tbuckley/cabot-search huggingface dataset:
Lung function decline in elderly in relation to phthalate metabolites and bisphenol A levels in serum: A 5-year prospective study
Authors: Dan Norbäck, P. Monica Lind, Gunilla Wieslander, Lars Lind
Journal: European Respiratory Journal (2012)

Background: Some recent studies report associations between phthalate exposure and asthma in pre-school children. We investigated if circulating levels of phthalates and bisphenol A (BPA) predicts lung function decline in an elderly population.

Methods: PIVUS is a cohort, based on a population sample of subjects, aged 70 years in Uppsala, Sweden. Circulating levels of BPA and phthalate metabolites in serum was measured at baseline by LC-MS/MS. Lung function was measured at baseline and after 5 years in 668 subjects. Change of forced expiratory volume in 1 s (FEV1) was calculated. Associations were analysed by multivariate modelling adjusting for height, smoking at 70 and 75 y, pack years of tobacco at 70 y, education level, exercise habits and gender, using ln transformed values for circulating levels, excluding 36 subjects with asthma or COPD at baseline

Results: BPA median level was 3.75 ng/mL, Monethyl hexyl phtalate (MEHP) 4.51 ng/mL, monethyl phtalate (MEP) 11.6 ng/mL, Monoisobutyl phtalate (MiBP) 13.5 ng/mL, and Monomethyl phtalate (MEHP) 1.51 ng/mL, with no gender differences. The annual decline in FEV1 was -55.6 ml/year. MEHP was associated with an additional decline in FEV1 of -6.0 ml/year (95% CI -8.6 to -3.4) (p<0.001), while MMP was associated with an additional improvement in FEV1 of 6.6 ml/year (95% CI 3.2 to 9.8) (p<0.001), The association for MEHP was significant in both men and women, while the association for MMP was significant in women, only.

Discussion: Associations between circulating levels of some phthalates metabolites and the five year decline of FEV1 were found, with MEHP as a risk factor for lung function decline.
Mycobacteria-Specific Cytokine Responses Detect Tuberculosis Infection and Distinguish Latent from Active Tuberculosis
Authors: Marc Tebruegge, Binita Dutta, Susan Donath, Nicole Ritz, Benjamin Forbes, Kattia Camacho-Badilla, Vanessa Clifford, Christel Zufferey, Roy Robins-Browne, Willem Hanekom, Stephen M. Graham, Tom Connell, Nigel Curtis
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-γ release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management.To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB.A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays.IFN-γ, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-α, IL-1ra, IL-2, IL-13, and MIP-1β (macrophage inflammatory protein-1β) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF-α, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-α, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-α/IL-1ra and TNF-α/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively.We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone.
Radiation therapy for relapsed CNS germinoma after primary chemotherapy.
Authors: T E Merchant, B J Davis, J M Sheldon, S A Leibel
Journal: Journal of Clinical Oncology (1998)

PURPOSE To retrospectively evaluate the ability of radiation therapy to salvage patients with CNS germinoma who relapsed after treatment with primary chemotherapy on a multiinstitution trial that included carboplatin, etoposide, and bleomycin (PEB). PATIENTS AND METHODS Eight patients with CNS germinoma received carboplatin, etoposide, and bleomycin as their only nonsurgical treatment following their initial diagnosis. At the time of relapse each patient received high-dose cyclophosphamide (one to three cycles) followed by craniospinal irradiation (25.2 to 36 Gy) and a boost to the site of recurrent disease (45 to 54 Gy). Six of eight patients had disease at relapse that was more extensive than at diagnosis. One patient had magnetic resonance imaging (MRI) evidence of leptomeningeal enhancement in the cauda equina although CSF cytology was negative, and one patient had cytologic evidence of CSF involvement. The median time to relapse following primary chemotherapy was 17 months. RESULTS Although myelosuppression was prolonged following the administration of preirradiation chemotherapy, all patients completed a continuous course of radiation therapy. With a median follow-up after radiation therapy of 32 months (range, 16 to 47 months), no failures have occurred. CONCLUSION Radiation therapy has a proven record of efficacy in the treatment of intracranial germinoma and it remains the standard therapy with which others are compared for treatment response, local control, and overall survival. Arguments can be made for alternative approaches when patients face hormonal or neurocognitive dysfunction as a result of radiation therapy; however, any reduction in late effects will have to be weighed against the probability of survival if alternative approaches prove to be inferior.
Sporadic duodenal adenoma and colorectal neoplasia
Authors: A C Ford, O Rotimi, S M Everett
Journal: Gut (2004)

We read with great interest Murray et al ’s article concerning the association between sporadic duodenal adenoma and colorectal neoplasia ( Gut 2004; 53 :261–5).

