tbuckley/cabot-search huggingface dataset:
Cancer Risks After Radiation Exposure in Middle Age
Authors: I. Shuryak, R. K. Sachs, D. J. Brenner
Journal: JNCI Journal of the National Cancer Institute (2010)

Epidemiological data show that radiation exposure during childhood is associated with larger cancer risks compared with exposure at older ages. For exposures in adulthood, however, the relative risks of radiation-induced cancer in Japanese atomic bomb survivors generally do not decrease monotonically with increasing age of adult exposure. These observations are inconsistent with most standard models of radiation-induced cancer, which predict that relative risks decrease monotonically with increasing age at exposure, at all ages. We analyzed observed cancer risk patterns as a function of age at exposure in Japanese atomic bomb survivors by using a biologically based quantitative model of radiation carcinogenesis that incorporates both radiation induction of premalignant cells (initiation) and radiation-induced promotion of premalignant damage. This approach emphasizes the kinetics of radiation-induced initiation and promotion, and tracks the yields of premalignant cells before, during, shortly after, and long after radiation exposure. Radiation risks after exposure in younger individuals are dominated by initiation processes, whereas radiation risks after exposure at later ages are more influenced by promotion of preexisting premalignant cells. Thus, the cancer site–dependent balance between initiation and promotion determines the dependence of cancer risk on age at radiation exposure. For example, in terms of radiation induction of premalignant cells, a quantitative measure of the relative contribution of initiation vs promotion is 10-fold larger for breast cancer than for lung cancer. Reflecting this difference, radiation-induced breast cancer risks decrease with age at exposure at all ages, whereas radiation-induced lung cancer risks do not. For radiation exposure in middle age, most radiation-induced cancer risks do not, as often assumed, decrease with increasing age at exposure. This observation suggests that promotional processes in radiation carcinogenesis become increasingly important as the age at exposure increases. Radiation-induced cancer risks after exposure in middle age may be up to twice as high as previously estimated, which could have implications for occupational exposure and radiological imaging.
Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy.
Authors: P M Ravdin, I A Siminoff, J A Harvey
Journal: Journal of Clinical Oncology (1998)

A survey of breast cancer survivors in the United States was conducted to define what they had been told about their prognosis and the value of adjuvant therapy, what they estimated their prognosis to be with and without adjuvant therapy, and what level of improvement they would have found minimally worthwhile.Survey questionnaires were mailed to individual members and member organizations of the National Alliance of Breast Cancer Organizations (NABCO). Questionnaires were returned anonymously in prepaid mailers. Five hundred sixty-two women responded. Of these, the 318 women who received adjuvant chemotherapy were included in this analysis.Only 39% of the women recalled receiving quantitative estimates of their prognosis, and only 31% of women received a quantitative estimate both with and without adjuvant therapy. Sixty-eight percent of the women were able to provide a quantitative estimate for their outcome at 5 years both with and without adjuvant therapy. From these estimates, we calculated that the median estimated proportional risk reduction for recurrence that women thought they had achieved was 79%. Women were asked what degree of absolute benefit they would have found acceptable. The median acceptable extension of life expectancy was 3 to 6 months, and acceptable reduction in recurrence risk was 0.5% to 1.0%. However, there was considerable variation, with 27% of women not accepting less than 1 year and 26% not accepting a less than 5% reduction in recurrence risk.In general, American women in the surveyed population (1) do not recall being provided quantitative estimates of outcome during the process of making decisions about adjuvant therapy, (2) overestimate the value of their therapy, and (3) often will accept remarkably low degrees of net benefit. Overall, these observations can be used to support the argument that improvements in doctor/patient communication may be important to truly informed decision-making, and that flexibility for individual patients' preferences should not be superseded by rigid treatment guidelines.
Hypoxic Vasodilation by Red Blood Cells
Authors: Diana L. Diesen, Douglas T. Hess, Jonathan S. Stamler
Journal: Circulation Research (2008)

