tbuckley/cabot-search huggingface dataset:
Polymorphisms of the <i>thiopurine S-methyl transferase gene (TMPT)</i> in a Mexican population
Authors: M. Candelaria, L. Taja-Chayeb, S. Vidal, O. Gutiérrez, P. Ostrosky, A. Duenas-Gonzalez
Journal: Journal of Clinical Oncology (2006)

20049 Background: Polymorphisms at the thiopurine S-methyltransferase coding gene (TPMT) determine enzyme activity and as a consequence the development of toxicity of thiopurine drugs. Methods: To test the frequency of polymorphisms of TPMT gene in Mexican population. 36 DNA samples from volunteer donors were analyzed. Genomic DNA from peripheral leukocytes was isolated by standard methods. Known (wild type and polymorphic) sequenced PCR fragments of the TPMT gene were used used as controls. PCR amplification: Fragments of the TPMT gene were amplified using the following oligonucleotides primers: Exon 5: 5′-CTGCATGTTCTTTGAAACCCTATGAA-3′ and 5′-CTTGAGGACAGAGAGGCTTTGACCTC-3′; exon 7: 5′-CTCCACACCCAGGTCC-ACACATT-3′ and 5′-GTATAGTACTAAAAAATTAAGACAGCTAAAC-3′; exon 10: 5′-AATCCTGATGTCATTCTTCATAGTATTT-3′ and 5′-CATCCATTACATTTTCAGG-CTTTAGCATAAT-3′. PCR products were then analyzed by denaturating high performance liquid chromatography (DHPLC) for the most frequent mutant TPMT alleles, according to the method developed by Schaeffeler et al (Clin Chem 2001; 47: 548) on an analysis system from Transgenomics Results: A high frequency of gene polymorphisms was identified, particularly in the exon 7 (14/36 = 38%), followed by exon 10 (3/36 = 8.3%) and 5 (2/36 = 5.5%). After analysing the three exons, the presence of mutations discriminating for TPMT alleles showed that 7/36 (19.4 %) were silent and located at T474C, in exon 7 (*1S) and 7/36 (19.4 %) were functional, and located in TPMT alleles *2 (2/36 = 5.5%), *3B (2/36 = 5.5%), *4 (2/36 = 5.5%) and *3B/4 (1/36= 2.7%). Conclusions: This is the first analysis of the polymorphisms at this gene in a Mexican population. The frequency of known silent polymorphisms was higher than those reported in other world regions but the frequency of functional polymorphism is within the range found in other reports. DHPLC is a highly sensitive, rapid and efficient method to identify relevant TPMT gene mutations which allows the screening for genetic variability in the TPMT gene . This trial was supported by a grant of CONACYT. No significant financial relationships to disclose.
IL-18 and IL-12 induce inflammatory cytokines, chemokine ligand 9 (CXCL9) and T cell infiltration in pulmonary tissue
Authors: Fadila Telarevic Cero, Karl Otto Larsen, Vigdis Hillestad, Geir Christensen, Ole Henning Skjønsberg
Journal: European Respiratory Journal (2011)

Background: Increased levels of interleukin (IL)-18 and IL-12 have been found during experimental alveolar hypoxia and in patients with COPD.

Aims: To study the presence of IL-18 and IL-12 receptors (IL-18R/IL-12R) in the lungs and the effect of IL-18 and IL-12, alone or in combination, on the lungs with regard to inflammatory response and induction of emphysema related metalloproteinases (MMP2, MMP9, MMP12).

Methods: Expression of IL-18R and IL-12R was studied in lungs, heart, liver and spleen in C57Bl/6 mice. 24 hours after a single i.p. dose of recombinant murine IL-18 alone, recombinant IL-12, IL-18+IL-12 or PBS (controls), lungs were harvested for immunohistochemical (IHC) and RT-PCR analyses.

Results: The expression of IL-18R mRNA was 16-630-fold higher in lungs than in other organs. The expression of IL-12R was 4-fold higher in the spleen than in lungs. Mice treated with IL-18 or IL-12 alone showed significantly higher mRNA levels of interferon-γ, tumor necrosis factor-α and MMP12, than in controls (p<0,05). Mice treated with IL-18+IL-12 showed an even more pronounced induction of these mediators, as well as a significant increase in IL-6 and IL-1β(p<0,05). A marked increase in CXCL9 mRNA was induced by IL-18 (12-fold), IL-12 (19-fold), IL-18+IL-12 (153-fold). IHC showed perivascular T-cell infiltration following co-stimulation.

