tbuckley/cabot-search huggingface dataset:
Loss of DNA Mismatch Repair: Effects on the Rate of Mutation to Drug Resistance
Authors: M. M. de las Alas, S. Aebi, D. Fink, S. B. Howell, G. Los
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: The loss of the ability of cells to repair mismatches in doublestranded DNA is a common finding in human tumors. This defect results in genomic instability and in increased resistance to several of the drugs used in cancer chemotherapy. The human colon cancer cell line HCT116 is deficient in DNA mismatch repair (MMR) because of a genetic defect in the hMLH1 gene, which is located on chromosome 3. In this study, we investigated whether MMR-deficient HCT116+chr2 cells (i.e., HCT116 cells into which chromosome 2 has been transferred [as a control]) have a higher rate of mutation to resistance to commonly used chemotherapeutic agents (i.e., cisplatin, doxorubicin, paclitaxel [Taxol], and etoposide) than MMR-proficient HCT116+chr3 cells (i.e., HCT116 cells into which chromosome 3 has been transferred to provide a wild-type copy of the hMLH1 gene). Methods: Spontaneous mutation rates were calculated from measurements of the mutant fractions of cells before and after their expansion through a known number of generations (also known as the technique of maximum likelihood estimation). Aliquots of 500 000 cells were expanded in culture over a period of 2 weeks, and the mutant fractions were determined both before and after expansion of secondary cultures (each also with an initial 500 000 cells) in drug concentrations that produced survival fractions of 0.0002%. Results: Mutation rates in MMR-proficient and MMR-deficient cells did not differ on exposure to cisplatin, doxorubicin, or paclitaxel; however, the relative mutation rate was 2.4-fold higher in MMRdeficient cells exposed to etoposide ( P = .002). Conclusion: These results suggest that genes involved in the control of cellular sensitivity to etoposide are targets for mutation when the loss of MMR destabilizes the genome. Tumors containing large fractions of MMR-deficient cells may demonstrate more rapid emergence of clinical resistance to etoposide.
Circulating tumor cells and DNA as liquid biopsies
Authors: Ellen Heitzer, Martina Auer, Peter Ulz, Jochen B Geigl, Michael R Speicher
Journal: Genome Medicine (2013)

For cancer patients, the current approach to prognosis relies on clinicopathological staging, but usually this provides little information about the individual response to treatment. Therefore, there is a tremendous need for protein and genetic biomarkers with predictive and prognostic information. As biomarkers are identified, the serial monitoring of tumor genotypes, which are instable and prone to changes under selection pressure, is becoming increasingly possible. To this end, circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) shed from primary and metastatic cancers may allow the non-invasive analysis of the evolution of tumor genomes during treatment and disease progression through 'liquid biopsies'. Here we review recent progress in the identification of CTCs among thousands of other cells in the blood and new high-resolution approaches, including recent microfluidic platforms, for dissecting the genomes of CTCs and obtaining functional data. We also discuss new ctDNA-based approaches, which may become a powerful alternative to CTC analysis. Together, these approaches provide novel biological insights into the process of metastasis and may elucidate signaling pathways involved in cell invasiveness and metastatic competence. In medicine these liquid biopsies may emerge to be powerful predictive and prognostic biomarkers and could therefore be instrumental for areas such as precision or personalized medicine.
Small nucleolar RNA signatures of lung tumor-initiating cells
Authors: Kaiissar Mannoor, Jun Shen, Jipei Liao, Zhenqiu Liu, Feng Jiang
Journal: Molecular Cancer (2014)

Non-small cell lung cancer (NSCLC) is the number one cancer killer. Tumor-initiating cells (TICs) are responsible for tumor progression and recurrence. Emerging evidences suggest that small nucleolar RNAs (snoRNAs) play malfunctioning roles in lung tumorigenesis. This study aims to determine if snoRNAs have important function in lung TICs by: 1) profiling and comparing snoRNA expression patterns in lung ALDH1+/- cells of 28 primary NSCLC tissues to identify new signatures of TICs; 2) determining prognostic significance of the snoRNA signatures by analyzing the expression in 82 NSCLC tissues with different stages and histological types using quantitative PCR; 3) functionally investigating if the snoRNAs contribute to stemness of lung TICs using in vitro and in vivo assays. Twenty-two snoRNAs were identified whose changes were specific to the TICs. The expression of two snoRNAs (snoRA3 and snoRA42) was inversely associated with survival of NSCLC patients (P = 0.002, p = 0.001, respectively). Functional analysis indicated that snoRA42 was upregulated in CD133+ cells isolated from NSCLC cell lines compared with the CD133- counterparts. snoRA42 knockdown reduced the proliferation and self-renewal of TICs in vitro. However, ectopic expression of snoRA42 in non-TICs enhanced the potentials of cell proliferation and self-renewal. snoRA42 expression was associated with expression of stem cell-core transcription factors in lung TICs. Blocking snoRA42 expression in TIC xenografts decreased tumorigenesis in mice. The snoRNA signatures of lung TICs provide potential biomarkers for predicting outcome of NSCLC. snoRA42 is one of the important snoRNAs in regulating features of lung TICs, and thus contributes to lung tumorigenesis.
Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning
Authors: Michael N. Pollak
Journal: Cancer Discovery (2012)