Red blood cells (RBCs) have been ascribed an essential role in matching blood flow to local metabolic demand during hypoxic vasodilation. The vasodilatory function of RBCs evidently relies on the allosteric properties of hemoglobin (Hb), which couple the conformation of Hb to tissue oxygen tension (P o 2 ) and thereby provide a basis for the graded vasodilatory activity that is inversely proportional to Hb oxygen saturation. Although a large body of evidence indicates that the P o 2 -coupled allosteric transition from R (oxy)-state to T (deoxy)-state subserves the release from Hb of vasodilatory nitric oxide (NO) bioactivity, it has not yet been determined whether the NO-based signal is a necessary and sufficient source of RBC-mediated vasoactivity and it has been suggested that ATP or nitrite may also contribute. We demonstrate here by bioassay that untreated human RBCs rapidly and substantially relax thoracic aorta from both rabbit and mouse at low P o 2 (≈1% O 2 ) but not at high P o 2 (≈21% O 2 ). RBC-mediated vasorelaxation is inhibited by prior depletion of S -nitroso-Hb, potentiated by low-molecular-weight thiols, and dependent on cGMP. Furthermore, these relaxations are largely endothelium-independent and unaffected by NO synthase inhibition or nitrite. Robust relaxations by RBCs are also elicited in the absence of endothelial, neuronal or inducible NO synthase. Finally, contractions that appear following resolution of RBC-mediated relaxations are dependent on NO derived from RBCs as well as the endothelium. Our results suggest that an S -nitrosothiol–based signal originating from RBCs mediates hypoxic vasodilation by RBCs, and that vasorelaxation by RBCs dominates NO-based vasoconstriction under hypoxic conditions.
Mechanical Ventilation in a Cohort of Elderly Patients Admitted to an Intensive Care Unit
Authors: E. Wesley Ely, Gregory W. Evans, Edward F. Haponik
Journal: Annals of Internal Medicine (1999)

It has been argued that life support for the elderly should be limited to conserve resources. As this population increases, so will the importance of evaluating appropriate use of mechanical ventilation in this group.To determine whether age has an independent effect on the outcomes of patients treated with mechanical ventilation after admission to an intensive care unit (ICU).Prospective cohort study.University-based tertiary care medical center.63 patients 75 years of age or older and 237 patients younger than 75 years of age enrolled from medical and coronary ICUs.In-hospital mortality rate, duration of mechanical ventilation, lengths of stay in the ICU and in the hospital, and cost of care.Median duration of mechanical ventilation was 4.2 days (interquartile range, 2.1 to 9.3 days) for patients 75 years of age or older and 6.4 days (interquartile range, 3.4 to 11.4 days) for patients younger than 75 years of age (P = 0.14). When the length of time required to "pass" a daily screening test of weaning variables was used as an indicator of recovery from respiratory failure, elderly patients passed earlier than younger patients (risk ratio, 1.58 [95% CI, 1.13 to 2.22]; P = 0.03). The cost of ICU care was lower for older ($12,822 [CI, $9821 to $26,313] than for younger ($19,316 [CI, $9699 to $39,950]) patients (P = 0.03). Median hospital costs tended to be lower in the older group ($21,292 compared with $29,049; P = 0.17). After adjustment for ethnicity, sex, and severity of illness in a multivariate logistic regression analysis, patient age of 75 years or older was predictive of 1 less day on the ventilator (CI, -2.8 to 1.2 days). Lengths of stay in the ICU (beta-coefficient, -0.5 days [CI, -3.0 to 2.7 days]) and in the hospital (beta-coefficient, 0.3 days [CI, -3.7 to 5.5 days]) did not differ for persons 75 years of age or older after these adjustments (P > 0.1). Intensive care unit and hospital costs, however, were lower for elderly persons (P = 0.02). The in-hospital mortality rate was 38.1% among elderly patients and 38.8% among younger patients (P > 0.2); Cox proportional hazards analysis confirmed that survival did not differ between the two groups (relative risk for older patients, 0.82 [CI, 0.52 to 1.29]).After adjustment for severity of illness, elderly patients spent similar time on mechanical ventilation and in the ICU and hospital but had a lower cost of care than younger patients. These outcomes are not explained by differences in mortality rate and suggest that mechanical ventilation should not be restricted in elderly patients with respiratory failure on the basis of chronologic age.
IM-02 * A scFv-BASED CAR TO REDIRECT T CELLS TO IL13R 2-POSITIVE PEDIATRIC GLIOMA
Authors: G. Krenciute, S. Krebs, D. Torres, M. Lesniak, I. Balyasnikova, S. Gottschalk
Journal: Neuro-Oncology (2015)

