tbuckley/cabot-search huggingface dataset:
IGF-1R: A therapeutic target for colon cancer stem-like cells.
Authors: B. Patel, Y. Yu, A. P. Majumdar
Journal: Journal of Clinical Oncology (2010)

e14131 Background: A small subpopulation of chemotherapy resistant cancer stem cells (CSCs) drive majority of epithelial cancers including colon cancer. We have observed that chemosurviving (cells that survive acute chemotherapy insult) colon cancer cells are enriched in CSCs and express increased levels of IGF-1R (4.5-fold) (Transl Oncol. 2009;2:321). We hypothesized that depletion of IGF-1R levels by si-RNA would result in growth inhibition of cancer stem-like cells and restore growth inhibition mediated by chemotherapy. Methods: Chemosurviving HCT-116 (p53 wild type), HCT-116 p53-/- and HT-29 (p53 mutant) colon cancer cells were grown in DMEM media in the presence of oxaliplatin and 5-fluorouracil (5-FU). Western blot and quantitative RT-PCR were used for CSC marker expression. Cancer specific microRNA array (Invitrogen) and TaqMan Q-RT-PCR for miR levels were performed according to manufacturer's instructions. Results: Depletion of IGF-1R by si-RNA resulted in 35% inhibition of colonosphere formation, a CSC property, accompanied by a reduction in CD44 and CD166 levels particularly in p53 wild type (HCT-116) colon cancer cells. On miR array, we identified miR-215, a p53 regulated miR, which is normally downregulated in colon cancer, was upregulated by 2-fold (along with p21waf1/cip1) following IGF-1R inhibition only in p53 wild type cells. More importantly, we found that expression of miR-215 was decreased by 10-12 folds in chemosurviving or CD44+ fraction compared to parental or CD44- fraction of HCT-116 cells respectively. On the other hand, expression of thymidylate synthase (TS), the putative target of miR-215, overexpression of which is associated with 5-FU resistance in colon cancer was increased by 3- 10 fold in CD44+ and chemosurviving HCT-116 cells. Consistent with the above observation, treatment of colon cancer cells with 5-FU in combination with IGF-1R depletion resulted in robust 75% inhibition of colonosphere formation which was significantly higher than either modality alone only in p53 wild type HCT-116 cells. Conclusions: Depletion of IGF-1R resulted in reduction of CSC phenotype in colorectal cancer cells, which could partly be due to induction of p53 dependent miR-215 and down regulation of TS, its putative target. No significant financial relationships to disclose.
Cytoreductive surgery combined with peritoneal intraoperative heated chemotherapy for management of peritoneal carcinomatosis in 59 adults older than age 65
Authors: I. Bereder, O. Guerin, R. Boulahssass, A. Couderc, V. Mailland, F. Macone, N. Mounier, J. Habre, B. Karimdjee- Soilihi, J. Bereder
Journal: Journal of Clinical Oncology (2009)

e20657 Background: Peritoneal carcinomatosis (PC) has long been regarded as a terminal disease with short median survival. Recent success of new approach, combining surgery and intraperitoneal heated chemotherapy (HIPEC) are reported. But in the most studies patients over 65 years are excluded. We report our experience in this selected group of patients. Methods: A retrospective study was performed to evaluate toxicity and to identify the principal prognostic indicators with this combined treatment. All patients had cytoreductive surgery and HIPEC. This population of patients was compared with younger over the same period. We have excluded patient with frailty by comprehensive onco-geriatric assessment based upon cognitive, nutritional assessment and cormorbidities. Results: The study included 291 procedures in 249 patients between 2000 and 2008. 64 procedures were performed in 59 older patients (group 1) and 227 procedures in 190 younger patients (group 2). The principal etiologies of PC in group1 were recurrent ovarian cancer (N=33), colorectal cancer (N=9), peritoneal mesothelioma (N=6), pseudomyxoma (N=9) and sarcomatosis (N=2). No death occurred in post operative course and the procedure related morbidity rate was 10%. 5 years overall and free survival rate were respectively 33% and 15%. Median overall survival was 44 months and median disease free survival was 13 months. There were no difference between group1 and 2 for survival. Independent prognostic factors for survival by multivariate analysis were extent of carcinomatosis, completeness of cytoreductive surgery and performance status. Conclusions: Therapeutic approach combining cytoreductive surgery with HIPEC may achieve long-term survival in a selected group of patients with PC with acceptable mortality and morbidity. For elderly patients, this treatment could be performed in selected cases without frailty. No significant financial relationships to disclose.
Transmission of the Human Immunodeficiency Virus in the Health Care Setting — Time for Action
Authors: T A Brennan
Journal: New England Journal of Medicine (1991)