Laboratory research and pharmacoepidemiology are providing converging evidence that the widely used antidiabetic drug metformin has antineoplastic activity, but there are caveats. Although population studies suggest that metformin exposure is associated with reduced cancer risk and/or improved prognosis, these data are mostly retrospective and nonrandomized. Laboratory models show antineoplastic activity, but metformin concentrations used in many experiments exceed those achieved with conventional doses used for diabetes treatment. Ongoing translational research should be useful in guiding design of clinical trials, not only to evaluate metformin at conventional antidiabetic doses, where reduction of elevated insulin levels may contribute to antineoplastic activity for certain subsets of patients, but also to explore more aggressive dosing of biguanides, which may lead to reprogramming of energy metabolism in a manner that could provide important opportunities for synthetic lethality through rational drug combinations or in the context of genetic lesions associated with hypersensitivity to energetic stress.There are tantalizing clues that justify the investigation of antineoplastic activities of biguanides. The complexity of their biologic effects requires further translational research to guide clinical trial design.
Constrained Intron Structures in a Microsporidian
Authors: R. C. H. Lee, E. E. Gill, S. W. Roy, N. M. Fast
Journal: Molecular Biology and Evolution (2010)

The 2.9-Mbp genome of the microsporidian Encephalitozoon cuniculi is severely reduced and compacted, possessing only 16 known tiny spliceosomal introns. Based on motif and expression data, intron profiles were constructed to screen the genome. Twenty additional introns were predicted and verified, doubling the previous estimate. We further predict that accurate 3' splice site (3'SS) selection is accomplished via a scanning mechanism with specificity achieved by maintaining a constrained variable length between the branch point motif and 3'SS. Only introns in ribosomal protein genes exhibit positional bias, and we hypothesize that splicing could be regulating expression of these genes. The large set of new introns in non-ribosomal protein genes suggests that current models of intron loss are unlikely sufficient to explain the distribution of introns. Together, these results extend our understanding of the role of intron loss in genome evolution and contribute to a novel model for splice site selection.
Inhaled Insulin Using the AERx Insulin Diabetes Management System in Healthy and Asthmatic Subjects
Authors: Robert R. Henry, Sunder R.D. Mudaliar, William C. Howland III, Neelima Chu, Dennis Kim, Bob An, Rickey R. Reinhardt
Journal: Diabetes Care (2003)

OBJECTIVE—The AERx insulin Diabetes Management System (AERx iDMS) (Aradigm, Hayward, CA) delivers an aerosol of liquid human insulin to the deep lung for systemic absorption. This study examined the effects on pulmonary function, pharmacokinetics, and pharmacodynamics of inhaled insulin in asthmatic and nonasthmatic subjects without diabetes. RESEARCH DESIGN AND METHODS—A total of 28 healthy and 17 asthmatic (forced expiratory volume during the first second [ FEV1] 50–80% of predicted value) subjects were enrolled in a two-part, open-label trial. To assess insulin pharmacokinetics and pharmacodynamics, a single inhalation dose of 1.57 mg (45 IU) was given on each of the 2 dosing days in part 1. A dose of 4.7 mg (135 IU) of insulin was inhaled in part 2 to assess effects on pulmonary function. RESULTS—Inhaled insulin showed area under the curve (AUC)(0–360 min) values that were significantly greater for healthy subjects than for asthmatic subjects (P = 0.013), whereas no difference was observed for maximum concentration (Cmax) in the two groups. A greater reduction of serum glucose as indicated by area over the curve (AOC)(0–360 min) was observed in healthy subjects (P = 0.007). Asthmatic subjects had greater intrasubject variations in insulin AUC(0–360 min) and Cmax values than healthy subjects, but similar variations in glucose AOC(0–360 min). No significant changes in FEV1, forced vital capacity (FVC), and FEV1/FVC were observed from pre- to postdose times, and there were no observed safety issues. CONCLUSIONS—After inhaling insulin using the AERx iDMS, asthmatic subjects absorbed less insulin than healthy subjects, resulting in less reduction of serum glucose. No effects on airway reactivity were observed. Diabetic patients with asthma may need to inhale more insulin than patients with normal respiratory function in order to achieve similar glycemic control.
Effect of hepatitis C infection and renal transplantation on survival in end-stage renal disease
Authors: Brian J.G. Pereira, Svetlozar N. Natov, Beth A. Bouthot, B.V.R. Murthy, Robin Ruthazer, Christopher H. Schmid, Andrew S. Levey, None The New England Organ Bank Hepatitis C Study Group
Journal: Kidney International (1998)
The impact of psychological distress on allergic rhinitis and asthma control
Authors: Inês Franco, João Cruz, Ligia Carvalho, Aurora Carvalho, Ricardo Lima
Journal: European Respiratory Journal (2014)