The intent of this project is to develop antigen-specific T cells as an effective immunotherapy for diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM), the most aggressive, uniform fatal, primary human brain tumors in children. IL13Rα2 is expressed at a high frequency in DIPG and GBM but not in normal brain, making it is a promising target for CAR T-cell immunotherapy. While other investigators have generated IL13Rα2-targeted CARs using mutated forms of IL13 as CAR binding domains, our studies indicate that these CARs also recognize IL13Rα1, raising significant toxicity concerns. To overcome this limitation we have developed a high affinity IL13Rα2-specific scFv that does not recognize IL13Rα1. The goal of this project was to generate scFv-based IL13Rα2-specific CAR (IL13Rα2-CAR T cells) and evaluate their function. We constructed a panel of IL13Rα2-CARs that contain our IL13Rα2-specific scFv as an ectodomain, a short hinge (SH) or long hinge (LH), a CD28 transmembrane domain, and endodomains that contain signaling domains derived from CD3ζ and co-stimulatory molecules. IL13Rα2-CAR T cells were generated by retroviral transduction. CAR cell surface expression varied depending on used hinge and endodomain. In cytotoxicity assays, IL13Rα2-CAR T cells only killed target cells that expressed IL13Rα2 and not IL13Rα1 confirming specificity. While all IL13Rα2-CAR T cells secreted significant levels of IFNγ in co-culture assays with the IL13Rα2+ glioma cell line U373, only short hinge CAR T cells secreted significant amounts of IL2. In vivo, injection of IL13Rα2.SH.CD28.ζ-CAR T cells into U373-bearing mice resulted in regression of glioma xenografts as judged by bioluminescence imaging. IL13Rα2.LH.CD28.ζ- or IL13Rα2.Δ-CAR T cells had no antitumor effects. In conclusion, for the first time we have generated a CAR that only recognizes IL13Rα2 and not IL13Rα1. Our results warrant further active exploration of IL13Rα2-specific scFv-based CAR T cells for the adoptive immunotherapy of pediatric brain tumors.
ZIP4 Regulates Pancreatic Cancer Cell Growth by Activating IL-6/STAT3 Pathway through Zinc Finger Transcription Factor CREB
Authors: Yuqing Zhang, Uddalak Bharadwaj, Craig D. Logsdon, Changyi Chen, Qizhi Yao, Min Li
Journal: Clinical Cancer Research (2010)

Recent studies indicate a strong correlation of zinc transporter ZIP4 and pancreatic cancer progression; however, the underlying mechanisms are unclear. We have recently found that ZIP4 is overexpressed in pancreatic cancer. In this study, we investigated the signaling pathway through which ZIP4 regulates pancreatic cancer growth.The expression of cyclin D1, interleukin 6 (IL-6), and signal transducer and activator of transcription 3 (STAT3) in pancreatic cancer xenografts and cells were examined by real-time PCR, Bio-Plex cytokine assay, and Western blot, respectively. The activity of cAMP response element-binding protein (CREB) is examined by a promoter activity assay.Cyclin D1 was significantly increased in the ZIP4 overexpressing MIA PaCa-2 cells (MIA-ZIP4)-injected orthotopic xenografts and was downregulated in the ZIP4-silenced ASPC-1 (ASPC-shZIP4) group. The phosphorylation of STAT3, an upstream activator of cyclin D1, was increased in MIA-ZIP4 cells and decreased in ASPC-shZIP4 cells. IL-6, a known upstream activator for STAT3, was also found to be significantly increased in the MIA-ZIP4 cells and xenografts and decreased in the ASPC-shZIP4 group. Overexpression of ZIP4 led to a 75% increase of IL-6 promoter activity and caused increased phosphorylation of CREB.Our study suggest that ZIP4 overexpression causes increased IL-6 transcription through CREB, which in turn activates STAT3 and leads to increased cyclin D1 expression, resulting in increased cell proliferation and tumor progression in pancreatic cancer. These results elucidated a novel pathway in ZIP4-mediated pancreatic cancer growth and suggest new therapeutic targets, including ZIP4, IL-6, and STAT3, in pancreatic cancer treatment.
Monitoring sputum eosinophils in mucosal inflammation and remodelling: a pilot study
Authors: J. Chakir, L. Loubaki, M. Laviolette, J. Milot, S. Biardel, L. Jayaram, M. Pizzichini, E. Pizzichini, F. E. Hargreave, P. Nair, L-P. Boulet
Journal: European Respiratory Journal (2009)