We have also noted a lack of published literature regarding sporadic duodenal adenomas, with the exception of the two reports identified by the authors,1,2 as well as a more recent case series,3 and therefore welcome the addition of their large case series and comparison group. Although there is the potential for bias in the detection of colorectal neoplasia in their duodenal adenoma cases, as the indications for colonoscopy were somewhat different between cases and controls (with almost one third of cases of duodenal adenomas being endoscoped for investigation of anaemia or melaena), overall their data …
SEROEPIDEMIOLOGY OF HANTAAN-RELATED VIRUS INFECTIONS IN BELGIAN POPULATIONS
Authors: G. Van Der Groen, P. Piot, J. Desmyter, J. Colaert, L. Muylle, E.A. Tkachenko, A.P. Ivanov, R. Verhagen, C. Van Ypersele De Strihou
Journal: The Lancet (1983)
Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy.
Authors: B Fowble, R Gray, K Gilchrist, R L Goodman, S Taylor, D C Tormey
Journal: Journal of Clinical Oncology (1988)

Risk factors for isolated local-regional (LR) recurrence following mastectomy for breast cancer were analyzed in a review of 627 women entered into Eastern Cooperative Oncology Group (ECOG) adjuvant chemotherapy trials between 1978 and 1982. Premenopausal patients were randomized to cyclophosphamide, methotrexate, and fluorouracil (5-FU) (CMF), cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP), or cyclophosphamide, methotrexate, 5-FU, prednisone, and tamoxifen (CMFPT). Postmenopausal patients were randomized to observation, CMFP, or CMFPT. Median follow-up time was 4.5 years. At 3 years, 225 patients relapsed and in 70 (31% of failures, 11% of all patients) the initial site was LR without distant metastases. In a multivariate analysis, the risk of an isolated LR recurrence significantly correlated with the number of positive axillary nodes, the primary tumor size, the presence of tumor necrosis, and the number of axillary nodes examined. Factors that significantly discriminated between an isolated LR recurrence and distant metastasis were the number of positive nodes and primary tumor size. Patients with four to seven positive nodes or tumor size greater than or equal to 5 cm had a chance of developing an isolated LR recurrence almost equal to the risk of distant metastases. These findings suggest a potential for improved survival in this subset of patients with the addition of postmastectomy radiation to chemotherapy, and continue to emphasize the presence of a group of patients at high risk for isolated LR recurrence despite adjuvant chemotherapy.
Spatially Organized Differentiation of Mesenchymal Stem Cells within Biphasic Microparticle‐Incorporated High Cell Density Osteochondral Tissues
Authors: Loran D. Solorio, Lauren M. Phillips, Alexandra McMillan, Christina W. Cheng, Phuong N. Dang, Julia E. Samorezov, Xiaohua Yu, William L. Murphy, Eben Alsberg
Journal: Advanced Healthcare Materials (2015)

Giving rise to both bone and cartilage during development, bone marrow‐derived mesenchymal stem cells (hMSC) have the unique capacity to generate the complex tissues of the osteochondral interface. Utilizing a scaffold‐free hMSC system, biphasic osteochondral constructs are incorporated with two types of growth factor‐releasing microparticles to enable spatially organized differentiation. Gelatin microspheres (GM) releasing transforming growth factor‐β1 (TGF‐β1) combined with hMSC form the chondrogenic phase. The osteogenic phase contains hMSC only, mineral‐coated hydroxyapatite microparticles (MCM), or MCM loaded with bone morphogenetic protein‐2 (BMP‐2), cultured in medium with or without BMP‐2. After 4 weeks, TGF‐β1 release from GM within the cartilage phase promotes formation of a glycosaminoglycan‐ and type II collagen‐rich matrix, and has a local inhibitory effect on osteogenesis. In the osteogenic phase, type X collagen and osteopontin are produced in all conditions. However, calcification occurs on the outer edges of the chondrogenic phase in some constructs cultured in media containing BMP‐2, and alkaline phosphatase levels are elevated, indicating that BMP‐2 releasing MCM provides better control over region‐specific differentiation. The production of complex, stem cell‐derived osteochondral tissues via incorporated microparticles could enable earlier implantation, potentially improving outcomes in the treatment of osteochondral defects.
Liver Carcinomas Induced in Rats by Single Administration of Dimethylnitrosamine After Partial Hepatectomy
Authors: Valda M. Craddock
Journal: JNCI Journal of the National Cancer Institute (1971)