Psychological distress is prevalent in allergic rhinitis and asthma (ARA) patients and could influence disease control.  The aim of this study was to evaluate which dimensions of psychological distress are related to poor symptoms control in ARA patients.  We performed a cross-sectional study of patients (≥ 18 years-old) diagnosed with ARA, without psychiatric pathology, with at least 6 months of follow up in our outpatient asthma consultation. All patients completed 2 questionnaires: Symptom Checklist-90 Revised questionnaire and Control of Allergic Rhinitis and Asthma Test (CARAT). FEV1 and FEV1/FVC were also collected. Patients were divided according to the CARAT subscores: asthma control (CARATa) and rhinitis control (CARATr).  We included 115 patients, mostly female (n=78, 67.8%), with a mean age of 41.6+14.7 years. Psychological distress was more frequent in female patients and was associated with poor asthma control (p=0.027) but not with poor rhinitis control. Subscores of CARAT revealed that 74 (64.3%) patients had poorly controlled asthma (CARATa  0.001), obsessive-compulsive traits (p=0.014), depression (p=0.037),  sleep  difficulties (p=0.003) and  guilt feelings  (p=0.034). Poorly controlled rhinitis (CARATr ≤8) (n=86, 74.8%) was associated with  guilt feelings (p=0.022) . No significant differences were found respecting to FEV1 and FEV1/FVC between groups.  Patients with tendency to over-value their symptoms, self-centered, with obsessive traits, depressive symptoms and sleep disturbances have a higher risk of poorly controlled asthma. Psychological evaluation and management of patients presenting these traits may improve asthma control.
Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study
Authors: Marinus H J van Oers, Kazimierz Kuliczkowski, Lukáš Smolej, Mario Petrini, Fritz Offner, Sebastian Grosicki, Mark-David Levin, Ira Gupta, Jennifer Phillips, Vanessa Williams, Stephanie Manson, Steen Lisby, Christian Geisler
Journal: The Lancet Oncology (2015)
Issues of consent in colonoscopy: if a patient says ‘stop’ should we continue?
Authors: B Ward, S Shah, P Kirwan, J F Mayberry
Journal: Journal of the Royal Society of Medicine (1999)

Colonoscopy is generally performed under intravenous sedation, which may alter a patient's responses and perception. What should be done if, during the procedure, a patient withdraws the consent previously given? The views of gastroenterologists and patients were ascertained by mailing questionnaires to 100 members of the British Society of Gastroenterology and to 100 patients who had undergone colonoscopy with intravenous sedation. Only 1 of 59 eligible consultants who replied said they would stop the procedure after a single request, but a further 51 would stop if repeatedly asked to do so. Of the remaining 7 who would complete the procedure, 1 nevertheless believed that a sedated patient is capable of making a rational decision. Of the 51 patients who returned a usable questionnaire, 25 thought that the procedure should be stopped immediately following a request, while 26 felt that the doctor should continue. The divergent and sometimes inconsistent views found in this study highlighted the need for further clarification of the issue of informed consent for procedures conducted with the patient under sedation.
Inferotemporal Cortex and Object Vision
Authors: Keiji Tanaka
Journal: Annual Review of Neuroscience (1996)