Normalisation of eosinophil counts in sputum of asthmatic patients reduces eosinophilic exacerbations. However, the effect of this strategy on airway remodelling remains to be determined. We compared bronchial inflammation and collagen deposition after 2 yrs of treatment guided by either sputum eosinophils (sputum strategy, SS) or by clinical criteria (clinical strategy, CS). As a pilot study, 20 mild asthmatic patients were randomly assigned to CS or SS strategies. Bronchial biopsies were obtained when minimum treatment needed to maintain control was identified and this was continued for 2 yrs. Biopsies were immunostained for inflammatory cells, mucin 5A (MUC5A) and collagen. The mean dose of inhaled corticosteroids at the start and end of the study was similar in both SS and CS groups. Forced expiratory volume in 1 s increased in both groups at the study end. In SS, mucosal lymphocyte and eosinophil counts, but not neutrophils, were reduced at the end of the study. In CS, only activated eosinophil and neutrophil counts decreased. MUC5A staining decreased in SS but not CS. No change in collagen deposition underneath the basement membrane was observed in either strategy. Treatment strategies that normalise sputum eosinophils also reduce mucosal inflammatory cells and MUC5A expression, but do not change subepithelial collagen deposition in mild to moderate asthma.
Potential impacts of the Affordable Care Act on the clinical practice of hepatology
Authors: Jayant A. Talwalkar
Journal: Hepatology (2014)

The Patient Protection and Affordable Care Act (ACA), along with the Health Care and Education Reconciliation Act, was signed into law and upheld by the Supreme Court earlier this year. The ACA contains a variety of reforms that, if implemented, will significantly affect current models of healthcare delivery for patients with acute and chronic hepatobiliary diseases. One of the Act's central reforms is the creation of accountable care organizations (ACOs) whose mission will be to integrate different levels of care to improve the quality of services delivered and outcomes among populations while maintaining, or preferably reducing, the overall costs of care. Currently, there are clinical practice areas within hepatology, such as liver transplantation, that already have many of the desired features attributed to ACOs. The ACA is sure to affect all fields of medicine, including the practice of clinical hepatology. This article describes the components of the ACA that have the greatest potential to influence the clinical practice of hepatology. Conclusion: Ultimately, it will be the responsibility of our profession to identify optimal healthcare delivery models for providing high-value, patient-centered care. (Hepatology 2014;59:1681–1687)
Cognitive Training for Supported Employment: 2-3 Year Outcomes of a Randomized Controlled Trial
Authors: Susan R McGurk, Kim T Mueser, Karin Feldman, Rosemarie Wolfe, Alysia Pascaris
Journal: American Journal of Psychiatry (2007)

Objective: To address cognitive impairments that limit the effectiveness of supported employment services for patients with schizophrenia, a cognitive training program, the Thinking Skills for Work Program, was developed and integrated into supported employment services. Method: Patients with severe mental illness (N=44) and prior histories of job failures who were enrolled in supported employment programs at two sites in New York City were randomly assigned to receive either supported employment alone or supported employment with cognitive training. Measures at baseline and 3 months included a brief cognitive and symptom assessment. Work outcomes were tracked for 2–3 years. Results: Patients in the supported employment with cognitive training program demonstrated significantly greater improvements at 3 months in cognitive functioning, depression, and autistic preoccupation. Over 2–3 years, patients in the supported employment with cognitive training program were more likely to work, held more jobs, worked more weeks, worked more hours, and earned more wages than patients in the program offering supported employment alone. Conclusions: The findings support the feasibility of integrating cognitive rehabilitation into supported employment programs and suggest that more research is warranted to evaluate the effects of the Thinking Skills for Work Program.
The attachment disorders of muscle: failure to carb-load
Authors: Elizabeth M. McNally
Journal: Journal of Clinical Investigation (2012)