Conclusions: High levels of IL-18 receptor suggest that the lungs might be a target organ for IL-18. IL-18+IL-12 exert a synergistic effect on the lungs by inducing inflammatory cytokines and MMP12 which may promote inflammation and emphysema. Induction of CXCL9 may be of importance for the observed T cell infiltration in lung tissue.
A Patient‐Inspired Ex Vivo Liver Tissue Engineering Approach with Autologous Mesenchymal Stem Cells and Hepatogenic Serum
Authors: Dillip K. Bishi, Santosh Mathapati, Jayarama R. Venugopal, Soma Guhathakurta, Kotturathu M. Cherian, Rama S. Verma, Seeram Ramakrishna
Journal: Advanced Healthcare Materials (2016)

Design and development of ex vivo bioengineered liver tissue substitutes intended for subsequent in vivo implantation has been considered therapeutically relevant to treat many liver diseases that require whole-organ replacement on a long-term basis. The present study focus on patient-inspired ex vivo liver tissue engineering strategy to generate hepatocyte-scaffold composite by combining bone marrow mesenchymal stem cells (BMSCs) derived from cardiac failure patients with secondary hyperbilirubinemia as primers of hepatic differentiation and hepatocyte growth factor (HGF)-enriched sera from same individuals as hepatic inducer. A biodegradable and implantable electrospun fibrous mesh of poly-l-lactic acid (PLLA) and gelatin is used as supporting matrix (average fiber diameter = 285 ± 64 nm, porosity = 81 ± 4%, and average pore size = 1.65 ± 0.77 μm). The fibrous mesh supports adhesion, proliferation, and hepatic commitment of patient-derived BMSCs of adequate stemness using HGF-enriched sera generating metabolically competent hepatocyte-like cells, which is comparable to the hepatic induction with defined recombinant growth factor cocktail. The observed results confirm the combinatorial effects of nanofiber topography and biochemical cues in guiding hepatic specification of BMSCs. The fibrous mesh-hepatocyte construct developed in this study using natural growth factors and BMSCs of same individual is promising for future therapeutic applications in treating damaged livers.
Entecavir plus tenofovir versus entecavir plus adefovir in chronic hepatitis B patients with a suboptimal response to lamivudine and adefovir combination therapy
Authors: Jung Gil Park, Soo Young Park
Journal: Clinical and Molecular Hepatology (2015)

Background/Aims We compared the efficacies of entecavir (ETV) plus tenofovir (TDF) and ETV plus adefovir (ADV) in chronic hepatitis B (CHB) patients with genotypic resistance to lamivudine (LAM) who showed a suboptimal response to LAM and ADV combination therapy. Methods We reviewed 63 CHB patients with genotypic resistance to LAM who showed a suboptimal response to LAM and ADV combination therapy. Among these patients, 30 were treated with ETV + ADV and 33 were treated with ETV + TDF for 12 months. Results The only baseline characteristic that differed significantly between the two groups was the ETV resistance profile. The rate of a virologic response [serum hepatitis B virus (HBV) DNA level of <20 IU/mL] was significant higher for ETV+TDF than for ETV+ADV over 12 months (57.6% vs. 23.3%, P=0.006, at 6 months; 84.8% vs. 26.7%, P<0.001, at 12 months). The probability of a virologic response was significantly increased in ETV+TDF (P<0.001, OR=54.78, 95% CI=7.15-419.54) and decreased in patients with higher baseline viral loads (P=0.001, OR=0.18, 95% CI=0.07-0.50) in multivariate analysis. No serious adverse event occurred during the study period. Conclusions In patients with CHB who showed a suboptimal response to LAM and ADV combination therapy, ETV+TDF was superior to ETV+ADV in achieving a virologic response regardless of the HBV resistance profile. Further large-scale and long-term follow-up prospective studies are needed to explain these results. Keywords: Chronic hepatitis B; Lamivudine resistance; Combination therapy; Entecavir; Tenofovir
Abstract 14771: Angiopoietin Like-2 (angptl2) Knock-Down Limits High-Fat Diet-Induced Fat Accumulation, Hypercholesterolemia and Prevents Endothelial Dysfunction in Mice
Authors: Carol Yu, Caroline Daneault, Nathalie Thorin-Trescases, Christine Des Rosiers, Eric Thorin
Journal: Circulation (2013)
DNA sequence polymorphism within hominoid species exceeds the number of phylogenetically informative characters for a HOX2 locus.
Authors: G Ruano, J Rogers, A C Ferguson-Smith, K K Kidd
Journal: Molecular Biology and Evolution (1992)