Cells in area TE of the inferotemporal cortex of the monkey brain selectively respond to various moderately complex object features, and those that cluster in a columnar region that runs perpendicular to the cortical surface respond to similar features. Although cells within a column respond to similar features, their selectivity is not necessarily identical. The data of optical imaging in TE have suggested that the borders between neighboring columns are not discrete; a continuous mapping of complex feature space within a larger region contains several partially overlapped columns. This continuous mapping may be used for various computations, such as production of the image of the object at different viewing angles, illumination conditions. and articulation poses.
Follicular hormonal environment and embryo quality in women with endometriosis
Authors: N. Garrido
Journal: Human Reproduction Update (2000)

The use of in-vitro fertilization (IVF) as a therapeutic tool in patients with endometriosis has provided information about the disease and, in particular, aspects of the reproductive process in humans, particularly folliculogenesis, fertilization, embryo development and implantation. Retrospective analyses of IVF and oocyte donation programmes showed impaired implantation in patients with endometriosis. Otherwise, the observation that embryo development was blocked more frequently in cases of endometriosis, suggested that impaired embryo quality may be responsible for the reduced implantation rates. Similarly, women with the disease undergoing oocyte donation had the same chance of implantation as patients without endometriosis, suggesting that the endometrial milieu is not affected in patients with endometriosis. The quality of the oocyte may, therefore, be altered in patients with endometriosis. To investigate this, we studied steroid secretion in women undergoing IVF. Progesterone concentrations in follicular fluid increased with the severity of the disease and an increase in progesterone accumulation in vitro was observed in basal and human chorionic gonadotrophin (HCG)-induced granulosa cell cultures. We postulated that the pattern of progesterone secretion may be related to the release of cytokines by ovarian and/or immune cells. To test this, we measured interleukin (IL)-1, IL-6 and vascular endothelial growth factor (VEGF) concentrations in serum, follicular fluid and granulosa cell cultures. IL-6 concentrations in serum were increased in natural cycles in women with endometriosis and showed a significant decrease in stimulated cycles in IVF. Also, IL-6 concentrations were increased in the follicular fluid of women with endometriosis and released in higher amounts by granulosa–luteal cells from patients with endometriosis. VEGF was accumulated in lower concentrations in the follicular fluid of endometriosis patients. These observations show that the follicular environment is different in cases with endometriosis and suggest that infertility in patients with endometriosis may be related to alterations within the oocyte which, in turn, result in embryos of lower quality, and with a reduced ability to implant.
Characteristics of biliary lipid metabolism after liver transplantation
Authors: Bo-Göran Ericzon, Sharif Eusufzai, Keiichi Kubota, Kurt Einarsson, Bo Angelin
Journal: Hepatology (1990)

Biliary lipid metabolism was studied after 10 liver transplantations with continuous drainage of bile. Within 3 wk after transplantation, the new liver produced bile with concentrations of biliary lipids in agreement with those reported for T-tube bile in cholecystectolized nontransplanted subjects. Although changes in biliary lipid composition occurred swiftly in response to various forms of disturbed liver function, they did not provide substantially more information than did standard serum tests or simple measurements of bile flow in most patients. Secretion rates of phospholipids and cholesterol were found to be completely bile acid dependent. For each micromole of bile acids, 0.22 and 0.08 μmol of phospholipids and cholesterol were secreted, respectively. When bile flow was related to bile acid output, a linear relationship was found (r = 0.89), with a positive intercept indicating a bile acid-independent bile flow of approximately 44 μl/min. Analysis of individual bile acids showed almost exclusively primary bile acids. The relative proportion of chenodeoxycholic acid was more prominent during the first days after transplantation. Different explanations for this are discussed. (HEPATOLOGY 1990;12:1221-1228).
Phase II Trials Powered to Detect Tumor Subtypes
Authors: John D. Roberts, Viswanathan Ramakrishnan
Journal: Clinical Cancer Research (2011)