One of the most important challenges of the human immunodeficiency virus (HIV) epidemic is the potential for transmission of the virus in the health care setting, either from the patient to the health care provider or from the health care provider to the patient. To maintain the integrity of medical care for those infected with HIV, as well as to protect the rights of health workers, the leaders of health care institutions must consider the legal and ethical questions raised by fears of occupational transmission.At the beginning of the epidemic, little attention was paid to the occupational transmission of . . .
Metformin is backed as first line therapy for type 2 diabetes
Authors: Jacqui Wise
Journal: BMJ (2016)

The use of metformin as first line therapy for type 2 diabetes has been supported by a comprehensive systematic review and meta-analysis, given its relative safety and its beneficial effects on haemoglobin A1c, weight, and cardiovascular mortality.1

The US research, published in the Annals of Internal Medicine , included 179 trials and 25 observational studies of head to head monotherapy or …
OC-036 Stimulated expression of ileal fibroblast growth factor 19 by bile acids is impaired in patients with primary and secondary bile acid diarrhoea
Authors: JD Nolan, RN Appleby, GK Madhan, IM Johnston, K Sarah, JH Zhang, J Walters
Journal: Gut (2015)

<h3>Introduction</h3> Bile acid diarrhoea (BAD) results from excess luminal bile acids (BA) in the colon. Most BAs are reabsorbed at the terminal ileum. Increased colonic BA occur secondary to ileal disease or resection (common in Crohn’s disease [CD]) leading to BA malabsorption and secondary BAD (SBAD). Primary BAD (PBAD) occurs in the absence of overt ileal disease or malabsorption. The peptide FGF19 is produced from enterocytes in response to BA absorption and maintains homeostasis of the BA pool size by inhibiting hepatic BA synthesis. Impaired ileal FGF19 production may underlie the excess faecal BA observed in PBAD and may be contributory in CD as a result of increased hepatic BA synthesis. We aimed to investigate whether BA-induced expression of FGF19 in the ileum is reduced in patients with PBAD or CD. <h3>Method</h3> Patients attending for colonoscopy (n = 58) were prospectively recruited and gave informed consent to give additional ileal biopsies. 14 patients had CD (4 with previous right hemi colectomy and 10 without), 16 patients had unexplained diarrhoea and had SeHCAT tests, and 28 controls. Groups of 2–3 biopsies (explants) were incubated separately for 6 h with either BA-free culture media (unstimulated controls), chenodeoxycholate (CDCA) or glyco-CDCA (GCDCA), both at 50 µM. After RNA extraction and cDNA synthesis, FGF19 expression was quantified relative to GAPDH by RT-PCR. <h3>Results</h3> In patients with unexplained diarrhoea SeHCAT 7d retention values were &lt;15% in 7 patients, indicating primary BAD, and &gt;15% in 9 who were normal diarrhoea controls. A positive correlation was found between SeHCAT retention and the magnitude of the fold change in FGF19 expression stimulated by either CDCA (r = 0.50, n = 16, p = 0.02) or by GCDCA (r = 0.76, n = 7, p = 0.02). The median CDCA stimulated fold change in FGF19 expression was significantly lower in CD compared to controls (87, n = 12 vs 251, n = 28, p = 0.03) and a similar non-significant trend was observed for median GCDCA stimulated expression (97, n = 10 vs 156, n = 13, p = 0.18). <h3>Conclusion</h3> Ileal explants from patients with lower SeHCAT 7d retention had a lower response to both CDCA and GCDCA. Patients with CD had lower responses to CDCA. As uptake of GCDCA is dependent on carrier-mediated apical BA uptake but CDCA is not, this implies abnormalities in the intracellular ileal FGF19 response to BA. A reduced capacity to induce ileal FGF19 expression in response to absorbed BA is proposed to increase faecal BA due to increased hepatic BA synthesis in primary BAD. In secondary BAD an impaired ileal BA FGF19 response may lead to an increase in BA synthesis and faecal BA that is disproportionate to the degree of ileal BA malabsorption. <h3>Disclosure of interest</h3> None Declared.
Immunoelectron Microscopic Localization of a Tumor-Associated Antigen (TAA) in the Canine Transmissible Venereal Sarcoma by Anti-TAA-Antiferritin Hybrid Antibodies&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: D L Hill, T J Yang
Journal: JNCI Journal of the National Cancer Institute (1985)