Within- and between-species variability was examined in a noncoding 238-bp segment of the HOX2 cluster. DNA of 4-26 individuals of four species (Pongo pygmaeus, Pan troglodytes, Gorilla gorilla, and Homo sapiens) was PCR amplified and electrophoresed in a denaturing gradient gel to screen for variability. Coupled amplification and sequencing was used to determine the complete sequence for each of the different alleles identified, one each in humans and orangutans, two in chimpanzees, and four in gorillas. Maximum-parsimony methods were used to construct a gene tree for these sequences. Alleles in all four species cluster into groups consisting of only one species (i.e., alleles within a species are monophyletic). The number of base-pair differences observed among alleles within P. troglodytes and within G. gorilla is larger than the number of base-pair substitutions that phylogenetically link Pan with Homo. Given these and other published data, it is premature to accept any particular phylogenetic tree that relates these three genera through two separate speciation events.
US governors seek to limit opioid prescribing
Authors: Owen Dyer
Journal: BMJ (2016)

US state governors have proposed measures to tackle opioid addiction, including a plan for state governments to draw up rules on prescribing that would limit the number of pills physicians could prescribe to a new patient.

In this election year the fast growing opioid problem in the United States has come to loom large on the radar of many politicians. “This is really what keeps me up at night,” said Indiana’s Republican governor, Mike Pence. “There is no city, no town, in the state of Indiana that is not affected by this stuff.”

US citizens consumed 250 million opioid pills last year, double the per capita rate in the second highest prescribing country, Canada.

The changing face of drug addiction has brought a …
Characterization of innate responses elicited by neoadjuvant radio-chemotherapy for rectal cancer
Authors: A. Castiglioni, K. Bencardino, A. M. Tamburini, A. Monno, L. Albarello, C. Staudacher, M. Ronzoni, C. Doglioni, P. Rovere-Querini, A. Manfredi
Journal: Journal of Clinical Oncology (2009)

e15044 Background: The neoadjuvant chemo-radiotherapy (CT-RT) has improved the treatment of locally advanced rectal cancer reducing the local recurrence. However a survival benefit has not been reached yet. In order to increase the rate of pathological complete remissions in our Institution we intensified both the CT schedule adding oxaliplatin to 5-FU and the RT program with tomotherapy. The aim of this study was to verify: whether the pattern of innate response elicited by the neoadjuvant CT-RT is heterogeneous among pts and whether this information can be used to identify which pts will benefit from the treatment. Methods: We collected samples of T3N+M0 rectal cancer pts before, during and after neoadjuvant CT-RT (3 cycles of oxaliplatin + 5-FU; 45 Gy). At each time point we characterized circulating monocytes by flow cytometry, infiltrating macrophages by immunoistochemistry (IHC) and selected inflammatatory molecules by ELISA.Results: We recruited so far 25 pts, of whom 10 have reached the surgery with three pathological complete remission and four down staging. No substantial changes were detectable in the number of circulating monocytes. In contrast we observed a clear expansion of CD14/CD86 and CD14/CD163 double positive subsets. This event was transient and apparently causally related to the treatment since it abated at the later time point. Moreover, it correlated with sensitivity to the treatment: 5/7 pts who underwent disease regression had an early and transitory increase of the number of CD14/CD86 and CD14/CD163 positive cells, which was absent or negligible in non responder pts. The IHC study revealed a massive tumoral infiltration by macrophages which displayed clear features of alternative M2 polarization as assessed by expression of the CD163 and 206 scavenger receptors. A subset of pts had elevated PTX3 and low CRP concentration at the onset of treatment. PTX3 concentration abated after the first CT cycle. Conclusions: These data suggest that neoadjuvant CT-RT modulates the cellular components of innate immune responses, that could represent valuable predictive factors. No significant financial relationships to disclose.
Photodynamic therapy using NPe6 for bronchogenic carcinomas in central airways more than 1.0 cm in diameter.
Authors: J. Usuda, N. Ikeda, H. Kato, T. Ohira
Journal: Journal of Clinical Oncology (2010)