Classical phase II trial designs, including "adaptive" designs, require the prospective characterization of tumors. We propose a 2-stage phase II design that allows for characterization of tumors and selection of a tumor subtype of interest at the conclusion of stage 1. The stage 2 objective is either a classical estimate of the response rate for either the tumor or a subtype, or a formal test of the hypothesis that the response rate for a subtype is greater than the overall response rate. Considering likely scenarios, stage 1 sample sizes approximately range from 20 to 100 with a usual size of 50. This compares with typical classical stage 1 sample sizes of 12 to 30. Total sample sizes range from sizes identical to classical designs (tens to scores) to large sizes typical of phase III trials in metastatic disease (hundreds). Our design is more efficient than previous adaptive designs because it allows for the selection of a tumor subtype of interest on the basis of results from stage 1. It complements classical phase II and phase III designs in which investigators compare different treatments in similar patients and tumors by positioning a treatment as fixed (control) and using tumor subtype as the variable of interest.
Neoadjuvant Chemotherapy with or without Zoledronic Acid in Early Breast Cancer—A Randomized Biomarker Pilot Study
Authors: Matthew C. Winter, Caroline Wilson, Stuart P. Syddall, Simon S. Cross, Alyson Evans, Christine E. Ingram, Ingrid J. Jolley, Matthew Q. Hatton, Jennifer V. Freeman, Stefano Mori, Ingunn Holen, Robert E. Coleman
Journal: Clinical Cancer Research (2013)

To investigate the short-term biologic effects of neoadjuvant chemotherapy +/- zoledronic acid (ZOL) in invasive breast cancer.Forty patients were randomized to receive a single 4 mg infusion of ZOL 24 hours after the first cycle of FE100C chemotherapy, or chemotherapy alone. Randomization was stratified for tumor stage, ER, HER2, and menopausal status. All patients had repeat breast core biopsy at day 5 (D5) ± day 21 (D21). Effects on apoptotic index, proliferation (Ki67), growth index, surrogate serum markers of angiogenesis (VEGF), and serum reproductive hormones within the TGFβ family (activin-A, TGFβ1, inhibin-A, and follistatin) were evaluated and compared.Baseline clinicopathologic characteristics were well balanced. Cell growth index (increased apoptosis and reduced proliferation) fell at D5 in both groups but recovered more rapidly with chemotherapy + ZOL compared with chemotherapy alone by D21 (P = 0.006). At D5, a greater reduction in serum VEGF occurred with chemotherapy + ZOL compared with chemotherapy: median percentage change -23.8% [interquartile range (IQR): -32.9 to -15.8] versus -8.4% (IQR: -27.3 to +8.9; P = 0.02), but these effects were lost by D21. Postmenopausal women showed a decrease in follistatin levels from baseline in the chemotherapy + ZOL group at D5 and D21, compared with chemotherapy alone (P(interaction) = 0.051).In this pilot study, short-term changes in biomarkers suggest potentially relevant interactions between tumor biology, chemotherapy, modification of the bone microenvironment, and the endocrine status of the host. Larger studies with more frequent dosing of zoledronic acid are needed to assess these complex interactions more thoroughly.
HIV Infection Status, Immunodeficiency, and the Incidence of Non-Melanoma Skin Cancer
Authors: Michael J. Silverberg, Wendy Leyden, E. Margaret Warton, Charles P. Quesenberry, Eric A. Engels, Maryam M. Asgari
Journal: JNCI Journal of the National Cancer Institute (2013)

The incidence of non-melanoma skin cancers (NMSCs), including basal cell (BCC) or squamous cell carcinoma (SCC), is not well documented among HIV-positive (HIV+) individuals. We identified 6560 HIV+ and 36 821 HIV-negative (HIV−) non-Hispanic white adults who were enrolled and followed up in Kaiser Permanente Northern California from 1996 to 2008. The first biopsy-proven NMSCs diagnosed during follow-up were identified from pathology records. Poisson models estimated rate ratios that compared HIV+ (overall and stratified by recent CD4 T-cell counts and serum HIV RNA levels) with HIV− subjects and were adjusted for age, sex, smoking history, obesity diagnosis history, and census-based household income. Sensitivity analyses were adjusted for outpatient visits (ie, a proxy for screening). All statistical tests were two-sided. The NMSC incidence rate was 1426 and 766 per 100 000 person-years for HIV+ and HIV− individuals, respectively, which corresponds with an adjusted rate ratio of 2.1 (95% confidence interval [CI] = 1.9 to 2.3). Similarly, the adjusted rate ratio for HIV+ vs HIV− subjects was 2.6 (95% CI = 2.1 to 3.2) for SCCs, and it was 2.1 (95% CI = 1.8 to 2.3) for BCCs. There was a statistically significant trend of higher rate ratios with lower recent CD4 counts among HIV+ subjects compared with HIV− subjects for SCCs (Ptrend < .001). Adjustment for number of outpatient visits did not affect the results. HIV+ subjects had a twofold higher incidence rate of NMSCs compared with HIV− subjects. SCCs but not BCCs were associated with immunodeficiency.