Immunoferritin and immunoperoxidase reagents were used to localize a tumor-associated antigen (TAA) of the canine transmissible venereal sarcoma (CTVS). Round tumor cells from the CTVS at different stages of growth, i.e., progressive, steady state, and regressing, had TAA diffusely distributed throughout the cytoplasm. In general, TAA was not found on the plasma membrane, within the nucleus, between inner and outer membranes, in cytoplasmic vacuoles, or specifically with any part of the cytocavitary system. Transitional tumor cells, which are intermediate cell types between round cells and spindle-shaped cells and which appear in the tumors at steady state and regressing stages, contained less TAA in their cytoplasm than did the round cell type. The microvilli of tumor cells also contained TAA, suggesting that, in addition to whole cell lysis, shedding of all or parts of these processes may be a mechanism of TAA release as evidenced by the presence of antigenic activity in the extracellular material.
Results of Direct Coronary-Artery Surgery for the Treatment of Angina Pectoris
Authors: Edwin L. Alderman, Harvey J. Matlof, Lewis Wexler, Norman E. Shumway, Donald C. Harrison
Journal: New England Journal of Medicine (1973)

One hundred and two consecutive patients undergoing direct coronary surgery for the treatment of stable angina pectoris were evaluated extensively an average of 11.5 months after operation. Operative mortality was 3.9 per cent, and the incidence of early postoperative myocardial infarction was 6.9 per cent. Of the 102 patients, 62 per cent experienced complete relief of angina, 13 per cent were moderately improved, 16 per cent were unimproved, and 9 per cent were dead one year after surgery. Patients with prior myocardial infarction had a substantially diminished success rate for relief of angina. Sixty-three patients who had postoperative angiography demonstrated a very high correlation between clinical response and graft patency. We conclude that direct coronary surgery provides partial or complete relief of angina pectoris in 75 per cent of patients, and that this response to operative therapy can be directly related to surgical success as defined by angiographic evidence that the graft is patent.
A retrospective chart review study of relapsed or refractory multiple myeloma (MM) patients (Pts): A look into historical treatment (Tx) patterns
Authors: F. Zaman, D. E. Reece, B. L. Teixeira, K. Yoong, F. Camacho, R. K. Plante
Journal: Journal of Clinical Oncology (2009)

e19535 Background: New Tx options have become available on the market or as investigational agents in Canada for relapsed/refractory MM in the last few years. These new Tx options include IMiDs [thalidomide, lenalidomide (Revlimid)] and a proteosome inhibitor [bortezomib (Velcade)]. These new agents are changing both the Tx patterns as well as the clinical outcome of this disease. New combination regimens of both new agents and older generic drugs are also being investigated. Methods: This retrospective analysis included all relapsed/refractory MM Pts who initiated drug Tx between Jul-06 and Jun-07 at Princess Margaret Hospital, Toronto, ON. Historical data collection focused on prior Tx (types), duration and efficacy. Results: This analysis included all prior historical Tx data Dec-96 to Jul-07) from 151 Pts. 62% of Pts were male. Time from diagnosis to 1 st initial Tx was 1.7 (SD±4.2) months. Of the 25 Pts who had cytogenetics analyzed by FISH, 6 Pts had deletion 13q, 4 Pts had translocation involving chromosome 14 [including partner gene translocations on chromosomes 4 (2 Pts) and 11 (1 Pt)] and no Pts had deletion p53. 76.8% of Pts received at least 1 stem cell transplant (SCT) with 7.9% of Pts receiving 2 SCTs prior to current study Tx. Historical 1 st line &amp; 2 nd line Txs, respectively, were cyclophosphamide ± steroid (14.6%, 28.3%), IMiD-based (17.2%, 40.2%), melphalan + prednisone (14.6%, 9.8%), vincristine + adriamycin + dex (69.5%, 5.4%), steroid monotherapy (23.8%, 22.8%), bortezomib based (0.7%, 15.2%), and other (6.0%, 6.5%). Overall best RRs (≥MR) during historical 1 st &amp; 2 nd line Tx were 92.6% and 83.3% (≥ minimal response), respectively, with a corresponding 15.6% &amp; 11.9% combined CR + near CR rate, respectively, across all regimens reported. Historical median TTP following 1 st , 2 nd , and 3 rd line of Tx were 21.5 (95% CI: 18.9, 24.3), 20.2 (95% CI: 16.9, 22.8), and 10.0 (95% CI: 5.5, 16.6) months, respectively. Conclusions: This is the first known historical analysis of real world MM Txs in Canada from a large tertiary centre. Historical data suggests the common use of older drugs such as alkylating agents. This usage pattern may be different than in other countries where the accessibility of newer agents to treat MM is easier than in Canada. [Table: see text]
Abstract 4010: Prognostic role of miRNAs in resectable non-small cell lung cancer
Authors: Sandra Gallach, Eloisa Jantus-Lewintre, Silvia Calabuig-Fariariñas, Ana Blasco, Ricardo Guijarro, Miguel Martorell, Carlos Camps
Journal: Cancer Research (2015)