Female rats weighing 200 g were given a single injection of dimethylnitrosamine (DMN), 6–9 mg/kg, at a selected interval of time after partial hepatectomy, i.e., 0–2 hours, 6 hours, 24 hours (the peak time of DNA synthesis in the regenerating liver), or 31 hours (the time of maximum mitotic rate). The ratswere killed 1–2 years later. Many livers had developed distorted hemorrhagic hyperplastic nodules, and some had trabecular carcinomas. In the relatively small number of animals used,the incidence of liver cell carcinomas was highest in the rats treated with DMN 24 hours after partial hepatectomy. Four rats developed sarcomas at the site of liver excision. No rats partially hepatectomized only or receiving a single injection of DMN with dimethylformamide developed nodules or liver tumors. DMN was metabolized, although more slowly than normal, in regenerating liver. The results are consistent with the belief that replicating cells are especially sensitive to the action of carcinogens.
Remote Ischemic Preconditioning and Postoperative Renal Dysfunction—Reply
Authors: Jenny Szu-Chin Pan, David Sheikh-Hamad
Journal: JAMA (2015)

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Phase I study of AZD0530, an oral potent inhibitor of Src kinase: First demonstration of inhibition of Src activity in human cancers
Authors: J. Tabernero, A. Cervantes, K. Hoekman, H. I. Hurwitz, D. I. Jodrell, P. Hamberg, M. Stuart, T. P. Green, R. B. Iacona, J. Baselga
Journal: Journal of Clinical Oncology (2007)

3520 Background: Agents that specifically inhibit the invasive phenotype of cancers are urgently required. AZD0530 is a potent, orally administered inhibitor of Src that has been shown preclinically to prevent phosphorylation of downstream mediators of motility and invasion, paxillin (Pax) and focal adhesion kinase (FAK), with inhibition of metastasis in vivo. Although Src activation is associated with poor prognosis, inhibition of Src activity in human cancers has never been demonstrated. Methods: Patients with cancer received AZD0530 in dose cohorts of 50 mg to 250 mg daily in this 2-part Phase I study. Paired tumor biopsies were acquired for investigation of Src inhibition. Part A defined MTD, toxicity profile and PK. Part B expanded the 50 mg, 125 mg and 175 mg cohorts to characterize changes in phosphorylation of the Src substrates Pax and FAK by evaluating intensity and localization of staining by IHC. Biopsy samples were assigned as pre- or post-AZD0530 treatment by an independent pathology panel blinded to treatment status, and tested for 80% concordance at a 10% alpha. Markers of bone turnover were collected. Results: There were 81 patients evaluable for safety assessment. The median number of prior therapies was 5 (1–27). Part A: DLTs occurred in 3 patients at 250 mg (leukopenia; septic shock (grd5) with renal failure; asthenia) and in 2 patients at 200 mg (febrile neutropenia; dyspnea). Part B confirmed the 50, 125 and 175 mg doses to be tolerable. The mean duration of AZD0530 treatment was 44 days (6–217); 11 patients were treated for longer than 3 months. The pathology panel found consistent modulation of phosphorylation and/or cellular localization of tumor Pax (P=0.067) and FAK (P=0.002) consequent to AZD0530 therapy. There was a dose response trend for reductions in Pax phosphorylation. Bone biomarker and PK data will be presented. Conclusion: For the first time, biomarkers have confirmed inhibition of Src in human cancers. AZD0530 is well tolerated at doses that demonstrate significant inhibition of Src activity. The trend for dose response changes in biomarkers of Src inhibition indicates that the MTD should be taken forward in further development. AZD0530 has a potential role in the prevention of metastases and invasion. No significant financial relationships to disclose.
The treatment of Wilms' tumor patients with pulmonary metastases detected only with computed tomography: a report from the National Wilms' Tumor Study.
Authors: D M Green, D J Fernbach, P Norkool, G Kollia, G J D'Angio
Journal: Journal of Clinical Oncology (1991)