Dystroglycan is a prominent cell surface protein that mediates attachment to the extracellular matrix. Although broadly expressed, glycosylated dystroglycan is critically important for muscle cell adherence to its surrounding matrix. A subgroup of muscular dystrophies, which often manifest in infancy, is associated with reduced glycosylation of dystroglycan. In this issue of the JCI, Beedle et al. used conditional gene targeting of Fktn, the gene responsible for Fukuyama congenital muscular dystrophy, to investigate a developmental requirement for glycosylation of dystroglycan.
Glomerular Structure in the Normal Human Kidney
Authors: M. Luiza Caramori, John M. Basgen, Michael Mauer
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Glomerular structure has been studied in tissues derived from normal living and cadaver kidney donors. Values obtained in such subjects were considered interchangeable and have been used to define the normal parameters when evaluating the effects of various renal diseases. The present study evaluated glomerular structure by light and electron microscopy in 83 living and 53 cadaver kidney donors. Glomerular basement membrane (GBM) width (356 ± 52 versus 329 ± 45 nm), glomerular volume (1.64 ± 0.47 versus 1.33 ± 0.39 × 106 μm3), and mesangial matrix volume per glomerulus (0.15 ± 0.05 versus 0.12 ± 0.04 × 106 μm3) were significantly greater in cadaver compared with living kidney donors, respectively. It is hypothesized that glomerular and extracellular matrix swelling is associated with the cadaver kidney preservation process. This study suggests that the normal values for glomerular structure should be derived only from living kidney donor tissues. E-mail: [email protected]
ONE HUNDRED YEARS AGO
Authors: T. W. Parry
Journal: BMJ (1995)

SIR,—It seems to me that Surgeon-General Jessop's letter, that appeared in the BRITISH MEDICAL JOURNAL of January 19th, contains more spirit than judgment. That it should be necessary for “a youth to be able to reply in good Latin to questions asked at a preliminary examination, and at the same time evince …
Screening an Irish cohort with colorectal cancer for Lynch Syndrome using immunohistochemistry for mismatch repair proteins
Authors: D. G. Power, M. P. Farrell, C. B. Muldoon, E. Fitzpatrick, C. Stuart, D. Flannery, M. J. Kennedy, R. B. Stephens, P. A. Daly
Journal: Journal of Clinical Oncology (2007)

10547 Background: Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is possible owing to recent technical advances. The care of those with inherited predisposition to breast and ovarian cancer is now becoming a mainstream component of medical care. It is more difficult to identify those with Lynch Syndrome (LS) as various criteria (Amsterdam and Bethesda) have not proved definitive. An important development is the examination of tumor tissue to detect mismatch repair (MMR) protein loss using immunohistochemical (IHC) techniques. When coupled with family history those at risk of harbouring a mutation for LS can be identified. Once a mutation is identified predictive testing can be offered to family members, risk-reduction measures applied and mortality from colorectal cancer reduced. Methods: Screening for MMR protein expression (MLH1, MSH2, MSH6, PMS2) was planned on all colorectal cancer (CRC) cases using IHC on formalin-fixed tumor tissue from January 1st 2002. Local ethics committee approval was obtained and then written informed-consent from patients. Family history data was gathered from the index case or an appropriate relative. An aliquot of blood was stored from index cases for subsequent genetic screening if indicated by IHC analysis and genetic counseling. Results: 108 cases with CRC (62 male, 46 female, median age 59 years) from a potential total of 612 have been screened for MMR protein expression by a gastrointestinal pathologist and independently validated. Turn-around time for IHC analysis was 9 weeks. 5 patients (4.6%) had loss of MMR proteins, MSH2/MSH6- 2 cases, MSH6 alone- 1 case and MLH1/PMS2- 2 cases. All 5 have opted for genetic counselling and sequencing of relevant genes. Conclusion: These early results in an Irish cohort with CRC showing MMR loss in 4–5% of cases is consistent with other population findings. Microsatellite instability analysis is difficult, expensive and relatively unavailable. IHC, however, is an established technique in pathology departments and can be the cheapest and most reproducible approach to identify LS cases. IHC results along with robust family data can guide the genetic counseling process towards preventing deaths from CRC and other LS-associated cancers. No significant financial relationships to disclose.