Abstract BACKGROUND MicroRNAs (miRNA) are a class of small RNAs that regulate gene expression, and are implicated in several diseases including cancer. The aim of this study was to analyze the prognostic implications of deregulated miRNAs identified by NGS in a previous study performed on resectable-NSCLC tumor samples. MATERIAL AND METHODS Fresh-frozen tumor and normal adjacent lung tissue samples (N = 195) were obtained by surgical resection from NSCLC patients and storage in RNAlater® at -80°C until analysis. RNA was isolated biological specimens by Trizol based-methods. 22 deregulated miRNA were analyzed in paired tumor/normal samples by RTqPCR using TaqMan® microRNA assays. Statistical analyses were considered significant at p&amp;lt;0.05. RESULTS Patient's median age was 64 years [26-85], 88.2% were male, 66.7% had good performance status (PS = 0), 39.5% were adenocarcinomas and 54.9% presented stage I at the time of the diagnosis. For survival analysis, continuous variables were dichotomized as high (≥ median) and low (&amp;lt; median), using the median expression of each miRNA as a cutoff. Of the 22 miRNAs analyzed only miR-21 and miR-188-5p had prognostic value. We found that patients with high levels of miR-21 and miR-188-5p had a significant reduction in PFS and OS rates. Interestingly, the group of patients with the combined high expression of both miRNAs (miR-21high &amp; miR-188-5phigh) showed shorter PFS and OS (Table 1). Clinico-pathological and analytical variables were included in the multivariate analysis revealing that combined miRNAs is an independent prognostic marker for PFS (HR 0.485 [0.313-0.753]; p = 0.001) and OS (HR 0.389 [0.237-0.638]; p&amp;lt;0.0001]. a P value with Bonferroni correction are shown in parenthesesOSOSPFSPFSMedian (months)PaMedian (months)PamiR-21 (High vs low)42.60 vs 82.600.01622.13 vs 66.970.017miR-188-5p (High vs low)46.67 vs NR0.00524.03 vs 66.970.023Combined miRNAs (miR21 high miR-188 high vs combonations)21.13 vs 83.570.002 (0.008)16.97 vs 56.830.001 (0.004) CONCLUSION Expression of miR-21 and miR-188-5p seems to have a prognostic role in NSCLC, and the combination of both could be an independent prognostic marker in early-stage NSCLC. Table 1. OS and PFS for miR-21 and miR-188-5p in NSCLC patients (univariate analysis) Supported by grants RTICC (RD12/0036/0025 and RD06/0020/1024), TRACE (TRA09-0132) and Beca Roche Oncohematología. Citation Format: Sandra Gallach, Eloisa Jantus-Lewintre, Silvia Calabuig-Fariariñas, Ana Blasco, Ricardo Guijarro, Miguel Martorell, Carlos Camps. Prognostic role of miRNAs in resectable non-small cell lung cancer. [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 4010. doi:10.1158/1538-7445.AM2015-4010
Anomalous Effects of Certain Preparations of Desiccated Thyroid on Serum Protein-Bound Iodine
Authors: Lewis E. Braverman, Sidney H. Ingbar
Journal: New England Journal of Medicine (1964)