To evaluate the prognosis of patients with Wilms' tumor who have pulmonary densities identified on a computed tomographic (CT) scan of the chest, but have a negative plain chest radiograph, we reviewed the treatments and outcome of 32 patients randomized or followed on National Wilms' Tumor Study (NWTS)-3. The 4-year event-free and overall survival percentages of 18 of these patients who had a favorable histology tumor and were treated as stage IV tumors with three or four drugs plus whole-lung irradiation were 88.1% and 94.0%, respectively. The 4-year event-free and overall survival percentages for nine favorable histology patients treated less aggressively based on the extent of locoregional disease with two or three drugs and without whole-lung irradiation were 88.9% and 88.0%, respectively. There were no statistically significant differences in the 4-year event-free or overall survival percentages between the two groups. The current data do not demonstrate improved survival for favorable histology patients treated with whole-lung irradiation for pulmonary metastases identified only on chest CT scan. However, due to the small number of patients included, no statistically valid conclusions regarding the roles of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and/or whole-lung irradiation in the treatment of these patients can be drawn from the present analysis. Additional patients need to be systematically studied to determine if these preliminary observations can be confirmed.
Survival and Reproductive Function After Treatment of Malignant Germ Cell Ovarian Tumors
Authors: Gerardo Zanetta, Cristina Bonazzi, Maria Grazia Cantù, Sergio Bini†, Anna Locatelli, Giorgio Bratina, Costantino Mangioni
Journal: Journal of Clinical Oncology (2001)

Germ cell ovarian tumors are curable. The possible sequelae of chemotherapy on long-term survivors are still unknown, but these patients may expect normal lives. The aim of this study was to evaluate the outcome and reproductive function in a population of women treated since 1982.Between 1982 and 1996, 169 women with malignant germ cell ovarian tumors were seen (70 dysgerminomas, 28 endodermal sinus tumors, 24 mixed tumors, and 47 immature teratomas). Seventy-one had advanced or recurrent disease. Fertility-sparing surgery was performed in 138 (81%) women, 81 of whom received postoperative chemotherapy.With a median follow-up of 67 months, the survival rate was 94% for dysgerminoma, 89% for endodermal sinus tumors, 100% for mixed types, and 98% for immature teratoma. For women who were treated conservatively, the survival rate was 98%, 90%, 100%, and 100%, respectively. Two women had adnexal recurrences, and both received salvage treatment. After treatment, all but one postpubertal woman had recovery of menses within 9 months. During follow-up, 12 untreated and 20 treated patients had 55 conceptions. We recorded 40 pregnancies at term, six terminations, and nine miscarriages. Four malformations were observed: one in 14 conceptions of patients who had not received chemotherapy and three in 41 conceptions of treated patients.Irrespective of subtype and stage, conservative surgery should become the standard approach to treating most patients with malignant ovarian germ cell tumors. Fertility seems to be only marginally affected by treatments. Miscarriages are in the expected range for the general population. The malformation rate is slightly higher than in the general population, but no significant difference was seen between patients who did and did not receive chemotherapy.
Abstract IA03: Mutations, drugs, and breast cancer: How are we going to figure it out?
Authors: Matthew J. Ellis
Journal: Clinical Cancer Research (2015)

Abstract Massively parallel DNA and RNA sequencing approaches have generated high dimensional data on thousands of breast cancer genomes. Broad-based conclusions include challenges to the multistep model of breast carcinogenesis and the monoclonality of cancer, a link between leukemogenesis and luminal breast cancer and the discovery of new mutagenesis mechanisms. Unfortunately novel and immediately applicable therapeutic insights have been somewhat sparse. Many of the processes that are disrupted by newly discovered somatic mutations include genes with roles in splicing, histone methylation and long non-coding RNA function. Drugs targeting these processes are in the earliest stages of development, emphasizing a pressing unmet need to move drug discovery efforts beyond our current intense focus on kinase inhibitors. Despite the evident complexity, promising examples are emerging including new efforts to target mutations in two well-established drivers in breast cancer: HER2 in HER2 mutant breast cancer and mutant ESR1 in ESR1 endocrine refractory luminal-type breast cancer. A case for the importance of genome-annotated patient-derived breast cancer xenografts (PDX) will also be made. PDX models are potentially more reliable preclinical setting than cell lines and are a setting in which the biological rules for genome driven therapeutic planning could be developed. A call is also made for a new generation of prospective clinical trials that are fully focused on exploring interactions between cancer genomics and drug outcomes as a primary objective. Finally the integration of DNA and RNA based sequencing studies with mass-spectrometry-based peptide sequencing promises a more complete view of the biochemistry of breast cancer cells and represents a new discovery horizon in efforts to drug the pathophysiology of complex epithelial malignancies. Citation Format: Matthew J. Ellis. Mutations, drugs, and breast cancer: How are we going to figure it out? [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA03.