7081 Background: Photodynamic therapy (PDT) is recommended as a treatment option for centrally located early lung cancers (CLELCs), meaning roentgenographically occult squamous cell carcinomas that are located no more distally than segmental bronchi and, histologically, are either carcinoma in situ or carcinoma associated with only limited invasion. Since CLELC patients who are heavy smokers are at fairly high risk of developing a second primary lung cancer, they require treatment that will preserve their cardiopulmonary function. Most centrally located early lung cancers (CLELCs) less than 1.0 cm in diameter do not invade beyond the bronchial cartilage, and photodynamic therapy (PDT) with Photofrin is currently recommended as a treatment option for such lesions. NPe6 is a second-generation photosensitizer, and since it has a longer absorption band (664 nm) than Photofrin (630 nm), we hypothesized that NPe6-PDT would exert a strong antitumor effect against cancer lesions greater than > 1.0 cm in diameter, which are assumed to involve extracartilaginous invasion and to be unsuitable for treatment with Photofrin-PDT. Methods: Between June 2004 and December 2008, 75 patients (91 lesions) with CLELC underwent NPe6-PDT after the extent of their tumors had been assessed by fluorescence bronchoscopy for photodynamic diagnosis (PDD) and tumor depth had been assessed by optical coherence tomography (OCT). Results: Seventy-four cancer lesions Å…1.0 cm in diameter and 21 lesions >1.0 cm in diameter were identified, and the CR rate was 94.0% (66/70) and 90.4% (19/21), respectively. After the mass of large tumors and deeply invasive tumors, had been reduced by electrocautery, NPe6-PDT was capable of destroying the residual cancer lesions. Conclusions: NPe6-PDT has a strong antitumor effect against CLELCs >1.0 cm in diameter that have invaded beyond the bronchial cartilage, thereby enabling the destruction of residual cancer lesions after mass reduction of large nodular or polypoid type-lung cancers by electrocautery. The PDT guidelines for lung cancers should therefore be revised, because use of NPe6-PDT will enable expansion of the clinical indications for PDT. No significant financial relationships to disclose.
Endometrial effects of tamoxifen (T) and exemestane (E) in early breast cancer patients (EBCP). A randomized phase III trial
Authors: O. Garrone, E. Principe, M. Occelli, B. Favilla, S. Giubergia, P. D. Rattazzi, M. Merlano
Journal: Journal of Clinical Oncology (2004)

819 Background: T represents the treatment of choice in hormonal receptor positive EBCP. It is known that patients under T are considered at higher risk of endometrial carcinoma. During the last years several trials have been conducted to evaluate endometrial changes under T. Many of them revealed an increase in endometrial thickness (ET) in most patients by transvaginal ultrasound (TVUS) or hysterosonography. These abnormalities are due to stromal hypertrophy and cystic proliferations. Although such changes correlate with a minimum increase in risk of uterine cancer, the fear of it induces some women to discontinue the treatment. The availability of aromatase inhibitors (AI), and their lack of uterine toxicity, make them interesting in long term treatment such as in EBCP. However, a direct comparison between T and E induced uterine effects is still lacking. In order to compare the endometrial changes in EBCP receiving either T or E we started a phase III trial. Methods: Postmenopausal hormonal receptor positive patients were randomly assigned to receive T or E. A baseline TVUS was performed and repeted after 6 and 12 months. The primary end-point (endometrial thickness) is evaluated with T-test. Results: Up to date 47 of 114 planned patients have been enrolled. Patients' characteristics are well balanced in each arm. Preliminary results at the end of the evaluation (12 months) of the first 26 patients (13 per each arm) are summarized in the table: No significant financial relationships to disclose.
Higher order relationships and the Medicinal Algorithmic Combinatorial Screen (MACS)
Authors: R. G. Zinner, B. L. Barrett, A. Y. Volgin, J. G. Gelovani, J. Huang, H. T. Tran, G. B. Mills, W. K. Hong, Y. Fu, L. Mao
Journal: Journal of Clinical Oncology (2005)

