteosome inhibitor to block degredation of SLiPs and DRiPs and promote their accumulation in autophagic-like vesicles (DRibbles) that were isolated by differential centrifugation. Vaccination with irradiated MCA-310 tumor cells protected mice from a subsequent challenge, 14 days later, with viable MCA-310 (10/10) but not MCA-311 (0/10). In contrast, vaccination with DRibbles isolated from either of two unique sarcomas demonstrated delay in tumor growth and increased survival (p<0.05) following challenge with either tumor. These results impact our understanding of how tumor immunity is obtained; specifically how increasing the antigen repertoire to include SLiPs and DRiPs can lend protection where it otherwise does not exist. Supported by RO1s CA80964 (BAF), CA107243 (HH) the Chiles Foundation and the Murdoch Trust.
Preclinical Evidence and Clinical Cases of Azd9291 Activity in Egfr-Mutant Non-Small Cell Lung Cancer (Nsclc) Brain Metastases (Bm)
Authors: D. Kim, J. Yang, D. Cross, P. Ballard, P. Yang, J. Yates, L. Xie, M. Cantarini, S. Ghiorghiu, P.A. Janne
Journal: Annals of Oncology (2014)
Abstract LB-149: A novel strategy to inhibit CpG island hypermethylation and restore BRCA1 expression
Authors: Yoo Jeong Han, Jing Zhang, Aleix Prat, Toshio Yoshimatsu, Maria Gomez-Vega, John Kwon, Charles M. Perou, Prasanth Kannanganattu, Olufunmilayo I. Olopade
Journal: Cancer Research (2015)

Abstract BRCA1 promoter methylation is observed in 20-60% of sporadic triple negative breast cancer (TNBC) and may be an important mechanism contributing to the loss of BRCA1 function in sporadic TNBC and other cancers with low BRCA1 expression. Demethylation and consequent reactivation of tumor suppressor genes are rational approaches being used in the treatment of cancer. However, currently available nucleoside-based DNMT inhibitors affect genome-wide DNA methylation and cannot specifically target tumor suppressor genes like BRCA1. Here, we describe a novel approach to modulate local DNA methylation by silencing a neighboring long non-coding RNA (lncRNA) which tethers DNMT1 at the BRCA1 genomic locus. The human genomic region encompassing the BRCA1 gene is complex and includes two protein coding genes (BRCA1 and NBR1), a non-coding RNA gene (NBR2), and a pseudogene of BRCA1 (BRCA1P1), within a ∼170kb region of chromosome 17q21. The BRCA1 gene on the minus strand is located head-to-head with NBR2 on the plus strand, whereas BRCA1P1 on the minus strand is located head-to-head with NBR1 on the plus strand. The promoter between the BRCA1 and NBR2 genes and that between the BRCA1P1 and NBR1 genes are bidirectional, expressing transcripts in opposite directions through convergent transcription. The BRCA1P1 pseudogene was generated by a recent evolutionary event: partial duplication of BRCA1 gene followed by insertion of a processed pseudogene of RPLP1. It expresses a chimeric lncRNA retained in nuclei. Interference with the nuclear expression of BRCA1P1 lncRNA using a specific anti-sense oligonucleotide (ASO) decreased the promoter methylation of BRCA1 and increased BRCA1 expression. RNA immunoprecipitation (RIP) assays revealed DNMT1 interactions with BRCA1 mRNA and BRCA1P1 lncRNA at the locus. Chromosome conformation capture (3C) will assess whether there is a long-range interaction between the BRCA1 and BRCA1P1 promoters through DNMT1 and mediators. Our data support a long-range cis-regulation of BRCA1 expression by neighboring BRCA1P1 lncRNA through an interaction with DNMT1 at the locus. Depleting BRCA1P1 with ASO could be developed as a therapeutic method to inhibit BRCA1 promoter methylation and restore BRCA1 expression. Citation Format: Yoo Jeong Han, Jing Zhang, Aleix Prat, Toshio Yoshimatsu, Maria Gomez-Vega, John Kwon, Charles M. Perou, Prasanth Kannanganattu, Olufunmilayo I. Olopade. A novel strategy to inhibit CpG island hypermethylation and restore BRCA1 expression. [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 LB-149. doi:10.1158/1538-7445.AM2015-LB-149
Capecitabine and oxaliplatin as first-line treatment in patients with metastatic colorectal cancer (MCRC): A pooled analysis of randomized phase II-III trials
Authors: R. Porschen, H. Arkenau, D. Arnold, J. Cassidy, E. Díaz-Rubio, J. Douillard, A. Grothey, A. Hinke, W. Schmiegel, H. Schmoll
Journal: Journal of Clinical Oncology (2008)

4055 Background: 5 randomized phase II and III trials have yet investigated the role of oxaliplatin in combination with either capecitabine (XELOX/CAPOX) or infusional 5-FU. The aim of these studies was to show non-inferiority of the oral versus the infusional combination. This meta-analysis was performed to compare the efficacy of capecitabine/oxaliplatin compared with infusional 5-fluorouracil (5- FU)/oxaliplatin regimens. Methods: This meta-analysis was based on all published summary data from reported randomized [phase II-III] trials comparing XELOX/CAPOX versus different infusional 5-FU/oxaliplatin. In total 2,575 patients (5-FU: 1,278 pts, capecitabine 1,297 pts) were included and analyzed for response rates (RR), progression free and overall survival (PFS, OS) (fixed effect & random effects models). The required estimates and standard deviations were derived from the published RR, hazard ratios (HR) and their confidence intervals (CI) or logrank p values, respectively. Results: With the exception of the PFS finding in a smaller phase II trial (chi² test on heterogeneity: p=0.11, I²=46%), there was no striking inter-study heterogeneity, despite of different standard therapies in each of the five trials. The fixed effect pooled estimation for RR showed a slightly increased RR for 5-FU based regimens (Odds ratio (OR) 0.76, 95% CI 0.61 - 0.95, p=0.02), excluding the bevacizumab containing NO 16966 trial. The inclusion of the latter trial to this analysis revealed an OR of 0.86, 95% CI 0.75 - 0.99, p=0.04). However, for PFS (HR 1.05, 95% CI 0.97 - 1.14, p=0.25) and OS (HR 1.05, 95% CI 0.95 - 1.15, p=0.34) all models suggested similar clinical outcome for both regimens with HR´s and 95% CI’s being clearly within the range of non-inferiority. Conclusions: The results of this meta-analysis demonstrate that the combination of capecitabine and oxaliplatin is associated with a slightly reduced RR but similar PFS and OS compared with infusional 5-FU/oxaliplatin regimens in first-line MCRC. No significant financial relationships to disclose.
<scp>C</scp>hronic lymphocytic leukemia (CLL)—<scp>T</scp>hen and now
Authors: Kanti R. Rai, Preetesh Jain
Journal: American Journal of Hematology (2015)

The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO‐1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo‐immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kδ inhibitor) and novel anti‐CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT‐199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. Am. J. Hematol. 91:330–340, 2016. © 2015 Wiley Periodicals, Inc.
Novel antioxidative nanotherapeutics in a rat periodontitis model: Reactive oxygen species scavenging by redox injectable gel suppresses alveolar bone resorption
Authors: Makiko Saita, Junya Kaneko, Takenori Sato, Shun-suke Takahashi, Satoko Wada-Takahashi, Ryota Kawamata, Takashi Sakurai, Masaichi-Chang-il Lee, Nobushiro Hamada, Katsuhiko Kimoto, Yukio Nagasaki
Journal: Biomaterials (2015)