MEASUREMENT of the concentration of protein-bound iodine (PBI) in the serum is perhaps the single most reliable laboratory method in the diagnosis of thyrotoxicosis or hypothyroidism and is also of great value as an indication of the adequacy of treatment in these disorders. In the treatment of myxedema, however, it is recognized that the concentration of the PBI associated with restoration of a normal metabolic state depends upon the particular thyroid hormone employed. Thyroxine (T4) and L-3,5,3′-tri-iodothyronine (T3), both natural products of thyroidal secretion, differ widely in this respect. T3, a highly potent hormone . . .
Nifedipine in Unstable Angina
Authors: Gary Gerstenblith, Pamela Ouyang, Stephen C. Achuff, Bernadine H. Bulkley, Lewis C. Becker, E. David Mellits, Kenneth L. Baughman, James L. Weiss, John T. Flaherty, Clayton H. Kallman, Michaelene Llewellyn, Myron L. Weisfeldt
Journal: New England Journal of Medicine (1982)

We assessed the efficacy of adding nifedipine to the conventional treatment of unstable angina in 138 patients in a prospective, double-blind, randomized, placebo-controlled trial. There was no difference between the two groups in the dose of conventional antianginal medication or in age, prior myocardial infarction, ejection fraction, or other risk factors. Failure of medical treatment (defined as sudden death, myocardial infarction, or bypass surgery within four months) occurred In 43 of 70 patients given placebo and in 30 of 68 given nifedipine. KapIan–Meier survival-curve analysis of the number and time dependence of treatment failures demonstrated a benefit of nifedipine over placebo (P = 0.03). The benefit was particularly marked in patients with ST-segment elevation during angina (P = 0.02). Side effects (transient hypotension or diarrhea) required with-drawal of the drug from four patients given nifedipine and from one given placebo. We conclude that the addition of nifedipine to conventional therapy is safe and effective in unstable angina. (N Engl J Med. 1982; 306:885–9.)
Abstract B28: Genomic analysis of osteosarcoma for identification of targeted therapies
Authors: Leanne Sayles, Marcus Breese, E. Alejandro Sweet-Cordero
Journal: Cancer Research (2016)

Abstract Osteosarcoma (OS) is an aggressive pediatric bone malignancy that affects 400 children per year in the United States. OS is characterized by genomic instability and numerous copy number alterations (CNA). We hypothesized that CNA may be drivers of OS and that targeting cancer genes with CNAs may be a novel approach for treatment of OS. We have established a robust approach for generation of patient-derived xenografts (PDX) from patients with OS. To date, 15 PDX have been established from OS patients. Using whole-genome sequencing (WGS), we have identified possible target CNAs for individual patients and are currently testing them in their corresponding PDX. In two patients, an amplification in c-myc suggested possible susceptibility to the BRD4 inhibitor JQ1 or the CDK9 inhibitor AT7519. In a third patient sample, amplification of Cyclin D and Cyclin E in the setting of wild-type Rb suggested responsiveness to a CDK inhibitor. A fourth patient had a FOXM1 amplification which suggests a vulnerability to Palbociclib, a CDK4/6 specific inhibitor. This patient sample also had an Aurora kinase B amplification, suggesting susceptibility to inhibition of this kinase as a therapeutic approach. We treated the corresponding PDX with the drug predicted to target the patient sample based on CNA. In all cases, treatment of the PDX with the drugs predicted show a significant reduction in tumor growth compared to vehicle alone or to the drugs predicted for the other patient CNAs. As a follow up we are currently submitting several more patient samples and paired PDX for WGS as well as RNAseq to determine other potential targeted therapeutics based on CNA. In summary, our work suggests that WGS can be used to identify potential novel therapies for patients with OS. Further work will be needed to determine whether response in PDX models correlates with clinical response in patients. Citation Format: Leanne Sayles, Marcus Breese, E. Alejandro Sweet-Cordero. Genomic analysis of osteosarcoma for identification of targeted therapies. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B28.