3079 Background: Targeted therapeutics are highly promising in combination because they are both well tolerated and interact with the signals that cause cancer. We propose a direct functional screen of combinations in the lab as a complement to the molecular insight based approach. However, with each drug added to the list, the number of possible combinations rises exponentially quickly beyond the capacity of any foreseeable technology to fully screen. We propose the MACS to identify combinations otherwise impossible to be found through a simple screen alone. The foundation of MACS is a genetic algorithm. One of the requirements for MACS will be the presence of some degree of higher order relationships among combinations. This means that knowing the behavior of some combinations formed from a set of drugs enables prediction of the behavior of other combinations formed from the same drugs. However, little is known of the degree of relatedness larger combinations of anticancer agents have. We performed experiments to evaluate this. Methods: A549 cells were plated at 2000/well and incubated in 96-well plates with drug for 66 hours before being read using the WST-1 proliferative assay (Roche). The agents were LY294002, PI-3-kinase inhibitor (Tocris); Anisomycin, activator JNK/SAPK activator (Tocris), Rapamycin, cdk inhibitor (Tocris); SP600125, JNK inhibitor (Tocris), Indirubin-3’-oxime, inhibits CDKs (Tocris); Bortezomib, proteasome inhibitor (Millennium Pharms). These were combined in all 64 combinations (pairs, triplets, quads etc.) done in triplicate at the single agent IC 20 dose of each drug with the experiment repeated another day. Results: Using regression analyses, reproducible modest higher order relationships were observed. Conclusion: We have preliminary evidence that knowledge of some of the combinations is modestly predictive of others, not enough to avoid a screen but enough to make a MACS possible. Further work will entail study of additional agents, altered doses and sequences, other NSCLC cell lines and non cancerous immortalized cell lines to represent host tissue, which will be presented at the poster. Ultimately, a pilot MACS system will be constructed the parameters for which will be guided by these data. No significant financial relationships to disclose.
General practitioners should be trained in cardiopulmonary resuscitation
Authors: A Ravalia, P Jones
Journal: BMJ (1995)

and a defibrillator as well as my medical bag up five flights of stairs in a block of flats, where the lift is invariably out of order or its floor swimming in urine?What do I do with the equipment while visiting patients who do not require it?If I leave it in the car the possibility of its being stolen is high.Have the authors considered the practical implications of their advice?
Multigene panel testing in patients suspected to have Lynch syndrome.
Authors: Matthew B. Yurgelun, Brian Allen, Rajesh R. Kaldate, Karla Bowles, Benjamin Roa, Richard J. Wenstrup, Anne-Renee Hartman, Sapna Syngal
Journal: Journal of Clinical Oncology (2014)

1509 Background: Multigene panels are increasingly used for assessing hereditary cancer risk due to their ability to analyze numerous cancer susceptibility genes in parallel. Our aim was to study the outcomes of multi-gene panel testing in patients undergoing clinical testing for Lynch syndrome (LS). Methods: The study cohort was 1,260 consecutive patients with a history of LS-associated cancer and/or polyps who had undergone clinical genetic testing for LS in a commercial laboratory. Genomic DNA mutations were identified using a 25-gene hereditary cancer panel based on emulsion PCR and next generation sequencing. Germline sequence variations and large rearrangements were classified for pathogenicity. Patients’ personal/family histories of cancer were obtained from test request forms submitted with clinical LS testing. Results: Panel testing found ≥1 pathogenic mutation in 160/1,260 (13%) patients and ≥1 variant of uncertain significance in 552/1,260 (44%) patients. Of the 160 mutation carriers, 116 (73%) had a mutation in one of the 5 LS genes, whereas 48 (30%) had a mutation in one of the 20 non-LS genes tested including 4 (3%) with both LS and non-LS mutations. Of the 48 non-LS mutations, 15 (31%) were in BRCA1/2, 10 (21%) were in genes underlying other hereditary colorectal cancer syndromes (APC, biallelic MUTYH, PTEN, and STK11), and the remaining 23 (48%) were in other cancer susceptibility genes (ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, and RAD51C). Based on their personal/family histories, a large majority of patients met NCCN criteria for LS testing but not hereditary breast/ovarian cancer (HBOC) testing (Table). Conclusions: In this large cohort of patients suspected to have LS, 30% of mutation carriers identified by panel testing had non-LS cancer susceptibility gene mutations. With more comprehensive genetic testing approaches, many unexpected mutations will be found in patients who do not fulfill classic clinical criteria for their syndrome. Met NCCN LS criteria Met NCCN HBOC criteria Total cohort 1112/1,260 (88%) 312/1,260 (25%) All mutation carriers 150/160 (94%) 30/160 (19%) LS carriers 111/116 (96%) 20/116 (17%) All non-LS carriers 43/48 (90%) 11/48 (23%) BRCA1/2 carriers 14/15 (93%) 5/15 (33%) Rows/columns are not mutually exclusive.